Protein deposition resistant contact lens care solution based on nanotechnology

Abstract

The invention belongs to the technical field of care solutions, and provides an anti-proteolysis contact lens care solution based on a nanotechnology. The protein deposition resistant contact lens care solution based on the nanotechnology is prepared from sulphobetaine, nano-liposome, hyaluronic acid, a complexing agent, an antibacterial agent, a pH regulator, an osmotic pressure regulator and water. The mass percent of each raw material is limited. The nano lipidosome with a core-shell structure is introduced, and the nutritional component is the core material, so that the nano lipidosome has the effects of resisting oxidation and relieving fatigue; the shell material is nano-liposome modified by alkyl glycoside and has excellent hydrophilicity; the nano-liposome, the sulphobetaine and the hyaluronic acid have a synergistic effect, so that the deposition of protein is destroyed; the complexing agent and metal ions form a complex, so that the metal ions are prevented from participating in protein deposition, and protein deposition is further prevented and reduced; the nanotechnology is successfully applied to moisturizing / lubricating components, protein deposition can be synergistically prevented, and the comfort of long-time wearing is improved.

Description

Technical Field

[0001] This invention relates to the field of contact lens solution technology, and more particularly to an anti-protein deposition contact lens solution based on nanotechnology. Background Technology

[0002] With the improvement of living standards, colored, monthly, and yearly contact lenses have emerged, and more and more beauty enthusiasts have come to regard contact lenses as an essential part of their lives. Contact lens care solutions are care products that provide contact lens users with cleaning, disinfection, and storage services. Deposits and pathogens on the lens surface must first be removed with care solutions in order to effectively sterilize and preserve the lenses.

[0003] Contact lens solutions typically contain moisturizers, lubricants, chelating agents, antibacterial agents, osmotic pressure regulators, and pH adjusters, primarily for sterilization, cleaning, and maintenance. During use, contact lenses absorb proteins and other lipids, and current contact lens solutions are not very effective at removing these proteins. Furthermore, the moisturizing and lubricating effects of these solutions often fail to meet the comfort and fatigue requirements of prolonged wear.

[0004] In addition, the application of nanotechnology to contact lens care solutions is currently mostly achieved by introducing nano-antibacterial materials, such as nano-silver as an antibacterial agent. The use of nanotechnology in protein components or moisturizing / lubricating components is not common.

[0005] Therefore, it is of great significance to develop a contact lens care solution that utilizes nanotechnology for other functional components and can effectively resist protein deposition. Summary of the Invention

[0006] The purpose of this invention is to provide a nanotechnology-based anti-protein deposition contact lens solution to address the shortcomings of existing technologies.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0008] This invention provides a nanotechnology-based anti-protein deposition contact lens solution, comprising the following raw materials in weight percentages:

[0009] Sulfobetaine 0.1-1%, nanoliposomes 0.01-1%, hyaluronic acid 0.5-2%, complexing agent 0.02-0.7%, antibacterial agent 0.01-0.08%, pH adjuster 0.1-1%, osmotic pressure adjuster 0.5-2%, balance is water.

[0010] Preferably, the nanoliposomes have a core-shell structure;

[0011] The core material of the nanoliposomes is a nutrient component, and the shell material is an alkyl glycoside modified nanoliposome.

[0012] Preferably, the nutrient components include oil-soluble nutrient components and water-soluble nutrient components, wherein the oil-soluble nutrient components include lutein and / or zeaxanthin.

[0013] The water-soluble nutrient components include water-soluble vitamins.

[0014] Preferably, the method for preparing the nanoliposomes includes the following steps:

[0015] 1) Dissolve phospholipids and cholesterol in an organic solvent to obtain the oil phase;

[0016] 2) Dissolve water-soluble nutrients in water to obtain an aqueous phase;

[0017] The oil-soluble nutrient components are dissolved in an organic solvent to obtain a second oil phase;

[0018] 3) The oil phase, the second oil phase, the aqueous phase, and the surfactant are emulsified to obtain a mixed system;

[0019] 4) React the mixture, 2-iminothione hydrochloride and alkyl glycoside to obtain nanoliposomes.

[0020] Preferably, the mass ratio of phospholipids, cholesterol and organic solvent in step 1) is 3-4:1:8-10;

[0021] In step 2), the mass ratio of the water-soluble nutrient component to water is 1:3 to 5.

