Eutectic liposome and preparation method thereof

Abstract

The invention provides eutectic lipidosome and a preparation method thereof, and relates to the technical field of lipidosome. An amphiphilic block copolymer and an active substance containing a hydrogen bond donor form an eutectic solution, and then the eutectic solution and a surfactant interact in water to form the eutectic liposome, wherein the surfactant contains a phospholipid compound, a lipid compound, cholesterol and / or poloxamer. The eutectic liposome disclosed by the invention is simple in raw material and simple in preparation process, and can realize efficient loading and controllable release of active substances.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of liposomes and relates to a low eutectic liposome and a preparation method. BACKGROUND

[0002] Liposomes have a bilayer structure and are usually used for loading and delivering active ingredients (such as drugs) into cells, especially for some active ingredients with poor water solubility and pH sensitivity, and have good delivery effect. In addition, liposomes have good effects on the skin and are often used for delivering moisturizers to improve the moisturizing effect of moisturizers. Commonly used preparation methods of liposomes include solvent injection method, film dispersion method, reverse evaporation method, freeze-drying method and the like, but usually need to use organic solvents. The removal and residue of organic solvents are a challenge for liposomes. Therefore, the industry has proposed some improvement methods. Chinese Patent CN120678764A proposes a low eutectic white willow extract, the raw materials of which include soybean phospholipid, cholesterol and low eutectic white willow extract, and the raw materials of the low eutectic white willow extract include white willow extract, amino acid and glycerol.

[0003] Therefore, the existing preparation method of the low eutectic liposome is relatively complex and needs to be improved. SUMMARY

[0004] To solve the above technical problems, the application provides a low eutectic liposome and a preparation method.

[0005] The technical scheme of the application is as follows: A low eutectic liposome is composed of raw material components including an amphiphilic block copolymer, an active substance, a surfactant and water; The amphiphilic block copolymer contains a hydrogen bond acceptor. The active substance contains a hydrogen bond donor. The weight proportion of phospholipid compounds, lipid compounds, cholesterol and / or poloxamer in the surfactant is not less than 5%.

[0006] Preferably, the amphiphilic block copolymer has the structure shown in the following formula (1), (2), (3) and / or (4), A-b-B (1); A-b-B-b-A (2); BA3 (3); B-b-A-b-B (4); wherein A is a hydrophobic segment and B is a hydrophilic segment. The hydrophilic segment contains a plurality of oxygen atoms.

[0007] More preferably, the viscosity of the amphiphilic block copolymer at 25℃ is not more than 10000 mPa·s. The hydrophilic segment is selected from polyethylene glycol segment and / or glycerol polyethylene glycol segment; The hydrophobic segment has biodegradability. The hydrophobic segment is selected from one or more of the following: polylactic acid segment, polycaprolactone segment, polyglycolic acid segment, polyhydroxybutyric acid segment, polydioxanone segment, polytrimethylene carbonate segment, polybutylene succinate segment, polysebacic anhydride segment, polybutylene adipate-terephthalate copolymer segment, and polyortho ester segment.

[0008] More preferably, the average polymerization degree of the hydrophobic segment accounts for 2-60% of the average polymerization degree of the amphiphilic block copolymer.

[0009] Preferably, the number of hydrogen bond donors in the active substance is not less than 2. The active substance is selected from one or more of the following: palmitoyl pentapeptide-4, palmitoyl tetrapeptide-7, blue ketone peptide, palmitoyl tripeptide-1, ganoderma triterpene, ginsenoside Rg3, ferulic acid, astaxanthin, resveratrol, glabridin, quercetin, nicotine, caffeine, penicillin G, metformin, omeprazole, imatinib, ephedrine, berberine, quinine, metformin hydrochloride, chitosan hydrochloride, insulin, water-soluble polysaccharide, amino acid compound, water-soluble vitamin, water-soluble polypeptide, water-soluble flavonoid compound, hydrogenated castor oil, and polyphenol compound.

