Honokiol liposome lyophilized agent and preparation method therefor

Abstract

Provided are a honokiol liposome lyophilized agent and a preparation method therefor, belonging to the technical field of the preparation of liposome formulations. Provided is a honokiol liposome lyophilized agent. The active ingredient of the lyophilized agent is honokiol, and a protective agent povidone is contained. Further, the lyophilized agent is prepared from 1 part of honokiol, 2-8 parts of phospholipid, 0.3-2.2 parts of cholesterol, 0.1-1.5 parts of polyethylene glycol or phospholipid treated by polyethylene glycol, and 30-300 parts of a protective agent. The liposome lyophilized agent has low impurity content, better stability, and lower requirements on the storage environment.

Description

A lyophilized agent containing magnolol liposomes and its preparation method Technical Field

[0001] This invention belongs to the field of liposome preparation technology, specifically relating to a honokiol liposome lyophilization agent and its preparation method. Background Technology

[0002] Magnolia officinalis is the dried bark of Magnolia officinalis var. ...

[0003] Studies have shown that magnolol has a wide range of pharmacological effects, including antibacterial, anti-inflammatory, anti-anxiety, anti-morphine withdrawal, inhibition of catecholamine secretion, calmodulin antagonism, antiviral, antitumor, and anti-aging effects. [1] Therefore, magnolol has great potential for clinical application. The structural formula of magnolol is as follows.

[0004] However, due to the presence of phenolic hydroxyl groups in its structure, magnolol has poor water solubility and is easily oxidized and degraded, resulting in low oral bioavailability and a short elimination half-life in vivo. [2] This greatly limits the absorption and utilization of the medicinal ingredient, and its clinical application effect needs to be improved.

[0005] Liposomes, as a drug delivery system, can improve the transmembrane capacity and oral bioavailability of drugs with poor water solubility and stability. [3] Therefore, extensive work has been carried out on the preparation of magnolol liposomes.

[0006] Liposomes are phospholipid vesicles composed of one or more concentric lipid bilayers, which are closed, discrete water-containing spaces. Liposome vesicles can encapsulate a variety of lipophilic and hydrophilic drugs. Hydrophobic molecules are inserted into the lipid bilayer, while hydrophilic molecules can be embedded in the aqueous centers. [4] .

[0007] Although liposomes have shown good loading and drug delivery performance for magnolol, their chemical stability remains a concern. Studies have reported that high temperature, high humidity, and light exposure all affect magnolol raw materials, indicating poor stability. Furthermore, the lyophilized powder of magnolol liposomes exhibits a significant increase in oxidation index and leakage rate when stored at 25°C and 40°C, thus requiring storage at temperatures below 2-8°C. Moreover, under high humidity and high temperature conditions, especially high humidity, the average particle size, leakage rate, and oxidation index all increase over time. [2]The storage conditions for honokiol liposome lyophilized agents are extremely demanding.

[0008] Currently, there are still some shortcomings in the formulation and process research of honokiol liposome lyophilization agents. The products suffer from stability issues such as easy degradation and leakage, which places high demands on the storage environment. This invention addresses these technical problems and has been completed.

[0009] The relevant literature is as follows:

[0010] [1] Master's Thesis of Hubei University [D], "Preparation and Pharmacokinetic Study of Honokiol Long-Circulating Liposomes", Author: Chen Yizhen.

[0011] [2] Chen Yizhen et al. Preparation and pharmacokinetic study of magnolol long-circulating liposomes [J]. Chinese Traditional and Herbal Drugs, 2017.

[0012] [3] Que Huiqing et al. Study on the formulation and preparation process of Tripterygium wilfordii lactone nanoliposomes [J]. Chinese Traditional and Herbal Drugs, 2016.

[0013] [4]Metselaar JM, Storm G.Liposomes in the treatment of inflammatory disorders[J].Expert Opin Drug Deliv, 2005. Summary of the Invention

[0014] The purpose of this invention is to solve the above-mentioned technical problems and provide a honokiol liposome lyophilization agent and its preparation method. The liposome lyophilization agent has low impurity content, better stability, and reduced requirements for storage environment.

