POCD treatment medicine composition with dendrobine delivered by nano-carrier and application of POCD treatment medicine composition

Abstract

The invention provides a POCD treatment medicine composition with dendrobine delivered by a nano-carrier and application, and belongs to the technical field of medicine. The composition consists of dendrobine, a nano-carrier material and a stabilizer, wherein a nano-carrier is PLGA (poly (lactic-co-glycolic acid)) nanoparticles or lipidosome. The particle size of the composition is 50-150nm, the polydispersity index is less than 0.3, and the loading capacity of dendrobine is 5-15%. The invention also provides two preparation methods of the composition. The PLGA nanoparticles are prepared by adopting an emulsification-solvent evaporation method; the liposome is prepared by adopting a film hydration-ultrasonic extrusion method, and each process parameter is specifically limited. The pharmaceutical composition can significantly improve the brain targeting and bioavailability of dendrobine, and can be used for preparing drugs for preventing or treating postoperative cognitive impairment (POCD), and the administration route can be intravenous injection or nasal administration.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a POCD treatment drug composition of nanocarrier delivered dendrobine and application thereof. BACKGROUND

[0002] Postoperative cognitive dysfunction (POCD) is a common neurological complication after anesthesia and surgery, especially in elderly patients, with a high incidence. The clinical manifestations include decline in cognitive domains such as memory, attention, learning ability and executive function. At present, the pathological mechanism of POCD has not been fully elucidated, but it is generally believed to be closely related to neural inflammation, neuronal apoptosis, impaired synaptic plasticity and blood-brain barrier disruption triggered by surgical trauma and anesthetic drugs. At present, there is a lack of specific treatment drugs for POCD in clinical practice, and the main treatment is mainly symptomatic support and prevention.

[0003] Dendrobine is an important alkaloid extracted from traditional Chinese medicine plants of the genus Dendrobium. Modern studies have shown that dendrobine has significant neuroprotective activity. It has been confirmed in models of Alzheimer's disease, diabetic encephalopathy and other diseases that it can improve cognitive function through multiple pathways such as anti-inflammatory, anti-apoptotic, inhibition of Aβ deposition and Tau protein hyperphosphorylation. This provides a theoretical basis for its application in the treatment of POCD.

[0004] However, dendrobine itself has poor water solubility, low oral bioavailability, and difficulty in crossing the blood-brain barrier (BBB) to reach the central nervous system target, which severely limits its potential for clinical application. Therefore, the development of a new drug delivery system that can efficiently deliver dendrobine and improve its brain targeting and bioavailability is of great significance for its conversion into an effective POCD treatment drug.

[0005] Nanotechnology provides an effective strategy to solve the above problems. Poly (lactic-co-glycolic acid) (PLGA) nanoparticles and liposomes are two widely studied biodegradable nanocarriers that can effectively encapsulate hydrophobic drugs and achieve active brain targeting through surface modification, thereby improving drug distribution in the brain.

[0006] Based on this, the present application creatively constructs PLGA nanoparticles and liposomes loaded with dendrobine, aiming to solve the problem of low delivery efficiency of dendrobine and provide an effective new solution for the prevention and treatment of POCD. SUMMARY

[0007] The present application provides a POCD treatment drug composition of nanocarrier delivered dendrobine and application thereof, which can improve the stability, brain targeting and bioavailability of dendrobine, thereby solving the technical problem of low delivery efficiency of dendrobine in the prior art.

[0008] In a first aspect, the present application provides a nanocarrier-delivered Dendrobium alkaloid POCD therapeutic pharmaceutical composition, which is composed of Dendrobium alkaloid, nanocarrier material and stabilizer; the nanocarrier is PLGA nanoparticle or liposome; the particle size of the nanocarrier-delivered Dendrobium alkaloid POCD therapeutic pharmaceutical composition is 50-150 nm, the polydispersity index is <0.3, and the loading amount of Dendrobium alkaloid is 5-15%.