[0010] Preferably, the phospholipid compound is selected from one or more of the following: lecithin, cephalin, soybean phospholipid, sphingomyelin, sunflower phospholipid, dipalmitoyl phosphatidylcholine, distearoyl phosphatidyl ethanolamine, dioleoyl phosphatidyl glycerol, dimyristoyl phosphatidyl choline, phosphatidyl serine, cationic phospholipid DOTAP, cationic phospholipid DOTMA, and cationic phospholipid DODAC. The lipid compound is selected from one or more of the following: distearoyl phosphatidyl ethanolamine, dioleoyl phosphatidyl ethanolamine, palmitoyl homocysteine, PEGylated phospholipid and its derivatives, glycosylated lipid, polylactic acid modified phospholipid, and polycaprolactone modified phospholipid.

[0011] Preferably, the surfactant further contains one or more of the following: non-ionic surfactant, anionic surfactant, and cationic surfactant.

[0012] Preferably, the weight ratio of the amphiphilic block copolymer, the active substance, and the surfactant is 2-10:0.01-25:1-20.

[0013] Preferably, the weight of the water in the raw material component is not less than 55%.

[0014] A method for preparing the low eutectic liposome according to any one of the above embodiments, mixing and stirring the amphiphilic block copolymer and the active substance uniformly, then adding the surfactant, mixing and stirring uniformly, then adding the water, mixing and stirring uniformly, and obtaining.

[0015] The beneficial effects of the present application are: (1) The present application uses an amphiphilic block copolymer as a eutectic solvent to form a low eutectic solution with an active substance containing a hydrogen bond donor, and then interacts with a surfactant (the surfactant contains components that can form liposomes) and adds water to form a low eutectic liposome.

[0016] (2) In the present application, the active substance forms a low eutectic solution with the amphiphilic block copolymer, and is also wrapped in the liposome formed by the amphiphilic block copolymer and the surfactant, so that the active substance has high loading and good release performance.

[0017] (3) The present application uses an amphiphilic block copolymer that is liquid at room temperature, which can prepare liposomes without using organic solvents, avoiding the problems of use, removal and residue of organic solvents; also without heating, the process is simple, and suitable for temperature-sensitive active substances. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 TEM picture of the low eutectic liposome of Example 1.

[0019] Figure 2 Picture of the appearance of solution two in Example 1.

[0020] Figure 3 Picture of the appearance of solution two in Example 2.

[0021] Figure 4 Picture of the appearance of solution two in Example 3.

[0022] Figure 5 Picture of the appearance of solution two in Example 5.

[0023] Figure 6 TEM picture of the low eutectic liposome of Example 7. DETAILED DESCRIPTION

[0024] The technical solutions of the present application are further described and explained by the specific embodiments below.

[0025] On the one hand, the present application proposes a low eutectic liposome composed of raw material components including an amphiphilic block copolymer, an active substance, a surfactant and water; The amphiphilic block copolymer contains a hydrogen bond acceptor; The active substance contains a hydrogen bond donor; The weight percentage of phospholipid compounds, lipid compounds, cholesterol and / or poloxamer in the surfactant is not less than 5%.

[0026] The active substance containing a hydrogen bond donor refers to a group containing an H atom (i.e. a reactive hydrogen group) in the molecule of the active substance, and the group contains an atom with strong electronegativity (such as O, N, S) directly connected to the H atom. The group can be -OH, -SH, -NH2, -NH-, -SO3H, -CONH-, -COOH, etc. These groups can form hydrogen bonds with the electronegative atoms (such as O, N, F) of other substances.

[0027] In the present application, the amphiphilic block copolymer contains a hydrogen bond acceptor, which forms a eutectic solution with the active substance containing a hydrogen bond donor. The eutectic solution further interacts with the surfactant (the surfactant contains components that can form liposomes, such as phospholipid compounds, lipid compounds, cholesterol and / or poloxamer) in water to form liposomes. A multi-layer membrane structure is formed in the liposome, achieving efficient loading and controlled release of the active substance. If the surfactant does not contain components that can form liposomes, but only contains other surfactants (such as nonionic surfactants, anionic surfactants and / or cationic surfactants), nano-aggregate particles with liposome structure cannot be obtained, but micelles or vesicles are obtained.

[0028] For example, the weight percentage of phospholipid compounds, lipid compounds, cholesterol and / or poloxamer in the surfactant can be 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, etc. Further, the weight percentage of phospholipid compounds, lipid compounds, cholesterol and / or poloxamer in the surfactant is not less than 10%. Phospholipid compounds, lipid compounds, cholesterol and / or poloxamer can form liposome structures alone. In the present application, phospholipid compounds, lipid compounds, cholesterol and / or poloxamer form liposome structures with eutectic solutions (amphiphilic block copolymer and active substance), which improves the loading capacity of active substances and has good release performance.