[0015] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0016] The first aspect of the present invention provides a honokiol liposome lyophilization agent, wherein the active ingredient of the lyophilization agent is honokiol, the lyophilization agent contains a protectant, the protectant contains povidone, and the protectant is added before lyophilization.

[0017] A second aspect of the present invention provides a specific honokiol liposome lyophilization agent, said lyophilization agent being composed of the following components in the following weight ratio:

[0018] The mixture contains 1 part magnolol, 2-8 parts phospholipids, 0.3-2.2 parts cholesterol, 0.1-1.5 parts polyethylene glycol or polyethylene glycol-modified phospholipids, and 30-300 parts protective agent.

[0019] The preferred composition is 1 part magnolol, 2-8 parts phospholipids, 0.3-1.2 parts cholesterol, 0.1-0.5 parts polyethylene glycol or polyethylene glycol-modified phospholipids, and 30-300 parts protective agent.

[0020] Furthermore, the protective agent is selected from a combination of povidone and mannitol, or a combination of povidone and trehalose, or a combination of povidone and sucrose.

[0021] Furthermore, the protective agent is povidone and sucrose, and the weight ratio of povidone to sucrose is 0.01 to 2:10, preferably 0.05 to 1:10.

[0022] Furthermore, the povidone includes any one or a combination of povidone K15, povidone K17, povidone K25, povidone K30, and povidone K60.

[0023] Furthermore, the povidone is povidone K25.

[0024] Furthermore, the protective agent is composed of povidone K25 and sucrose in a weight ratio of 0.9:10.

[0025] Furthermore, the polyethylene glycol or polyethylene glycolated phospholipid has a molecular weight of 800 to 20,000 Da.

[0026] Furthermore, the polyethylene glycol or polyethylene glycolated phospholipid has a molecular weight of 1000-8000 Da.

[0027] The phospholipids described in this invention may be any one or a combination of soybean phospholipids, hydrogenated soybean lecithin, egg yolk lecithin, hydrogenated egg yolk lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, sphingomyelin, dimyristoyl phosphatidylcholine, dioleoyl phosphatidylcholine, dilauroyl phosphatidylcholine, distearate phosphatidylcholine, or phosphatidylinositol, but are not limited thereto. Preferably, they are soybean phospholipids, egg yolk lecithin, or phosphatidylcholine.

[0028] The polyethylene glycol described in this invention can be any one or a combination of polyethylene glycol 1000, polyethylene glycol 2000, polyethylene glycol 4000, and polyethylene glycol 8000, but is not limited thereto. Preferably, it is polyethylene glycol 2000.

[0029] The polyethylene glycol-modified phospholipids described in this invention can be any one or a combination of phosphatidylcholine-polyethylene glycol 2000 (PC-PEG2000), phosphatidylethanolamine-polyethylene glycol 2000 (PE-PEG2000), distearylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000), distearylphosphatidylcholine-polyethylene glycol 2000 (DSPC-PEG2000), dipalmitoylphosphatidylcholine-polyethylene glycol 2000 (DPPC-PEG2000), and dipalmitoylphosphatidylethanolamine-polyethylene glycol 2000 (DPPE-PEG2000), but are not limited thereto. Preferably, it is distearylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000).

[0030] The preparation method of the honokiol liposome lyophilization agent of the present invention includes the following steps:

[0031] (1) Take phospholipids, cholesterol, polyethylene glycol or polyethylene glycol-modified phospholipids, and honokiol, mix them evenly, add organic solvent to the mixture to dissolve it completely, stir for 15 to 60 minutes, and then remove the organic solvent by rotary evaporation at 25 to 60°C and 80 to 150 rpm to obtain a uniform phospholipid film, and remove the residual organic solvent by vacuum treatment.

[0032] (2) Add water for injection to the phospholipid film and stir for 1 to 1.5 h at 25 to 70 °C and 200 to 2000 rpm. Homogenize the product to obtain a liposome solution.