[0009] According to the present application, a nanocarrier-delivered Dendrobium alkaloid POCD therapeutic pharmaceutical composition is provided, the nanocarrier is PLGA nanoparticle, the monomer molar ratio of lactic acid to glycolic acid of the PLGA is 50:50 to 75:25, and the stabilizer is polyvinyl alcohol or poloxamer.

[0010] According to the present application, a nanocarrier-delivered Dendrobium alkaloid POCD therapeutic pharmaceutical composition is provided, the nanocarrier is liposome, the membrane material of the liposome includes distearoyl phosphatidylcholine, cholesterol and DSPE-PEG2000, the mass ratio of distearoyl phosphatidylcholine, cholesterol and DSPE-PEG2000 is (50-70):(25-40):(3-8), and the stabilizer is sucrose or trehalose.

[0011] According to the present application, a nanocarrier-delivered Dendrobium alkaloid POCD therapeutic pharmaceutical composition is provided, the nanocarrier surface is covalently connected with brain-targeting ligand, and the brain-targeting ligand is lactoferrin or Angiopep-2 peptide.

[0012] In a second aspect, the present application provides a preparation method of a nanocarrier-delivered Dendrobium alkaloid POCD therapeutic pharmaceutical composition, which comprises the following steps: (1) dissolving Dendrobium alkaloid and PLGA in dichloromethane as an oil phase; (2) preparing polyvinyl alcohol aqueous solution as an aqueous phase; (3) injecting the oil phase into the aqueous phase to perform primary emulsification, and obtaining primary emulsion; (4) performing probe ultrasonic treatment on the primary emulsion, and then performing magnetic stirring to volatilize organic solvent; (5) after centrifugation and water washing, adding 5% sucrose solution for redissolution, and performing freeze-drying to obtain the nanocarrier-delivered Dendrobium alkaloid POCD therapeutic pharmaceutical composition.

[0013] According to the preparation method of the POCD therapeutic pharmaceutical composition of the nanocarrier delivered Dendrobium alkaline provided by the application, the concentration of the polyvinyl alcohol aqueous solution is 1-3%; the initial emulsification is high-speed shearing at a rotating speed of 10000-15000 rpm for 2-5 minutes; the ultrasonic treatment is performed at a power of 200-400 W for 2-5 minutes; the magnetic stirring is performed at a rotating speed of 300-500 rpm for 4-6 hours; the centrifugal treatment is performed at 4℃ and 15000-20000xg for 20-40 minutes; and the freeze-drying is pre-freezing at-40℃ to-80℃ for 2-4 hours, then drying at-20℃ to-10℃ and a vacuum degree of ≤10 Pa for 20-28 hours in the main drying stage, and finally desorption drying at 20-25℃ for 2-4 hours.

[0014] In a third aspect, the application provides a preparation method of a POCD therapeutic pharmaceutical composition of a nanocarrier delivered Dendrobium alkaline, comprising the following steps: (1) dissolving distearoyl phosphatidylcholine, cholesterol and DSPE-PEG2000 in chloroform, and performing rotary evaporation under reduced pressure to form a uniform lipid film; (2) adding a PBS buffer containing Dendrobium alkaline to the lipid film for hydration treatment; (3) performing ultrasonic treatment on the hydrated suspension, and then sequentially performing extrusion through polycarbonate membranes with pore sizes of 0.2 μm and 0.1 μm; (4) mixing the obtained liposome solution with a 5% trehalose solution, and performing freeze-drying to obtain the POCD therapeutic pharmaceutical composition of the nanocarrier delivered Dendrobium alkaline.