[0029] In some embodiments, the amphiphilic block copolymer has a structure as shown in the following formula (1), (2), (3) and / or (4), A-b-B (1); A-b-B-b-A (2); BA3 (3); B-b-A-b-B (4); Wherein, A is a hydrophobic segment, and B is a hydrophilic segment. The hydrophilic segment contains multiple oxygen atoms.

[0030] In the structures represented by the above formulae (1), (2), (3) and (4), b represents block, such as A-b-B represents a two-block copolymer composed of A segment and B segment; A-b-B-b-A represents a three-block copolymer composed of A segment and B segment, and the segment order is A, B, A; BA3 represents a branched structure with 1 B segment grafting 3 A segments at the center of the B segment. The hydrophilic segment contains multiple oxygen atoms, which can form more hydrogen bonds with the active substance, thereby improving the effect of eutectic.

[0031] In some embodiments, the viscosity of the amphiphilic block copolymer at 25°C is not more than 10000 mPa·s; The viscosity can be tested by an NDJ-5S rotary viscometer.

[0032] The amphiphilic block copolymer is liquid at room temperature, and does not need to add organic solvent or heat when forming a eutectic solution with the active substance. There is no particular limitation on the viscosity of the amphiphilic block copolymer at 25°C, which can be, for example, 10000 mPa·s, 8000 mPa·s, 5000 mPa·s, 3000 mPa·s, 2000 mPa·s, 1000 mPa·s, 800 mPa·s, 600 mPa·s, etc.

[0033] In some embodiments, the hydrophilic segment is selected from polyethylene glycol segments and / or glycerol polyethylene glycol segments; for the polyethylene glycol segment, the number average molecular weight can be, for example, 200 g / mol (denoted as PEG-200, and the like), 400 g / mol, 600 g / mol, 800 g / mol, 1000 g / mol, 1200 g / mol, 2000 g / mol, 4000 g / mol, 6000 g / mol, etc. Glycerol polyethylene glycol, also known as polyethylene glycol triol, contains three polyethylene glycol branched structures, which are obtained by ring-opening reaction of ethylene oxide with glycerol as a starter. For example, the average polymerization degree of each polyethylene glycol branched structure can be 3-20, i.e., the average number of ethylene oxide groups in each polyethylene glycol branched structure is 3-20.

[0034] The hydrophobic segment is biodegradable; The hydrophobic segment is selected from one or more of polylactic acid (PLA) segment, polycaprolactone (PCL) segment, polyglycolic acid (PGA) segment, polyhydroxybutyrate (PHB) segment, polydioxanone segment, polytrimethylene carbonate segment, polybutylene succinate (PBS) segment, polysebacic anhydride (PSPA) segment, polybutylene adipate-co-terephthalate (PBAT) segment, and polyortho ester (POE) segment, or a combination of two or more thereof. The hydrophobic segment in the amphiphilic block copolymer is biodegradable, which gradually degrades in the human body, thereby destroying the liposome structure and the eutectic solution, so that the active substance is gradually released and controlled release is achieved.

[0035] There is no particular limitation on the preparation method of the above-mentioned amphiphilic block copolymer, which is well known to those skilled in the art. For example, the method of active polymerization can be used, such as active cationic polymerization, using polyethylene glycol, polyethylene glycol monomethyl ether, or glycerol polyethylene glycol as an initiator, and catalyzing ring-opening polymerization of cyclic monomers such as lactide and ε-caprolactone under the catalysis of a cationic catalyst (such as stannous octoate). The above-mentioned amphiphilic block copolymer can also be obtained by the method of direct reaction of polymers, such as addition reaction of isocyanate double-terminated polyethylene glycol and single-ended hydroxyl polymer, or addition reaction of polyethylene glycol or glycerol polyethylene glycol and single-ended isocyanate polymer. Specifically, taking PCL-PEG-PCL triblock copolymer as an example, the preparation method can be: purifying ε-caprolactone monomer by distillation treatment under reduced pressure at 100-130°C, vacuum treating polyethylene glycol (such as PEG-200, PEG-600) at 80-100°C for 1-5h, then warming to 130-170°C, adding stannous octoate and purified ε-caprolactone monomer, reacting for 1-48h, dissolving in chloroform after cooling, then pouring into a large amount of 0-10°C diethyl ether for precipitation, and vacuum freeze-drying the product to obtain the above-mentioned triblock copolymer. The molecular weight of the PCL segment in the triblock copolymer can be adjusted according to the molar amount of ε-caprolactone monomer and PEG.