[0033] (3) The liposome solution obtained in step (2) is filtered through a 0.22 μm filter at 2-10℃, a protective agent is added, and the mixture is stirred at 200-500 rpm for 10-30 min. After standing for 10-60 min, it is freeze-dried to prepare honokiol liposome freeze-dried agent.

[0034] Further, the organic solvent mentioned in step (1) is any one or any combination of anhydrous ethanol, chloroform, dichloromethane, and methanol; preferably a mixed solution of chloroform and anhydrous ethanol in a volume ratio of 1:1 to 10 or a mixed solution of chloroform and methanol in a volume ratio of 1:1 to 10.

[0035] The beneficial effects of the present invention are as follows:

[0036] The honokiol liposome lyophilizer provided by this invention, with the addition of a lyophilization protectant composed of povidone and sucrose, not only facilitates the formation of the lyophilized powder but also incorporates honokiol into the polymeric structure of povidone, forming a protective effect and increasing the stability of the honokiol liposomes. Simultaneously, by controlling the ratio of povidone to sucrose, the stability of the lyophilizer under high temperature, high humidity, and light exposure is further enhanced. The prepared honokiol liposome lyophilizer does not show a significant increase in impurity content and leakage rate with prolonged storage time, exhibiting lower sensitivity to temperature, humidity, and light, thus achieving a longer shelf life. Detailed Implementation

[0037] To make the objectives, technical solutions, and advantages of this invention clearer, the invention is described in detail below with reference to embodiments. It should be noted that the following embodiments are for explanation and illustration only and are not intended to limit the invention. Non-essential improvements and adjustments made by those skilled in the art based on the above description are still within the scope of protection of this invention.

[0038] The purity of magnolol used in the specific embodiments of this invention is ≥99%.

[0039] In a specific embodiment of the present invention, impurity A in the honokiol liposome lyophilized agent was determined to be 8',9'-dihydroxy and honokiol, which are oxidation derivatives of honokiol, and their chemical structures are as follows:

[0040] The specific embodiments of the present invention and the method for detecting impurity A in magnolol liposome lyophilization agent are as follows:

[0041] Weigh an appropriate amount of magnolol liposome lyophilized reagent into a volumetric flask, add methanol solution, filter the solution through a 0.22 μm filter membrane, and then inject it into a high-performance liquid chromatograph for analysis. HPLC column: Diomonsil TM C18 column (250 mm × 4.6 mm, 5 μm), eluent: water-methanol gradient elution. Flow rate 1.0 mL / min, injection volume 10 μL, detection wavelength 256 nm, column temperature 35 °C.

[0042] The specific embodiments of the present invention and the method for detecting the leakage rate of magnolol liposome lyophilization agent are as follows:

[0043] The encapsulation efficiency of the lyophilized agent before and after storage was determined, and the leakage rate (LR) was calculated using the following formula: LR(%) = (EE) / (E ... 贮藏前 -EE 贮藏后 )×100% / EE 贮藏前

[0044] The encapsulation efficiency of liposomes was determined using a centrifugation-ultrafiltration method. First, the free drug precipitate was removed by centrifugation, then ultrafiltration was performed to obtain a free drug solution, and the drug content was determined by HPLC. The encapsulation efficiency was calculated using the following formula: Encapsulation efficiency (%) = (W 总 -W 游 ) / W 总 ×100%

[0045] In the formula, W 总 W represents the total drug quality. 游 This indicates the mass of the free drug.

[0046] Example 1 Preparation of magnolol liposome solution

[0047] (1) Take magnolol (6g), soybean lecithin, cholesterol and polyethylene glycol-2000 and mix them in a weight ratio of 1:4.5:0.8:0.4. Then add anhydrous ethanol to the mixture to dissolve it completely, stir for 30 min, and remove the organic solvent by rotary evaporation at 35℃ and 120 rpm to obtain a uniform phospholipid film.

[0048] (2) Add water for injection to the phospholipid membrane and stir magnetically for 1 hour at 60°C and 2000 rpm. The resulting product is then homogenized in a high-pressure homogenizer (homogenization pressure is 15000 psi) to obtain a liposome solution. Add water for injection to bring the volume to 6L.