[0015] According to the preparation method of the POCD therapeutic pharmaceutical composition of the nanocarrier delivered Dendrobium alkaline provided by the application, the rotary evaporation under reduced pressure is performed at a vacuum degree of ≤0.02 MPa, a temperature of 45-50℃, a rotating speed of 30-60 rpm, and for 1-2 hours; the concentration of Dendrobium alkaline in the PBS buffer is 0.5-2 mg / mL; the hydration treatment is performed at a temperature of 55-60℃ for 30-60 minutes; the ultrasonic treatment is performed at a power of 100-200 W for 5-10 minutes; and the freeze-drying is pre-freezing at-40℃ to-80℃ for 2-4 hours, then drying at-20℃ to-10℃ and a vacuum degree of ≤10 Pa for 20-28 hours in the main drying stage, and finally desorption drying at 20-25℃ for 2-4 hours.

[0016] In a fourth aspect, the application provides a use of the POCD therapeutic pharmaceutical composition of the nanocarrier delivered Dendrobium alkaline in the preparation of a drug for preventing or treating postoperative cognitive dysfunction.

[0017] The application of the POCD treatment drug composition of nanocarrier delivered dendrobium alkaloid provided by the application in preparing a drug for preventing or treating postoperative cognitive dysfunction, wherein the administration route of the drug is intravenous injection or nasal administration.

[0018] The POCD treatment drug composition of nanocarrier delivered dendrobium alkaloid and the application provided by the application have the following advantages compared with the prior art. (1) The POCD treatment drug composition of nanocarrier delivered dendrobium alkaloid and the application provided by the application can effectively promote dendrobium alkaloid to cross the blood-brain barrier, target delivery to the central nervous system and directly act on the lesion site, thereby significantly enhancing the effect of treating POCD.

[0019] (2) The POCD treatment drug composition of nanocarrier delivered dendrobium alkaloid and the application provided by the application can prepare nanometer preparations with uniform particle size (PDI < 0.3), high drug loading (5-15%) and good physical stability and reproducibility by optimizing the prescription and process.

[0020] (3) The POCD treatment drug composition of nanocarrier delivered dendrobium alkaloid and the application provided by the application not only utilizes the functions of dendrobium alkaloid itself such as anti-inflammatory, anti-apoptosis and synapse protection, but also may have certain passive targeting and sustained release effects, and the two can synergistically relieve the pathological process of POCD from multiple pathways.

[0021] (4) The POCD treatment drug composition of nanocarrier delivered dendrobium alkaloid and the application provided by the application use carrier materials (PLGA, phospholipid, etc.) that are biodegradable materials with high safety and good clinical application prospects. BRIEF DESCRIPTION OF DRAWINGS

[0022] In order to more clearly illustrate the technical solutions of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or prior art description. Obviously, the drawings in the following description are some embodiments of the present application, and those skilled in the art can also obtain other drawings according to these drawings without creative labor.

[0023] Figure 1 is the process flow chart of the preparation method of the POCD treatment drug composition of nanocarrier delivered dendrobium alkaloid provided by the application in embodiment 1; Figure 2 is the process flow chart of the preparation method of the POCD treatment drug composition of nanocarrier delivered dendrobium alkaloid provided by the application in embodiment 2. DETAILED DESCRIPTION

[0024] In order to make the objects, technical solutions and advantages of the present application clearer, the technical solutions in the present application will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the protection scope of the present application.

[0025] The present application provides a nanocarrier delivery shihuchai base POCD treatment drug composition, which is composed of shihuchai base, nanocarrier material and stabilizer; the nanocarrier is PLGA nanoparticle or liposome; the particle size of the nanocarrier delivery shihuchai base POCD treatment drug composition is 50-150 nm, the polydispersity index is <0.3, and the loading capacity of shihuchai base is 5-15%; in some preferred embodiments, the average particle size of the PLGA nanoparticle is 80-120 nm, and the average particle size of the liposome is 90-130 nm.

[0026] In the present application, the nanocarrier is PLGA nanoparticle, wherein the monomer molar ratio of lactic acid to glycolic acid of PLGA is 50:50 to 75:25, and the stabilizer is polyvinyl alcohol or poloxamer; in some preferred embodiments, the monomer molar ratio of lactic acid to glycolic acid of PLGA is 60:40 to 75:25.