[0036] In some embodiments, the ratio of the average degree of polymerization of the hydrophobic segment to the average degree of polymerization of the amphiphilic block copolymer is 2-60%. For example, if the amphiphilic block copolymer is A-b-B-b-A, the hydrophilic segment is PEG, and the average degree of polymerization of PEG is 12, the hydrophobic segment is PCL, and the average degree of polymerization of PCL is 3, then the ratio of the average degree of polymerization of the hydrophobic segment to the average degree of polymerization of the amphiphilic block copolymer is (3+3) / (12+3+3)=33%. For example, the ratio of the average degree of polymerization of the hydrophobic segment to the average degree of polymerization of the amphiphilic block copolymer can be any value or any value between 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, etc., without particular limitation. When the ratio of the average degree of polymerization of the hydrophobic segment to the average degree of polymerization of the amphiphilic block copolymer is low, such as 2-10%, it means that the average degree of polymerization of the hydrophobic segment in the amphiphilic block copolymer is low, such as the average degree of polymerization of the hydrophobic segment can be 1-3. Further, the ratio of the average degree of polymerization of the hydrophobic segment to the average degree of polymerization of the amphiphilic block copolymer is 3-60%.

[0037] In some embodiments, the number of hydrogen bond donors in the active substance is not less than 2; The active substance is selected from one or more of the following: palmitoyl pentapeptide-4, palmitoyl tetrapeptide-7, blue ketone peptide, palmitoyl tripeptide-1, ganoderma triterpenes, ginsenoside Rg3, ferulic acid, astaxanthin, resveratrol, glabridin, nicotine, caffeine, penicillin G, metformin, omeprazole, imatinib, ephedrine, berberine, quinine, metformin hydrochloride, chitosan hydrochloride, insulin, water-soluble polysaccharides (such as fucoidan, astragalus polysaccharide, and wolfberry polysaccharide), amino acid compounds (such as lysine and tryptophan), water-soluble vitamins (such as B vitamins and vitamin C), water-soluble polypeptides (such as glutathione, soybean peptides, and whey protein peptides), water-soluble flavonoids (such as quercetin, rutin, and catechin), hydrogenated castor oil, and polyphenol compounds. The number of hydrogen bond donors in the active substance is not less than 2, i.e., the number of active hydrogen groups in the active substance is not less than 2, which can form more hydrogen bonds with the amphiphilic block copolymer. Through the interaction of multiple hydrogen bond donors and multiple hydrogen bond acceptors, the stability of the eutectic solution formed is better.

[0038] The low eutectic liposome of the application is suitable for active substances with low solubility in water, and also suitable for active substances with good water solubility. For example, the solubility of metformin in water at 20-25 DEG C is 10-20 mg / ml, which is relatively low, and the solubility in water can be increased by 2-10 times after loading the low eutectic liposome of the application, and controlled release can be achieved. The solubility of metformin hydrochloride in water at 20-25 DEG C is relatively high, and the low eutectic liposome of the application can achieve efficient loading and controlled release. Astaxanthin is a typical hydrophobic active substance, and the solubility in water at 20-25 DEG C is 0.1-1 μg / ml, and the solubility in water can be increased by more than 100 times after loading the low eutectic liposome of the application, and controlled release can be achieved. Insulin is a water-soluble bioactive substance, and the low eutectic liposome of the application can effectively protect and achieve controlled release after loading.