[0049] (3) The liposome solution obtained in step (2) is filtered at 4°C using a 0.22 μm filter to obtain the filtered intermediate liposome solution, which is stored at 4°C for later use.

[0050] Example 2: Preparation of lyophilized magnolol liposomes containing different protective agents

[0051] According to Example 1, an intermediate solution of magnolol liposomes was prepared, and each of the formulation components in Table 1 was added (each formulation is based on an addition amount of magnolol of 6g). Lyophilized agents containing different protective agents were prepared according to the following methods (PVP-K25 in Table 1 refers to povidone K25).

[0052] Table 1 Prescriptions 1-16

[0053] Preparation method:

[0054] A protective agent was added to the intermediate solution of honokiol liposomes prepared in Example 1, and the mixture was freeze-dried to prepare honokiol liposome lyophilized agent.

[0055] Example 3: Stability determination of lyophilizing agent

[0056] The lyophilized agents of formulations 1-16 prepared in Example 2 were placed at a temperature of 25°C and a relative humidity of 65% for 12 months. Samples were taken at 0 months, 3 months, 6 months, 9 months and 12 months to determine the percentage content of impurity A in the lyophilized powder. The results are shown in Table 2.

[0057] Table 2 Results of Impurity A Content (%) in Formula 1-16 Liposome Lyophilized Agents

[0058] The results showed that formulations 6, 10, 14 and 16 with added PVP-K25 had lower levels of impurity A content from 0 to 12 months compared to other formulations. In particular, formulation 16 had the lowest impurity A content and the growth was slow, indicating that the addition of PVP, especially PVP and sucrose as a protective agent can significantly inhibit the growth of impurity A.

[0059] Example 4: Effect of different methods of adding protective agent on impurities

[0060] Formula 17: Prepare an intermediate solution of magnolol liposomes according to the method of Example 1, and prepare a lyophilizing agent according to the formulation of Formula 6. The preparation method is as follows: freeze-dry the intermediate solution of liposomes, then add PVP-K25 and mix well to obtain the final product.

[0061] Formula 18: Prepare an intermediate solution of magnolol liposomes according to the method of Example 1, and prepare a lyophilizing agent according to the formulation of Formula 16. The preparation method is as follows: freeze-dry the intermediate solution of liposomes, then add sucrose and PVP-K25, and mix well to obtain the final product.

[0062] Formula 19: Prepare an intermediate solution of honokiol liposomes according to the method of Example 1, and prepare a lyophilized agent according to the formulation of Formula 16. The preparation method is as follows: add the protectant PVP-K25 and sucrose to the intermediate solution of honokiol liposomes, stir at 200 rpm for 15 min, let stand for 30 min, and then freeze dry to prepare the honokiol liposome lyophilized agent.

[0063] The lyophilized agent of prescription 17-19 was placed at a temperature of 25℃ and a relative humidity of 65% for 6 months. Samples were taken at 0, 3 and 6 months to determine the percentage content of impurity A in the lyophilized powder. The results are shown in Table 3.

[0064] Table 3. Results of Impurity A Content (%) in Formulas 17-19 Liposome Lyophilized Formulations

[0065] Comparing prescription 17 with prescription 6, and prescription 18 with prescription 16, it can be seen that adding protective agents such as PVP-K25 after lyophilizing the liposome solution first does not inhibit impurity A. Only by adding PVP-K25 as a protective agent to the liposome solution before lyophilization can the inhibition of impurity A be achieved.

[0066] Comparing Formula 19 with Formula 16, it can be seen that after adding the protectant to the liposome intermediate solution, and after a certain period of stirring and standing, the content level of impurity A is lower, which is more conducive to the stabilizing effect of the protectant on the lyophilized agent.

[0067] Example 5: Effect of different PVP models on impurity A

[0068] According to Example 1, an intermediate solution of magnolol liposomes was prepared, and each of the prescription components in Table 4 was added (each prescription is based on the amount of magnolol added being 6g). The mixture was stirred at 200 rpm for 15 min, allowed to stand for 30 min, and then freeze-dried to prepare a magnolol liposome lyophilized agent.