[0022] In step 2), the mass ratio of the oil-soluble nutrient component to the organic solvent is 1:3 to 5.

[0023] Preferably, in step 3), the ratio of the total mass of the second oil phase and the water phase to the mass of the oil phase is 1:5 to 8, and the mass ratio of the oil phase to the surfactant is 5 to 8:1.

[0024] The ratio of the total mass of phospholipids and cholesterol in step 1) to the mass of the alkyl glycoside in step 4) is 3-8:1;

[0025] In step 4), the mass ratio of the alkyl glycoside to 2-iminothione hydrochloride is 1:6 to 10.

[0026] Preferably, the temperature of the emulsification reaction in step 3) is 60-80°C, and the time of the emulsification reaction is 10-20 min;

[0027] During the emulsification process, stirring is performed at a speed of 5000–10000 r / min.

[0028] Preferably, the reaction in step 4) is carried out under a protective atmosphere, at a temperature of 20–30°C, and for a time of 1–3 hours.

[0029] Preferably, the phospholipids in step 1) comprise phospholipids containing maleimide groups and other phospholipids, wherein the other phospholipids comprise one or more of lecithin, phosphatidylethanolamine and phosphatidylserine;

[0030] The molar ratio of the other phospholipids and the phospholipids containing maleimide groups is 8 to 15:1.

[0031] The beneficial effects of this invention include the following:

[0032] 1) This invention introduces nanoliposomes with a core-shell structure. The nutrient component is the core material, which protects the retina and has antioxidant and fatigue-relieving effects. The shell material is a nanoliposome modified with alkyl glycosides, which has excellent hydrophilicity and improves the wettability of the eyeglass lens. The high hydrophilicity of the nanoliposomes, together with sulfobetaine and hyaluronic acid, works synergistically to destroy the deposition of proteins on the surface of the eyeglass lens, thereby removing proteins. The complexing agent can form complexes with metal ions, preventing metal ions from participating in protein deposition, and further preventing and reducing protein deposition.

[0033] 2) This invention introduces nanoliposomes, enabling nanotechnology to be successfully applied to moisturizing / lubricating components, and can synergistically prevent protein deposition, thereby improving the wettability while maintaining the cleanliness and transparency of the eyeglasses and improving comfort during long-term wear. Detailed Implementation

[0034] This invention provides a nanotechnology-based anti-protein deposition contact lens solution, comprising the following raw materials in weight percentages:

[0035] Sulfobetaine 0.1-1%, nanoliposomes 0.01-1%, hyaluronic acid 0.5-2%, complexing agent 0.02-0.7%, antibacterial agent 0.01-0.08%, pH adjuster 0.1-1%, osmotic pressure adjuster 0.5-2%, balance is water.

[0036] The nanotechnology-based anti-protein deposition contact lens solution of the present invention comprises the following raw materials in weight percentages:

[0037] The following components are present: sulfobetaine 0.1–1%, preferably 0.3–0.8%, more preferably 0.5%; nanoliposomes 0.01–1%, preferably 0.08–0.7%, more preferably 0.2–0.5%; hyaluronic acid 0.5–2%, preferably 0.8–1.5%, more preferably 1%; complexing agent 0.02–0.7%, preferably 0.08–0.6%, more preferably 0.2–0.4%; antibacterial agent 0.01–0.08%, preferably 0.02–0.06%, more preferably 0.04%; pH adjuster 0.1–1%, preferably 0.3–0.8%, more preferably 0.5%; osmotic pressure adjuster 0.5–2%, preferably 0.8–1.5%, more preferably 1%; the balance being water.

[0038] In this invention, the complexing agent is preferably ethylenediaminetetraacetic acid; the antibacterial agent is preferably polyhexamethylene biguanide hydrochloride and / or polyquaternary ammonium salt; the pH adjuster is preferably boric acid; and the osmotic pressure adjuster is preferably sodium chloride and / or potassium chloride.

[0039] In this invention, the nanoliposomes are preferably of a core-shell structure;

[0040] The core material of the nanoliposomes is preferably a nutrient component, and the shell material is preferably an alkyl glycoside modified nanoliposome.