[0039] In some embodiments, the phospholipid compound is selected from one or a combination of two or more of lecithin, cephalin, soybean phospholipid, sphingomyelin, sunflower phospholipid, dipalmitoyl phosphatidylcholine, distearoyl phosphatidyl ethanolamine, dioleoyl phosphatidyl glycerol, dimyristoyl phosphatidyl choline, phosphatidyl serine, cationic phospholipid DOTAP, cationic phospholipid DOTMA, and cationic phospholipid DODAC; the phospholipid compound can be a natural phospholipid or a synthetic phospholipid; The lipid compound is selected from one or a combination of two or more of distearoyl phosphatidyl ethanolamine, dioleoyl phosphatidyl ethanolamine, palmitoyl homocysteine, PEGylated phospholipid and its derivatives (such as DSPE-PEG, DPPE-PEG, folate-PEG-DSPE, etc.), glycosylated lipids (such as galactose-modified phospholipids, mannose-modified phospholipids), polylactic acid-modified phospholipids, and polycaprolactone-modified phospholipids.

[0040] In some embodiments, the surfactant further comprises one or more than two combinations of non-ionic surfactants, anionic surfactants and cationic surfactants. The phosphatidylcholine compound can form liposomes with the low eutectic solution in water with other types of surfactants. The non-ionic surfactant is not particularly limited and can be polyoxyethylene fatty acid ester (such as LAE-4, LAE-9, SG-6), sorbitan ester (such as Span-60, Span-85), polysorbate (Tween-20, Tween-60, Tween-80), polyoxyethylene hydrogenated castor oil (such as CO-40, CO-60), PEG-20 hydrogenated castor oil, PEG-40 hydrogenated castor oil, glycerol polyether ester (such as glycerol polyoxyethylene ether stearate, glycerol polyoxyethylene ether oleate); the anionic surfactant is not particularly limited and can be sodium cholate, sodium dodecyl sulfate (SDS), sodium stearate, sodium lauryl sulfate (SLS) and magnesium lauryl sulfate (MLS), etc.; the cationic surfactant can be cetyltrimethylammonium bromide, dioctadecyldimethylammonium chloride, etc.

[0041] In some embodiments, the weight ratio of the amphiphilic block copolymer, the active substance and the surfactant is 2-10:0.01-25:1-20. For example, the weight ratio of the amphiphilic block copolymer, the active substance and the surfactant can be any value or any value between 2:0.01:1, 2:0.1:1, 2:1:1, 5:0.1:5, 5:0.5:5, 5:1:3, 5:1:10, 8:3:10, 8:3:12, 10:3:10, 10:3:15, 10:5:10, 10:5:15, 10:5:20, 5:10:10, 5:15:10, 5:10:15, 5:10:20, 5:15:20, 10:10:10, 10:15:10, 10:10:15, 10:10:20, 10:15:20, 5:20:10, 5:20:10, 5:20:15, 5:20:20, 5:25:20, 10:25:10, 10:25:10, 10:25:15, 10:25:20, etc., without particular limitation. From the perspective of the loading rate of the active substance, the weight ratio of the amphiphilic block copolymer, the active substance and the surfactant can be 2-10:1-25:1-20.

[0042] In some embodiments, the weight percentage of water in the raw material component is not less than 55%. For example, the weight percentage of water in the raw material component is any value or any value between 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, etc., without particular limitation. Further, the weight percentage of water in the raw material component is not more than 95%.

[0043] In another aspect, the present application also provides a method for preparing the low eutectic liposome as described in any of the above embodiments. The amphiphilic block copolymer and the active substance are mixed and stirred until uniform, then the surfactant is added and mixed and stirred until uniform, then water is added and mixed and stirred until uniform, and the low eutectic liposome is obtained. The method for preparing the low eutectic liposome of the present application is relatively simple, and has fewer raw materials and simple preparation process, and does not need heating or organic solvent, thereby avoiding the problems of removal and residue of the organic solvent, and being suitable for temperature-sensitive active substances.

[0044] The technical solutions of the present application are further described and explained below according to various embodiments. Unless otherwise specified, the parts in the following embodiments are parts by weight.

[0045] Example 1 The low eutectic liposome of this embodiment is composed of 15 g of hydrogenated castor oil, 10 g of block polymer, 10 g of sunflower lecithin, and 65 g of water. The block polymer is PCL-PEG-PCL, the number average molecular weight of PEG is 600 g / mol, the viscosity of the block copolymer at 25°C is 760 mPa·s, and the average polymerization degree of PCL accounts for 48% of the average polymerization degree of the block copolymer.