[0027] In the present application, the nanocarrier is liposome, the membrane material of which includes distearoylphosphatidylcholine, cholesterol and DSPE-PEG2000, and the mass ratio of distearoylphosphatidylcholine, cholesterol and DSPE-PEG2000 is (50-70):(25-40):(3-8), and the stabilizer is sucrose or trehalose; in some preferred embodiments, the mass ratio of distearoylphosphatidylcholine, cholesterol and DSPE-PEG2000 in the membrane material is (55-65):(28-35):(4-6).

[0028] In the present application, the surface of the nanocarrier is covalently connected with brain targeting ligand, and the brain targeting ligand is lactoferrin or Angiopep-2 peptide.

[0029] The present application provides a preparation method of a nanocarrier delivery shihuchai base POCD treatment drug composition, which comprises the following steps: (1) dissolving shihuchai base and PLGA in dichloromethane as an oil phase; (2) preparing an aqueous polyvinyl alcohol solution as an aqueous phase; (3) injecting the oil phase into the aqueous phase to perform primary emulsification, to obtain a primary emulsion; (4) performing probe ultrasonic treatment on the primary emulsion, and then performing magnetic stirring to volatilize organic solvents; (5) After centrifugation and washing with water, 5% sucrose solution was added to reconstitute the mixture, and then freeze-dried to obtain a POCD therapeutic drug composition for delivering dendrobine via a nanocarrier.

[0030] In this invention, the concentration of the polyvinyl alcohol aqueous solution is 1-3%; in some preferred embodiments, the concentration of the polyvinyl alcohol aqueous solution is 1.5-2.5%.

[0031] In this invention, the initial emulsification is performed by high-speed shearing at 10,000-15,000 rpm for 2-5 minutes; in some preferred embodiments, the initial emulsification is performed by high-speed shearing at 11,000-13,000 rpm for 3-4 minutes.

[0032] In this invention, the ultrasonic treatment power is 200-400W and the ultrasonic treatment time is 2-5 minutes; in some preferred embodiments, the ultrasonic treatment power is 250-350W and the ultrasonic treatment time is 3-4 minutes.

[0033] In this invention, the magnetic stirring speed is 300-500 rpm and the magnetic stirring time is 4-6 hours; in some preferred embodiments, the magnetic stirring speed is 350-450 rpm and the magnetic stirring time is 4.5-5.5 hours.

[0034] In this invention, the centrifugation conditions are 4°C and 15000-20000×g for 20-40 minutes; in some preferred embodiments, the centrifugation conditions are 4°C and 16000-18000×g for 25-35 minutes.

[0035] In this invention, the freeze-drying process involves pre-freezing at -40°C to -80°C for 2-4 hours, followed by drying at -20°C to -10°C and a vacuum of ≤10Pa for 20-28 hours during the main drying stage, and finally desorption drying at 20-25°C for 2-4 hours.

[0036] This invention provides a method for preparing a POCD therapeutic composition with dendrobine delivered by a nanocarrier, comprising the following steps: (1) Distearate phosphatidylcholine, cholesterol and DSPE-PEG2000 were dissolved in chloroform and evaporated under reduced pressure to form a uniform lipid film. (2) Hydrate the PBS buffer containing dendrobine into the lipid membrane; (3) The hydrated suspension was ultrasonically treated and then extruded through polycarbonate membranes with pore sizes of 0.2 μm and 0.1 μm in sequence; (4) The obtained liposome solution was mixed with 5% trehalose solution and freeze-dried to obtain a POCD therapeutic composition for delivering dendrobine via nanocarrier.