[0069] Table 4 Prescriptions 20-24

[0070] The lyophilized agent of prescription 20-24 was placed at a temperature of 25℃ and a relative humidity of 65% for 6 months. Samples were taken at 0 months, 3 months and 6 months to determine the percentage content of impurity A in the lyophilized powder. The results are shown in Table 5.

[0071] Table 5. Results of Impurity A Content (%) in Formula 20-24 Liposome Lyophilized Formulation

[0072] Comparing prescription 19 with prescriptions 20-24, it can be seen that all PVP models can inhibit the growth of impurity A. Among them, PVP-K25 has the best effect, PVP-K15, PVP-K17, and PVP-K30 have similar effects, PVP-K60 is second best, and PVP-K90 is slightly worse than the other models.

[0073] Example 6: Effect of PVP to Sucrose Ratio on the Stability of Lyophilizing Agent

[0074] According to Example 1, an intermediate solution of magnolol liposomes was prepared, and each of the prescription components in Table 6 was added (each prescription is based on the amount of magnolol added being 6g). The mixture was stirred at 200 rpm for 15 min, allowed to stand for 30 min, and then freeze-dried to prepare a magnolol liposome lyophilized agent.

[0075] Table 6 Prescriptions 25-30

[0076] The lyophilized agents prepared by prescriptions 19 and 25-30 were placed under high humidity conditions of 95% for 10 days. The appearance of the lyophilized powder at different times was observed and its leakage rate was measured. The results are shown in Table 7.

[0077] Table 7. Stability (Leakage Rate) Results of High Humidity Tests for Formulas 19 and 25-30

[0078] The high humidity test results showed that the lyophilized powders prepared by each formulation were full and without collapse at 0 and 5 days. At 10 days, formulations 19 and 25-28 were full and without collapse, while formulations 29 and 30 showed slight collapse. Regarding leakage rate, formulations 19 and 25-27 had slightly better leakage rates than formulation 28-30, indicating that when the weight ratio of povidone to sucrose is 0.01–2:10, especially 0.05–1:10, the prepared lyophilized powder has better moisture resistance and product stability.

[0079] The lyophilizing agents prepared by formulations 19 and 25-30 were placed at a high temperature of 40℃ and under strong light irradiation of 5000lx for 10 days, and their appearance and content were examined. The results showed that the leakage rate of each formulation was less than 5% after 10 days under high temperature or strong light, and the leakage rate of formulations 19 and 25-27 was lower than that of formulations 28-30. This indicates that when the weight ratio of povidone to sucrose is 0.01 to 2:10, especially when it is 0.05 to 1:10, the prepared lyophilized powder has better resistance to high temperature and strong light, better stability, and less impact of external storage environment on product quality.

[0080] Example 7

[0081] The freeze-dried powder was prepared according to the following method.

[0082] (1) Take magnolol (6g), egg yolk lecithin, cholesterol, distearate phosphatidylethanolamine-polyethylene glycol 2000 and mix them in a weight ratio of 1:8:1.2:0.5. Then add anhydrous ethanol to the mixture to dissolve it completely, stir for 30 min, and remove the organic solvent by rotary evaporation at 35℃ and 120 rpm to obtain a uniform phospholipid film.

[0083] (2) Add water for injection to the phospholipid membrane and stir magnetically for 1 hour at 60°C and 2000 rpm. The resulting product is then homogenized in a high-pressure homogenizer (homogenization pressure is 15000 psi) to obtain a liposome solution. Add water for injection to bring the volume to 6L.

[0084] (3) The liposome solution obtained in step (2) was filtered at 4°C using a 0.22 μm filter. Based on the weight of honokiol, a protective agent of 200 times its weight was added. The protective agent was made of povidone K17 and sucrose in a weight ratio of 0.5:10. The mixture was stirred at 500 rpm for 10 min, allowed to stand for 20 min, and then freeze-dried to prepare honokiol liposome freeze-dried agent.