[0046] At room temperature, the block copolymer and the hydrogenated castor oil are mixed and stirred at a stirring speed of 200 rpm until transparent (solution 1), then the sunflower lecithin is added and continuously stirred until transparent (solution 2), then water is added and stirred uniformly at a stirring speed of 500 rpm, and the low eutectic liposome is obtained. The TEM picture of the low eutectic liposome of this embodiment is shown in FIG. 1, and it can be seen that there is a clear multilayer membrane structure on the outer layer; the appearance of solution 2 is shown in FIG. 2. Figure 1 Figure 2 After the solution 2 is sealed and placed in an environment at 60°C for 1 month, it still maintains a transparent state, indicating good stability.

[0047] The average particle size of the low eutectic liposome is tested by using a laser particle size analyzer, and the average particle size is 317 nm.

[0048] The release test method of the hydrogenated castor oil in the low eutectic liposome is as follows: a nylon membrane with a pore size of 0.2 μm is used to simulate a cell membrane, a tube with a pore size of 1 cm is divided into upper and lower parts, ethanol / water (50:50, v / v) is added to the lower part as the receptor part, the low eutectic liposome is injected into the upper part as the donor part, then the tube opening is sealed, 200 μL of the upper liquid is taken every 1 h, and the decrease of the hydrogenated castor oil is tested by using HPLC, and at the same time, 200 μL of an aqueous solution containing 10 wt% of the block copolymer and 10 wt% of the sunflower lecithin is added every time after sampling. The cumulative amount of the release of the hydrogenated castor oil with time is shown in Table 1.

[0049] Table 1 Cumulative amount of release of hydrogenated castor oil / %​

[0050] Therefore, according to the above embodiment 1, it can be known that the eutectic liposome of the present application can obviously improve the solubility of the poorly soluble hydrogenated castor oil in water, and the loading amount of the hydrogenated castor oil can reach 15 / (15+10+10)=43%.

[0051] Embodiment 2 The difference between this embodiment and embodiment 1 is that in embodiment 1, 15 g of hydrogenated castor oil is adjusted to a combination of 15 g of hydrogenated castor oil and 5 g of polydeoxyribonucleotide PDRN, and the water is adjusted from 65 g to 60 g. The remaining steps remain unchanged. The appearance of the corresponding solution two (a mixture of hydrogenated castor oil, block polymer, sunflower lecithin and PDRN) is shown in FIG. 2B, and the transparency is high. The average particle size of the eutectic liposome of this embodiment is measured to be 455 nm. Figure 3

[0052] The release performance of PDRN in the eutectic liposome of this embodiment is tested according to the method of testing the cumulative release amount of hydrogenated castor oil in embodiment 1, and the results are shown in Table 2 below.

[0053] Table 2 Cumulative release amount of PDRN / %

[0054] Embodiment 3 The eutectic liposome of this embodiment is composed of 5 g of astaxanthin, 10 g of block polymer, 10 g of glycerol polyether-5 lactate, 1.2 g of soybean lecithin and 75 g of water. The block copolymer is PLLA-PEG-PLLA, the number average molecular weight of PEG is 200 g / mol, the viscosity of the block copolymer at 25°C is 3560 mPa·s, and the average polymerization degree of PLLA accounts for 14% of the average polymerization degree of the block copolymer.

[0055] At room temperature, the block copolymer and astaxanthin are mixed, stirred at a stirring speed of 250 rpm until transparent (solution one), then glycerol polyether-5 lactate and soybean lecithin are added, and continue to stir until transparent (solution two), then add water, and stir uniformly at a stirring speed of 600 rpm, to obtain the eutectic liposome.

[0056] The appearance of solution two is shown in FIG. 3B, and the transparency is high. After sealing, the solution two is placed in an environment of 60°C for 1 month, and still maintains a transparent state, indicating good stability. Figure 4

[0057] The average particle size of the eutectic liposome is tested by a laser particle size instrument, and the average particle size is 261 nm.

[0058] ​​The release performance of astaxanthin in the eutectic liposome of the present example was tested according to the method for testing the cumulative release amount of hydrogenated castor oil in Example 1, and the results are shown in Table 3 below.