[0037] In this invention, the vacuum degree of the reduced pressure rotary evaporation is ≤0.02MPa, the temperature is 45-50℃, the rotation speed is 30-60rpm, and the time is 1-2 hours; in some preferred embodiments, the temperature of the reduced pressure rotary evaporation is 48-50℃, the rotation speed is 40-50rpm, and the time is 1.2-1.8 hours.

[0038] In this invention, the concentration of dendrobine in the PBS buffer solution of dendrobine is 0.5-2 mg / mL; in some preferred embodiments, the concentration of dendrobine in the PBS buffer solution of dendrobine is 0.8-1.5 mg / mL.

[0039] In this invention, the hydration treatment temperature is 55-60°C and the hydration treatment time is 30-60 minutes; in some preferred embodiments, the hydration treatment temperature is 56-58°C and the hydration treatment time is 40-50 minutes.

[0040] In this invention, the ultrasonic treatment power is 100-200W and the ultrasonic treatment time is 5-10 minutes; in some preferred embodiments, the ultrasonic treatment power is 120-180W and the ultrasonic treatment time is 6-8 minutes.

[0041] In this invention, the freeze-drying process involves pre-freezing at -40°C to -80°C for 2-4 hours, followed by drying at -20°C to -10°C and a vacuum of ≤10Pa for 20-28 hours during the main drying stage, and finally desorption drying at 20-25°C for 2-4 hours.

[0042] This invention provides the use of a POCD therapeutic composition in which dendrobine is delivered by a nanocarrier in the preparation of a medicament for the prevention or treatment of postoperative cognitive impairment.

[0043] In this invention, the route of administration for the drug for preventing or treating postoperative cognitive impairment is intravenous injection or nasal administration.

[0044] Example 1 Weigh out 10 mg of dendrobine, 100 mg of PLGA (lactic acid: glycolic acid = 75:25), 20 mL of polyvinyl alcohol aqueous solution (concentration 2%), and 50 mg of sucrose; 10 mg of dendrobine and 100 mg of PLGA were dissolved together in 2 mL of dichloromethane to form the oil phase; Slowly pour the oil phase into 20 mL of a 2% polyvinyl alcohol aqueous solution; The emulsion was pre-emulsified by high-speed shearing at 12,000 rpm for 3 minutes under ice bath conditions to obtain the pre-emulsion. Place the colostrum in an ice bath and treat it with intermittent ultrasound for 3 minutes using a 300W probe ultrasound device; The emulsion was transferred to a beaker and magnetically stirred at 400 rpm for 5 hours at room temperature to evaporate the organic solvent. Centrifuge at 4℃ and 18000×g for 30 minutes, discard the supernatant, and wash the precipitate twice with ultrapure water. The mixture was reconstituted with 5 mL of 1% sucrose solution, pre-frozen at -50°C for 3 hours, dried at -15°C and 10 Pa vacuum for 24 hours, and finally desorbed and dried at 25°C for 3 hours to obtain a white, loose powder nanocarrier delivering dendrobine POCD therapeutic drug composition.

[0045] The POCD therapeutic drug composition for delivering dendrobine via nanocarrier prepared in this embodiment was tested and found to have a particle size of 82.1-88.5 nm, a PDI of 0.152, and a drug loading of 9.3-10.3%.

[0046] Example 2 Weigh out 60 mg of distearate phosphatidylcholine, 30 mg of cholesterol, 6 mg of DSPE-PEG2000, 8 mg of dendrobine, and 50 mg of trehalose. Dissolve 60 mg distearate phosphatidylcholine, 30 mg cholesterol, and 6 mg DSPE-PEG2000 in 10 mL of chloroform; In a 50°C water bath, the mixture was rotary evaporated at 50 rpm and a vacuum of -0.09 MPa for 1.5 hours until a uniform lipid film was formed on the bottle wall. 10 mL of PBS buffer (pH=7.4, containing 1 mg / mL dendrobine) was added to the lipid membrane in a 60°C water bath and hydrated for 45 minutes. The hydrated suspension was subjected to intermittent sonication at 150W for 8 minutes under ice bath conditions, with a 2-second on / 3-second off cycle. The sonicated suspension was squeezed five times each through 0.2 μm and 0.1 μm polycarbonate membranes. The resulting liposome solution was mixed with an equal volume of 10% trehalose solution; The mixture was pre-frozen at -50°C for 3 hours, then dried at -15°C and 10 Pa under vacuum for 24 hours, and finally desorbed and dried at 25°C for 3 hours to obtain a white, loose powder nanocarrier delivering dendrobine POCD therapeutic composition.