[0085] Example 8

[0086] The freeze-dried powder was prepared according to the following method.

[0087] (1) Take magnolol (6g), phosphatidylcholine, cholesterol, phosphatidylcholine-polyethylene glycol 2000 and mix them in a weight ratio of 1:2:0.3:0.1. Then add anhydrous ethanol to the mixture to dissolve it completely, stir for 30 min, and remove the organic solvent by rotary evaporation at 35℃ and 120 rpm to obtain a uniform phospholipid film.

[0088] (2) Add water for injection to the phospholipid membrane and stir magnetically for 1 hour at 60°C and 2000 rpm. The resulting product is then homogenized in a high-pressure homogenizer (homogenization pressure is 15000 psi) to obtain a liposome solution. Add water for injection to bring the volume to 6L.

[0089] (3) The liposome solution obtained in step (2) was filtered at 4°C using a 0.22 μm filter. Based on the weight of honokiol, a protective agent of 30 times its weight was added. The protective agent was made of povidone K15 and sucrose in a weight ratio of 0.6:10. The mixture was stirred at 300 rpm for 15 min, allowed to stand for 15 min, and then freeze-dried to prepare honokiol liposome freeze-dried agent.

[0090] Example 9

[0091] The freeze-dried powder was prepared according to the following method.

[0092] (1) Take magnolol (6g), phosphatidylserine, cholesterol, phosphatidylcholine-polyethylene glycol 2000 and mix them in a weight ratio of 1:6:0.8:0.35. Then add anhydrous ethanol to the mixture to dissolve it completely, stir for 30 min, and remove the organic solvent by rotary evaporation at 35℃ and 120 rpm to obtain a uniform phospholipid film.

[0093] (2) Add water for injection to the phospholipid membrane and stir magnetically for 1 hour at 60°C and 2000 rpm. The resulting product is then homogenized in a high-pressure homogenizer (homogenization pressure is 15000 psi) to obtain a liposome solution. Add water for injection to bring the volume to 6L.

[0094] (3) The liposome solution obtained in step (2) was filtered at 4°C using a 0.22 μm filter. Based on the weight of honokiol, a protective agent of 150 times its weight was added. The protective agent was made of povidone K30 and sucrose in a weight ratio of 0.4:10. The mixture was stirred at 200 rpm for 20 min, allowed to stand for 20 min, and then freeze-dried to prepare honokiol liposome freeze-dried agent.

[0095] Example 10

[0096] The freeze-dried powder was prepared according to the following method.

[0097] (1) Take magnolol (6g), phosphatidylethanolamine, cholesterol, dipalmitoylphosphatidylcholine-polyethylene glycol 2000 and mix them in a weight ratio of 1:5:0.6:0.3. Then add anhydrous ethanol to the mixture to dissolve it completely, stir for 30 min, and remove the organic solvent by rotary evaporation at 35℃ and 120 rpm to obtain a uniform phospholipid film.

[0098] (2) Add water for injection to the phospholipid membrane and stir magnetically for 1 hour at 60°C and 2000 rpm. The resulting product is then homogenized in a high-pressure homogenizer (homogenization pressure is 15000 psi) to obtain a liposome solution. Add water for injection to bring the volume to 6L.

[0099] (3) The liposome solution obtained in step (2) was filtered at 4°C using a 0.22 μm filter. Based on the weight of honokiol, a protective agent of 100 times its weight was added. The protective agent was made of povidone K60 and sucrose in a weight ratio of 0.2:10. The mixture was stirred at 500 rpm for 10 min, allowed to stand for 20 min, and then freeze-dried to prepare honokiol liposome freeze-dried agent.

[0100] Examples 7-10 of this invention are preferred embodiments. Testing showed that their liposome lyophilization agents exhibited good performance and stability. The leakage rate of the product was less than 5% after 10 days under high temperature (40°C), high humidity (90%), and light exposure (5000 lx). Furthermore, after long-term storage at 25°C and 65% relative humidity, the content of impurity A in the product did not show a significant increase. The various embodiments described in this invention are merely exemplary and do not represent any limitation on the scope of the invention in any way.