[0041] In this invention, the nutrient components preferably include oil-soluble nutrient components and water-soluble nutrient components, and the oil-soluble nutrient components preferably include lutein and / or zeaxanthin.

[0042] The water-soluble nutrient component preferably includes water-soluble vitamins.

[0043] In this invention, the method for preparing the nanoliposomes preferably includes the following steps:

[0044] 1) Dissolve phospholipids and cholesterol in an organic solvent to obtain the oil phase;

[0045] 2) Dissolve water-soluble nutrients in water to obtain an aqueous phase;

[0046] The oil-soluble nutrient components are dissolved in an organic solvent to obtain a second oil phase;

[0047] 3) The oil phase, the second oil phase, the aqueous phase, and the surfactant are emulsified to obtain a mixed system;

[0048] 4) React the mixture, 2-iminothione hydrochloride and alkyl glycoside to obtain nanoliposomes.

[0049] In this invention, the mass ratio of phospholipids, cholesterol and organic solvent in step 1) is preferably 3-4:1:8-10, more preferably 3.2-3.8:1:8.5-9.5, and even more preferably 3.5:1:9;

[0050] In step 2), the mass ratio of the water-soluble nutrient component to water is preferably 1:3 to 5, more preferably 1:3.5 to 4.5, and even more preferably 1:4.

[0051] In step 2), the mass ratio of the oil-soluble nutrient component to the organic solvent is preferably 1:3 to 5, more preferably 1:3.5 to 4.5, and even more preferably 1:4.

[0052] In this invention, in step 3), the ratio of the total mass of the second oil phase and the aqueous phase to the mass of the oil phase is preferably 1:5 to 8, more preferably 1:5.5 to 7.5, and even more preferably 1:6 to 7; the mass ratio of the oil phase to the surfactant is preferably 5 to 8:1, more preferably 5.5 to 7.5:1, and even more preferably 6 to 7:1.

[0053] The ratio of the total mass of phospholipids and cholesterol in step 1) to the mass of alkyl glycosides in step 4) is preferably 3 to 8:1, more preferably 4 to 7:1, and even more preferably 5 to 6:1;

[0054] In step 4), the mass ratio of the alkyl glycoside to 2-iminothione hydrochloride is preferably 1:6 to 10, more preferably 1:7 to 9, and even more preferably 1:8.

[0055] In this invention, the temperature of the emulsification reaction in step 3) is preferably 60-80°C, more preferably 65-75°C, and even more preferably 70°C; the time of the emulsification reaction is preferably 10-20 min, more preferably 13-18 min, and even more preferably 15 min.

[0056] Stirring is preferably performed during the emulsification process, and the stirring speed is preferably 5000-10000 r / min, more preferably 6000-9000 r / min, and even more preferably 7000-8000 r / min.

[0057] In this invention, the surfactant in step 3) is preferably a nonionic surfactant.

[0058] In this invention, the alkyl glycoside in step 4) is preferably an amino-modified alkyl glycoside.

[0059] In this invention, step 4) preferably involves first mixing alkyl glycosides and 2-iminothionine hydrochloride to perform alkyl glycoside thiolation modification, and then reacting with the mixed system to obtain nanoliposomes.

[0060] In this invention, the temperature for alkyl glycoside thiolation modification is preferably 20-30°C, more preferably 25°C; the time for alkyl glycoside thiolation modification is preferably 0.5-2 h, more preferably 1-1.5 h.

[0061] In this invention, the reaction in step 4) is preferably carried out under a protective atmosphere, the reaction temperature is preferably 20-30°C, more preferably 23-28°C, and even more preferably 25°C; the reaction time is preferably 1-3 hours, more preferably 1.5-2.5 hours, and even more preferably 2 hours.

[0062] In this invention, the phospholipids in step 1) preferably include phospholipids containing maleimide groups and other phospholipids, wherein the other phospholipids preferably include one or more of lecithin, phosphatidylethanolamine and phosphatidylserine;

[0063] The molar ratio of the other phospholipids and the phospholipids containing maleimide groups is preferably 8 to 15:1, more preferably 9 to 13:1, and even more preferably 10 to 12:1.