[0059] Table 3 Cumulative release amount of astaxanthin / %

[0060] Therefore, the eutectic liposome of the present application can significantly improve the solubility of the poorly soluble astaxanthin in water, and the content of astaxanthin in the eutectic liposome can be increased to 5wt%.

[0061] Example 4 The eutectic liposome of the present example was composed of 5g of peppermint leaf oil, 10g of block polymer, 10g of soybean lecithin, 10g of PEG-20 sorbitan triisostearate and 65g of water. Among them, the block copolymer was PCL-PEG-PCL, the number average molecular weight of PEG was 800g / mol, the viscosity of the block copolymer at 25℃ was 830mPa·s, and the average polymerization degree of PCL accounted for 3% of the average polymerization degree of the block copolymer.

[0062] The block copolymer and the peppermint leaf oil were mixed at room temperature, and stirred at a stirring speed of 200rpm until it became transparent (solution 1), then the soybean lecithin and PEG-20 sorbitan triisostearate were added, and continued to be stirred until it became transparent (solution 2), then the water was added, and stirred uniformly at a stirring speed of 500rpm, to obtain the eutectic liposome with high transparency.

[0063] After the solution 2 was sealed and placed in an environment of 60℃ for 1 month, it still maintained the transparent state, indicating good stability.

[0064] The average particle size of the eutectic liposome was tested by a laser particle size instrument, and the average particle size was 538nm.

[0065] The release performance of peppermint leaf oil in the eutectic liposome of the present example was tested according to the method for testing the cumulative release amount of hydrogenated castor oil in Example 1, and the results are shown in Table 4 below.

[0066] Table 4 Cumulative release amount of peppermint leaf oil / %

[0067] In the present example, the peppermint leaf oil was released slowly in the early stage, and there was a fast period in the release process, and the release was significantly accelerated.

[0068] Example 5 The low eutectic liposome of the present example is composed of 2 g quercetin, 10 g block polymer, 6 g dilaurylphosphatidylcholine, 14 g sodium cholate and 68 g water. The block copolymer is PLLA-PEG-PLLA, the number average molecular weight of PEG is 400 g / mol, the viscosity of the block copolymer at 25°C is 2780 mPa·s, and the average polymerization degree of PLLA accounts for 45% of the average polymerization degree of the block copolymer.

[0069] The block copolymer and quercetin are mixed at room temperature, stirred at a stirring speed of 150 rpm until transparent (solution 1), then dilaurylphosphatidylcholine and sodium cholate are added, continue to stir until the state is constant (solution 2), then add water, stir uniformly at a stirring speed of 500 rpm, and the low eutectic liposome is obtained.

[0070] The appearance of solution 2 is shown in FIG. 1, which is slightly turbid and translucent. After sealing, solution 2 is placed in an environment at 60°C for 1 month, and still maintains a slightly turbid and translucent state, indicating good stability. Figure 5

[0071] The average particle size of the low eutectic liposome is tested by a laser particle size analyzer, and the average particle size is 943 nm.

[0072] The release performance of quercetin in the low eutectic liposome of the present example is tested according to the method for testing the cumulative release amount of hydrogenated castor oil in Example 1, and the results are shown in Table 5 below.

[0073] Table 5 Cumulative release amount of quercetin / %

[0074] Example 6 The low eutectic liposome of the present example is composed of 1 g quercetin, 2 g block polymer in Example 5, 2 g dilaurylphosphatidylcholine, 2 g sodium cholate and 93 g water. The low eutectic liposome is prepared according to the method of Example 5. The release performance of quercetin is shown in Table 6 below.

[0075] Table 6 Cumulative release amount of quercetin / %

[0076] Example 7 The low eutectic liposome of the present example is composed of 1 g quercetin, 3 g block polymer in Example 5, 0.25 g distearoylphosphatidyl ethanolamine, 2.75 g sodium dodecylbenzenesulfonate and 93 g water. The TEM picture of the low eutectic liposome is shown in FIG. 2, and the surface has a clear multilayer membrane structure. The low eutectic liposome is prepared according to the method of Example 5. The release performance of quercetin is shown in Table 7 below. Figure 6

[0077] ​​Table 7 Cumulative amount of quercetin released / %

[0078] The basic principles, main features and advantages of the present application have been shown and described above. It should be understood by those skilled in the art that the present application is not limited by the above-described embodiments, which are merely preferred embodiments of the present application, and the scope of the present application is not limited by the above-described embodiments. Equivalent changes and modifications made in accordance with the scope of the present application and the content of the specification should still be within the scope of the present application. The scope of the present application is defined by the appended claims and their equivalents.