[0047] The POCD therapeutic drug composition for delivering dendrobine via nanocarrier prepared in this embodiment was tested and found to have a particle size of 108.4-116.6 nm, a PDI of 0.189, and a drug loading of 6.8-7.6%.

[0048] Example 3 A POCD model was established using 18-month-old aged male C57BL / 6 mice under 3.5% sevoflurane anesthesia via exploratory laparotomy (operation time 15 min, total anesthesia time 1.5 h). The sham surgery group only received anesthesia and simulated abdominal preparation, without incision or abdominal exploration.

[0049] The study included a sham surgery group, a POCD model group, and a drug treatment group (POCD model + PLGA nanoparticles loaded with dendrobine prepared in Example 1, 10 mg / kg, calculated as dendrobine). Drugs were administered by gavage for 7 consecutive days post-surgery.

[0050] Morris water maze: Compared with the sham-operated group, mice in the POCD model group showed a significantly prolonged latency to find the hidden platform, a significantly reduced number of times they crossed the original platform location, and a significantly reduced time spent in the target quadrant (p<0.01). In contrast, the drug-treated group showed significant improvement in all of these indicators (p<0.05), indicating a recovery in their spatial learning and memory abilities.

[0051] Novel object recognition: The novel object recognition index of mice in the POCD model group was significantly lower than that in the sham-operated group (p<0.01), while the recognition index of mice in the drug treatment group was significantly higher than that in the POCD model group (p<0.05), indicating that their recognition and memory abilities were improved.

[0052] Hippocampal tissue was collected for Western blotting and immunofluorescence analysis. The results showed that, compared with the POCD model group, the drug treatment group significantly reduced the expression of pro-inflammatory factors (TNF-α, IL-1β, IL-6), inhibited M1 polarization of microglia (downregulation of CD86 and iNOS), promoted M2 polarization (upregulation of CD206), reduced neuronal apoptosis (decreased Bax / Bcl-2 ratio, decreased expression of cleaved caspase-3), and increased the expression of synapse-related proteins (PSD95, SYN1).

[0053] The results of the above embodiments demonstrate that the dendrobium alkaloid-loaded nanoparticles provided by this invention can effectively improve cognitive dysfunction in POCD model mice. Their mechanism of action is closely related to reducing neuroinflammation, inhibiting neuronal apoptosis, and improving synaptic function. This invention has promising development prospects.

[0054] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A POCD therapeutic composition for delivering dendrobine via a nanocarrier, characterized in that, It is composed of dendrobine, nanocarrier material and stabilizer; the nanocarrier is PLGA nanoparticles or liposomes; the POCD therapeutic composition of the nanocarrier delivering dendrobine has a particle size of 50-150 nm, a polydispersity index of <0.3, and a dendrobine loading of 5-15%.

2. The POCD therapeutic composition for delivering dendrobine via a nanocarrier according to claim 1, characterized in that, The nanocarrier is PLGA nanoparticles, wherein the molar ratio of lactic acid to glycolic acid monomers in PLGA is 50:50 to 75:25, and the stabilizer is polyvinyl alcohol or poloxamer.

3. The POCD therapeutic composition for delivering dendrobine via a nanocarrier according to claim 1, characterized in that, The nanocarrier is a liposome, and its membrane material includes distearylphosphatidylcholine, cholesterol and DSPE-PEG2000, with a mass ratio of (50-70):(25-40):(3-8). The stabilizer is sucrose or trehalose.