[0064] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0065] The preparation method of the amino-modified alkyl glycoside in the embodiments and comparative examples of the present invention is as follows: alkyl glycoside (10 carbon atoms, degree of polymerization 1.4), phosphorus trichloride and ethylenediamine are mixed in a mass ratio of 1:3:5, and then 0.8% of p-toluenesulfonic acid of the total mass of the mixture is added. The mixture is reacted at 85°C for 3 hours. After the reaction is completed, the mixture is cooled to room temperature, filtered, and dried at 80°C for 2 hours to obtain the final product.

[0066] Example 1

[0067] The preparation method of core-shell structured liposomes is as follows:

[0068] Phospholipids, cholesterol, and dichloromethane were mixed in a mass ratio of 3.5:1:8, and the phospholipids and cholesterol were completely dissolved to obtain the oil phase. The phospholipids contained soybean lecithin and dioleoylphosphatidylethanolamine-maleimide in a mass ratio of 15:1. Vitamin B1 in a mass ratio of 1:3 was added. 12 Mix with deionized water to make vitamin B 12 Complete dissolution yields the aqueous phase. Lutein and dichloromethane are mixed in a mass ratio of 1:4 until the lutein is completely dissolved, yielding the second oil phase.

[0069] The oil phase, second oil phase, aqueous phase, and polyethylene glycol fatty acid ester (molecular weight of polyethylene glycol fatty acid ester is 600) were mixed and emulsified at 60°C and 7000 r / min for 20 min to obtain a mixed system. The mass ratio of the total mass of the second oil phase and aqueous phase to the oil phase was 1:6, and the mass ratio of the oil phase to the polyethylene glycol fatty acid ester was 8:1. The lutein in the second oil phase and the vitamin B in the aqueous phase... 12 The mass ratio is 1:1.

[0070] Under a nitrogen atmosphere, an amino-modified alkyl glycoside and 2-iminothione hydrochloride were mixed in a mass ratio of 1:8 and reacted at 25°C for 0.5 h to perform thiol modification of the alkyl glycoside. The mixture was then added to the final mixture and reacted at 20°C for 3 h to obtain lutein and vitamin B1 as the core materials. 12 Core-shell structured nanoliposomes with shell material being amino-modified alkyl glycosides.

[0071] This nanotechnology-based anti-protein deposition contact lens solution contains the following ingredients by weight percentage:

[0072] The composition includes: 0.5% hexadecyl ethoxysulfonate betaine, 1% core-shell structured nanoliposomes, 0.5% hyaluronic acid (molecular weight 200,000), 0.7% ethylenediaminetetraacetic acid, 0.04% polyhexamethylene biguanide hydrochloride, 0.1% boric acid, 0.8% sodium chloride, and the balance being purified water.

[0073] Example 2

[0074] The preparation method of core-shell structured liposomes is as follows:

[0075] Phospholipids, cholesterol, and dichloromethane were mixed in a mass ratio of 3:1:9, and the phospholipids and cholesterol were completely dissolved to obtain the oil phase. The phospholipids included soybean lecithin and dipalmitoylphosphatidylethanolamine-polyethylene glycol-maleimide in a mass ratio of 12:1. Vitamin B6 and deionized water were mixed in a mass ratio of 1:5, and the vitamin B6 was completely dissolved to obtain the aqueous phase. Zeaxanthin and dichloromethane were mixed in a mass ratio of 1:3, and the zeaxanthin was completely dissolved to obtain the second oil phase.

[0076] The oil phase, second oil phase, aqueous phase, and polyethylene glycol fatty acid ester (molecular weight of polyethylene glycol fatty acid ester is 600) were mixed and emulsified at 70°C and 5000 r / min for 10 min to obtain a mixed system. The mass ratio of the total mass of the second oil phase and aqueous phase to the oil phase was 1:5, the mass ratio of the oil phase to the polyethylene glycol fatty acid ester was 6:1, and the mass ratio of zeaxanthin in the second oil phase to vitamin B6 in the aqueous phase was 1:1.

[0077] Under a nitrogen atmosphere, an amino-modified alkyl glycoside and 2-iminothione hydrochloride were mixed at a mass ratio of 1:10 and reacted at 20°C for 2 hours to thiolize the alkyl glycoside. The mixture was then added to the mixture and reacted at 25°C for 1 hour to obtain core-shell nanoliposomes with zeaxanthin and vitamin B6 as the core material and amino-modified alkyl glycoside as the shell material.