Claims

1. A low eutectic liposome, characterized by, consists of raw material components including an amphiphilic block copolymer, an active substance, a surfactant, and water; The amphiphilic block copolymer contains a hydrogen bond acceptor; The active substance contains a hydrogen bond donor; The weight proportion of phospholipid compounds, lipid compounds, cholesterol, and / or poloxamer in the surfactant is not less than 5%.

2. The low eutectic liposome of claim 1, wherein, The amphiphilic block copolymer has a structure shown in the following formula (1), (2), (3), and / or (4), A-b-B (1); A-b-B-b-A (2); BA3 (3); B-b-A-b-B (4); A is a hydrophobic segment, and B is a hydrophilic segment; The hydrophilic segment contains multiple oxygen atoms.

3. The low eutectic liposome of claim 2, wherein, The viscosity of the amphiphilic block copolymer at 25°C is not more than 10,000 mPa·s; The hydrophilic segment is selected from polyethylene glycol segments and / or glycerol polyethylene glycol segments; The hydrophobic segment has biodegradability; The hydrophobic segment is selected from one or a combination of two or more of polylactic acid segments, polycaprolactone segments, polyglycolic acid segments, polyhydroxybutyrate segments, polydioxanone segments, polytrimethylene carbonate segments, polybutylene succinate segments, polysebacic anhydride segments, polybutylene adipate-co-terephthalate segments, and polyortho ester segments.

4. The low eutectic lipid according to claim 2, wherein, The average polymerization degree of the hydrophobic segment accounts for 2-60% of the average polymerization degree of the amphiphilic block copolymer.

5. The low eutectic lipid according to claim 1, wherein, The number of hydrogen bond donors in the active substance is not less than 2; The active substance is selected from one or a combination of two or more of palmitoyl pentapeptide-4, palmitoyl tetrapeptide-7, blue ketone peptide, palmitoyl tripeptide-1, ganoderma triterpenes, ginsenoside Rg3, ferulic acid, astaxanthin, resveratrol, glabridin, quercetin, nicotine, caffeine, penicillin G, metformin, omeprazole, imatinib, ephedrine, berberine, quinine, metformin hydrochloride, chitosan hydrochloride, insulin, water-soluble polysaccharides, amino acid compounds, water-soluble vitamins, water-soluble polypeptides, water-soluble flavonoids, hydrogenated castor oil, and polyphenol compounds.

6. The low eutectic liposome of claim 1, wherein, The phospholipid compound is selected from one or a combination of two or more of lecithin, cephalin, soybean phospholipid, sphingomyelin, sunflower phospholipid, dipalmitoyl phosphatidylcholine, distearoyl phosphatidyl ethanolamine, dioleoyl phosphatidyl glycerol, dimyristoyl phosphatidylcholine, phosphatidylserine, cationic phospholipid DOTAP, cationic phospholipid DOTMA, and cationic phospholipid DODAC. The lipid compound is selected from one or a combination of two or more of distearoyl phosphatidyl ethanolamine, dioleoyl phosphatidyl ethanolamine, palmitoyl homocysteine, PEGylated phospholipid and its derivatives, glycosylated lipids, polylactic acid modified phospholipids, and polycaprolactone modified phospholipids.

7. The low eutectic lipid according to claim 1, wherein, The surfactant further contains one or a combination of two or more of non-ionic surfactants, anionic surfactants, and cationic surfactants.

8. The low eutectic liposome of claim 1, wherein, The weight ratio of the amphiphilic block copolymer, the active substance, and the surfactant is 2-10:0.01-25:1-20.

9. The low eutectic liposome of claim 1, wherein, The weight proportion of water in the raw material components is not less than 55%.

10. A method of preparing the low eutectic liposome according to any one of claims 1 to 9, characterized in that, Mixing and stirring the amphiphilic block copolymer and the active substance uniformly, then adding the surfactant, mixing and stirring uniformly, then adding the water, mixing and stirring uniformly, and then the product is obtained.

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