4. The POCD therapeutic composition for delivering dendrobine via a nanocarrier according to claim 1, characterized in that, The surface of the nanocarrier is covalently linked to a brain-targeting ligand, which is lactoferrin or Angiopep-2 peptide.

5. A method for preparing a POCD therapeutic composition for delivering dendrobine via a nanocarrier as described in claim 2, characterized in that, Includes the following steps: (1) Dendrobine and PLGA were dissolved together in dichloromethane as the oil phase; (2) Use polyvinyl alcohol aqueous solution as the aqueous phase; (3) The oil phase is injected into the aqueous phase for primary emulsification to obtain a primary emulsion; (4) The colostrum was subjected to ultrasonic treatment with a probe, followed by magnetic stirring to evaporate the organic solvent; (5) After centrifugation and washing with water, 5% sucrose solution was added to reconstitute the mixture, and then freeze-dried to obtain a POCD therapeutic drug composition for delivering dendrobine via a nanocarrier.

6. The method for preparing the POCD therapeutic composition for delivering dendrobine via a nanocarrier according to claim 5, characterized in that, The concentration of the polyvinyl alcohol aqueous solution is 1-3%; the initial emulsification is performed by high-speed shearing at 10000-15000 rpm for 2-5 minutes; the ultrasonic treatment power is 200-400W, and the ultrasonic treatment time is 2-5 minutes; the magnetic stirring speed is 300-500 rpm, and the magnetic stirring time is 4-6 hours; the centrifugation conditions are 4℃ and 15000-20000×g for 20-40 minutes; the freeze-drying is performed by pre-freezing at -40℃ to -80℃ for 2-4 hours, then drying at -20℃ to -10℃ and vacuum degree ≤10Pa for 20-28 hours in the main drying stage, and finally desorption drying at 20-25℃ for 2-4 hours.

7. A method for preparing a POCD therapeutic composition for delivering dendrobine via a nanocarrier as described in claim 3, characterized in that, Includes the following steps: (1) Distearate phosphatidylcholine, cholesterol and DSPE-PEG2000 were dissolved in chloroform and evaporated under reduced pressure to form a uniform lipid film. (2) Hydrate the PBS buffer containing dendrobine into the lipid membrane; (3) The hydrated suspension was ultrasonically treated and then extruded through polycarbonate membranes with pore sizes of 0.2 μm and 0.1 μm in sequence; (4) The obtained liposome solution was mixed with 5% trehalose solution and freeze-dried to obtain a POCD therapeutic composition for delivering dendrobine via nanocarrier.

8. The method for preparing the POCD therapeutic composition for delivering dendrobine via a nanocarrier according to claim 7, characterized in that, The vacuum degree of the rotary evaporation is ≤0.02MPa, the temperature is 45-50℃, the rotation speed is 30-60rpm, and the time is 1-2 hours; the concentration of dendrobine in the PBS buffer solution is 0.5-2mg / mL; the temperature of the hydration treatment is 55-60℃, and the hydration time is 30-60 minutes; the power of the ultrasonic treatment is 100-200W, and the ultrasonic treatment time is 5-10 minutes; the freeze-drying is pre-freezing at -40℃ to -80℃ for 2-4 hours, then drying at -20℃ to -10℃ and vacuum degree ≤10Pa for 20-28 hours in the main drying stage, and finally desorption drying at 20-25℃ for 2-4 hours.

9. The use of a POCD therapeutic composition of a nanocarrier delivering dendrobine as described in any one of claims 1-4 in the preparation of a medicament for the prevention or treatment of postoperative cognitive impairment.

10. The use of the POCD therapeutic composition for delivering dendrobine via a nanocarrier according to claim 9 in the preparation of a medicament for the prevention or treatment of postoperative cognitive impairment, characterized in that, The drug can be administered via intravenous injection or nasal administration.

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