[0078] This nanotechnology-based anti-protein deposition contact lens solution contains the following ingredients by weight percentage:

[0079] Dodecyl ethoxysulfonate betaine 1%, core-shell structured nanoliposomes 0.2%, hyaluronic acid (molecular weight 500,000) 1%, ethylenediaminetetraacetic acid 0.4%, polyhexamethylene biguanide hydrochloride 0.01%, boric acid 0.5%, potassium chloride 2%, and the balance is purified water.

[0080] Example 3

[0081] The preparation method of core-shell structured liposomes is as follows:

[0082] Phospholipids, cholesterol, and chloroform were mixed in a mass ratio of 4:1:10, and the phospholipids and cholesterol were completely dissolved to obtain the oil phase. The phospholipids contained phosphatidylserine and distearate-polyethylene glycol-maleimide in a mass ratio of 8:1. Vitamin B1 was added in a mass ratio of 1:4. 12 Mix with deionized water to make vitamin B 12 Complete dissolution yields the aqueous phase. A mixture of oil-soluble nutrients (containing lutein and zeaxanthin in a 1:2 mass ratio) and chloroform at a mass ratio of 1:5 is then prepared to completely dissolve the oil-soluble nutrients, yielding the second oil phase.

[0083] The oil phase, second oil phase, aqueous phase, and polyethylene glycol fatty acid ester (molecular weight of polyethylene glycol fatty acid ester is 600) were mixed and emulsified at 80°C and 10000 r / min for 15 min to obtain a mixed system. The total mass ratio of the second oil phase and aqueous phase to the oil phase was 1:8, and the mass ratio of the oil phase to the polyethylene glycol fatty acid ester was 5:1. The oil-soluble nutrients in the second oil phase and vitamin B in the aqueous phase... 12 The mass ratio is 1:1.

[0084] Under a nitrogen atmosphere, an amino-modified alkyl glycoside and 2-iminothione hydrochloride were mixed in a mass ratio of 1:6 and reacted at 30°C for 1 h to perform thiol modification of the alkyl glycoside. The mixture was then added to the final mixture and reacted at 30°C for 2 h to obtain lutein, zeaxanthin, and vitamin B12 as the core materials. 12 The shell material is a core-shell structured nanoliposome modified with aminoalkyl glycosides.

[0085] This nanotechnology-based anti-protein deposition contact lens solution contains the following ingredients by weight percentage:

[0086] Octadecylethoxysulfonate betaine 0.1%, core-shell structured nanoliposomes 0.08%, hyaluronic acid (molecular weight 1 million) 2%, ethylenediaminetetraacetic acid 0.08%, polyquaternium salt 0.08%, boric acid 1%, sodium chloride 0.5%, balance is purified water.

[0087] Comparative Example 1

[0088] The core-shell structured nanoliposomes in Example 1 are omitted, and everything else is the same as in Example 1.

[0089] Comparative Example 2

[0090] The hexadecylethoxysulfonyl betaine in Example 1 is omitted, and everything else is the same as in Example 1.

[0091] Comparative Example 3

[0092] In Example 1, hexadecylethoxysulfonate was replaced with poloxamer 188, and everything else was the same as in Example 1.

[0093] Comparative Example 4

[0094] The core-shell structured nanoliposomes in Example 1 were replaced with hydroxypropyl methylcellulose, and everything else was the same as in Example 1.

[0095] Comparative Example 5

[0096] The core-shell structured nanoliposomes in Example 1 were replaced with lutein and vitamin B. 12 Lutein and Vitamin B 12 The mass ratio is 1:1, and other aspects are the same as in Example 1.

[0097] The contact lens solutions of Examples 1-3 and Comparative Examples 1-5 were tested for anti-protein deposition, contact angle, and wearing effect, and the results are shown in Table 1.

[0098] The contact angle test was performed using a contact angle measuring instrument.

[0099] Anti-protein deposition test: Contact lenses worn by the same wearer for 16 hours were immersed in the contact lens solution and left to soak overnight. The protein concentration of the solution was then measured using the Bradford Protein Concentration Assay Kit.