Claims

1. A lyophilized agent containing magnolol liposomes, characterized in that, The active ingredient of the lyophilizing agent is magnolol, and the lyophilizing agent contains a protectant, which contains povidone, and the protectant is added before lyophilization.

2. The honokiol liposome lyophilization agent according to claim 1, characterized in that, The lyophilizing agent is composed of the following components in the following weight ratio: The ingredients include 1 part magnolol, 2-8 parts phospholipids, 0.3-2.2 parts cholesterol, 0.1-1.5 parts polyethylene glycol or polyethylene glycol-modified phospholipids, and 30-300 parts protective agent.

3. The honokiol liposome lyophilization agent according to claim 2, characterized in that, The lyophilizing agent is composed of the following components in the following weight ratio: The ingredients include 1 part magnolol, 2-8 parts phospholipids, 0.3-1.2 parts cholesterol, 0.1-0.5 parts polyethylene glycol or polyethylene glycol-modified phospholipids, and 30-300 parts protective agent.

4. The honokiol liposome lyophilization agent according to claim 1, characterized in that, The protective agent is selected from a composition of povidone and mannitol, or a composition of povidone and trehalose, or a composition of povidone and sucrose.

5. The honokiol liposome lyophilization agent according to claim 4, characterized in that, The protective agent is povidone and sucrose, and the weight ratio of povidone to sucrose is 0.01 to 2:

10.

6. The honokiol liposome lyophilization agent according to claim 5, characterized in that, The weight ratio of povidone to sucrose is 0.05 to 1:

10.

7. The honokiol liposome lyophilization agent according to claim 1, characterized in that, The povidone includes any one or a combination of povidone K15, povidone K17, povidone K25, povidone K30, and povidone K60.

8. The honokiol liposome lyophilization agent according to claim 7, characterized in that, The povidone is povidone K25.

9. The honokiol liposome lyophilization agent according to claim 1, characterized in that, The protective agent is composed of povidone K25 and sucrose in a weight ratio of 0.9:

10.

10. The honokiol liposome lyophilization agent according to claim 2, characterized in that, The polyethylene glycol or polyethylene glycolated phospholipid has a molecular weight of 800 to 20,000 Da.

11. The honokiol liposome lyophilization agent according to claim 10, characterized in that, The polyethylene glycol or polyethylene glycolated phospholipid has a molecular weight of 1000-8000 Da.

12. The method for preparing the honokiol liposome lyophilized agent according to any one of claims 1-11, characterized in that, Includes the following steps: (1) Take phospholipids, cholesterol, polyethylene glycol or polyethylene glycol-modified phospholipids, and honokiol, mix them evenly, add organic solvent to the mixture to dissolve it completely, stir for 15 to 60 minutes, and then remove the organic solvent by rotary evaporation at 25 to 60°C and 80 to 150 rpm to obtain a uniform phospholipid film, and remove the residual organic solvent by vacuum treatment. (2) Add water for injection to the phospholipid film and stir for 1 to 1.5 h at 25 to 70 °C and 200 to 2000 rpm. Homogenize the product to obtain a liposome solution. (3) The liposome solution obtained in step (2) is filtered through a 0.22 μm filter at 2-10℃, a protective agent is added, and the mixture is stirred at 200-500 rpm for 10-30 min. After standing for 10-60 min, it is freeze-dried to prepare honokiol liposome freeze-dried agent.

13. The method for preparing the honokiol liposome lyophilized agent according to claim 12, characterized in that, The organic solvent mentioned in step (1) is any one of anhydrous ethanol, chloroform, dichloromethane, and methanol, or any combination thereof.

14. The method for preparing the honokiol liposome lyophilized agent according to claim 13, characterized in that, The organic solvent is a mixed solution of chloroform and anhydrous ethanol in a volume ratio of 1:1 to 10 or a mixed solution of chloroform and methanol in a volume ratio of 1:1 to 10.

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