[0100] Wearing effect test: 48 volunteers who experienced discomfort such as dryness and fatigue due to prolonged contact lens wear were selected and divided into 8 groups. The 8 groups of volunteers wore contact lenses soaked overnight in the solutions of Examples 1-3 and Comparative Examples 1-5, for 5 consecutive days, 16 hours per day. The wearing effect was scored, and the average score within each group was taken. Scoring criteria: 1 point - poor, 2 points - poor, 3 points - average, 4 points - good, 5 points - good, 6 points - very good.

[0101] Table 1. Performance Test Results of Contact Lens Solution

[0102]

[0103]

[0104] As shown in Table 1, the nanotechnology-based anti-protein deposition contact lens solution of the present invention has excellent hydrophilicity; the protein concentration after soaking contact lenses is high, indicating good protein removal ability and effective removal of protein deposits on contact lenses; according to wearer evaluations, the nanotechnology-based anti-protein deposition contact lens solution of the present invention can significantly relieve discomfort symptoms such as dryness and fatigue caused by long-term wear.

[0105] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A nanotechnology-based anti-protein deposition contact lens solution, characterized in that, It contains the following raw materials by weight percentage: Sulfobetaine 0.1-1%, nanoliposomes 0.01-1%, hyaluronic acid 0.5-2%, complexing agent 0.02-0.7%, antibacterial agent 0.01-0.08%, pH adjuster 0.1-1%, osmotic pressure adjuster 0.5-2%, balance is water.

2. The anti-protein deposition contact lens solution based on nanotechnology according to claim 1, characterized in that, The nanoliposomes have a core-shell structure; The core material of the nanoliposomes is a nutrient component, and the shell material is an alkyl glycoside modified nanoliposome.

3. The anti-protein deposition contact lens solution based on nanotechnology according to claim 2, characterized in that, The nutrient components include oil-soluble nutrient components and water-soluble nutrient components, wherein the oil-soluble nutrient components include lutein and / or zeaxanthin. The water-soluble nutrient components include water-soluble vitamins.

4. The nanotechnology-based anti-protein deposition contact lens solution according to any one of claims 1 to 3, characterized in that, The method for preparing the nanoliposomes includes the following steps: 1) Dissolve phospholipids and cholesterol in an organic solvent to obtain the oil phase; 2) Dissolve water-soluble nutrients in water to obtain an aqueous phase; The oil-soluble nutrient components are dissolved in an organic solvent to obtain the second oil phase; 3) The oil phase, the second oil phase, the aqueous phase, and the surfactant are emulsified to obtain a mixed system; 4) React the mixture, 2-iminothione hydrochloride and alkyl glycoside to obtain nanoliposomes.

5. The anti-protein deposition contact lens solution based on nanotechnology according to claim 4, characterized in that, The mass ratio of phospholipids, cholesterol, and organic solvent in step 1) is 3-4:1:8-10; In step 2), the mass ratio of the water-soluble nutrient component to water is 1:3 to 5. In step 2), the mass ratio of the oil-soluble nutrient component to the organic solvent is 1:3 to 5.

6. The anti-protein deposition contact lens solution based on nanotechnology according to claim 5, characterized in that, Step 3) The ratio of the total mass of the second oil phase and water phase to the mass of the oil phase is 1:5 to 8, and the mass ratio of the oil phase to the surfactant is 5 to 8:1; The ratio of the total mass of phospholipids and cholesterol in step 1) to the mass of the alkyl glycoside in step 4) is 3–8:1; In step 4), the mass ratio of the alkyl glycoside to 2-iminothione hydrochloride is 1:6 to 10.

7. The nanotechnology-based anti-protein deposition contact lens solution according to claim 5 or 6, characterized in that, The emulsification reaction in step 3) is carried out at a temperature of 60–80°C for 10–20 minutes. During the emulsification process, stirring is performed at a speed of 5000–10000 r / min.

8. The anti-protein deposition contact lens solution based on nanotechnology according to claim 7, characterized in that, The reaction in step 4) is carried out under a protective atmosphere, at a temperature of 20–30°C, and for a time of 1–3 hours.

9. The anti-protein deposition contact lens solution based on nanotechnology according to claim 8, characterized in that, Step 1) The phospholipids include phospholipids containing maleimide groups and other phospholipids, wherein the other phospholipids include one or more of lecithin, phosphatidylethanolamine and phosphatidylserine; The molar ratio of the other phospholipids and the phospholipids containing maleimide groups is 8 to 15:1.

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