CN114632072B - Preparation and application of ginsenoside Rg5 lipid nanoparticle sustained release preparation - Google Patents
Preparation and application of ginsenoside Rg5 lipid nanoparticle sustained release preparation Download PDFInfo
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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Abstract
The application discloses ginsenoside Rg5 liposome nanoparticles, and a preparation method and application thereof. The preparation method comprises the following specific preparation steps: dissolving ginsenoside Rg5 and polylactic acid-glycolic acid copolymer (PLGA) in an organic solution to form a nanoparticle solution, dissolving soybean lecithin, cholesterol and vitamin E in a phosphate buffer solution to form liposome vesicles, slowly adding the nanoparticle solution into the liposome vesicles, and homogenizing under high pressure to obtain the ginsenoside Rg5 lipid nanoparticle solution. Removing non-entrapped ginsenoside Rg5 by centrifugation, and concentrating under reduced pressure and drying to obtain granule. The ginsenoside Rg5 preparation obtained by the application has good stability, can effectively improve the bioavailability of the ginsenoside Rg5 in the body, improve the maximum blood concentration and the internal residence time of the medicine, and obviously reduce the clearance rate of the medicine.
Description
Technical Field
The application relates to the field of biotechnology pharmacy, in particular to a ginsenoside Rg5 sustained release preparation and a preparation method thereof.
Background
In recent years, with the development of separation and extraction technology of active ingredients of traditional Chinese medicines, the properties, functions and structures of a plurality of pharmaceutically active monomers are confirmed. The research in the field of traditional Chinese medicine shows the advantages in the aspect of treating a plurality of diseases, and reports that the ginsenoside has obvious curative effects in the aspects of resisting tumor, improving sleep, improving immunity, reducing blood fat, reducing blood sugar, inhibiting angiogenesis and the like. The laboratory study also shows that the ginsenoside Rg5 can reduce the blood sugar of a diabetic mouse and inhibit the growth of tumor cells in tumor model animals, but the solubility and the stability are poor, so that the ginsenoside Rg5 has low in vivo absorptivity, short half-life and poor bioavailability. Therefore, the application of the new technology to the development of a safer and more effective new formulation of the medicine is significant.
The existing novel drug formulation mainly comprises nanoparticles, polymer micelles, self-microemulsions, in-situ gels, precursor liposomes and the like, wherein the lipid nanoparticles are novel assemblies of lipid vesicles with certain concentration and nanoparticle cores, and are of great interest in biotechnology and drug formulation in recent years. The lipid nanoparticle has the characteristics of spontaneous formation under mild conditions, controllable particle size, stable structure, high drug loading, sustained release of the encapsulated drug and the like, combines the advantages of the nanoparticle and the liposome, ensures that the drug release is controllable, and is easy to be absorbed due to small particle size of the drug.
The ginsenoside Rg5 has poor solubility and stability and is difficult to be absorbed, after entering blood, the elimination speed in vivo is high, the half life of the drug is short, the ginsenoside Rg5 is prepared into nano particles by the polyacetic acid-glycolic acid copolymer, the water solubility and stability of the ginsenoside Rg5 can be increased, the bioavailability is improved, and the ginsenoside Rg5 nano particles are wrapped in vesicles prepared from soybean lecithin, cholesterol, vitamin E and the like by combining a microencapsulation technology, so that the drug effect can be obviously prolonged, the half life of the drug is increased, the slow release effect is achieved, and the systemic toxic and side effects of the drug are reduced. The technology for preparing the ginsenoside Rg5 into the lipid nanoparticle is not reported at present. The preparation method has a great application prospect for the development of new medicines.
Disclosure of Invention
The application aims to provide a preparation method of a ginsenoside Rg5 lipid nanoparticle system, which can solve the problems of poor water solubility, easiness in degradation, low in vivo bioavailability, high clearance rate of a medicine endosome, short residence time and the like of the conventional ginsenoside Rg5 monomer, can effectively reduce the dosage and improve the therapeutic effect of the medicine.
In order to achieve the above purpose, the application provides a method for preparing ginsenoside Rg5 lipid nanoparticles, which comprises the following specific technical scheme:
1. the preparation method of the ginsenoside Rg5 liposome nanoparticle is characterized by comprising the following steps of:
mixing ginsenoside Rg5 and polylactic acid-glycolic acid copolymer (PLGA) according to a certain proportion, dissolving into an organic solution, and performing ultrasonic vibration to form a ginsenoside Rg5 nanoparticle solution;
dissolving soybean lecithin, cholesterol and vitamin E in a phosphate buffer solution, and uniformly mixing to form a liposome solution;
adding the ginsenoside Rg5 nanoparticle solution into the liposome solution, and homogenizing under high pressure to form a lipid nanoparticle solution;
removing the non-entrapped ginsenoside Rg5 in the lipid nanoparticle solution, and concentrating and drying under reduced pressure to obtain the ginsenoside Rg5 liposome nanoparticle.
2. The method according to item 1, wherein the ginsenoside Rg5 and polylactic acid-glycolic acid copolymer (PLGA) are mixed in an amount of 1: 12-1: 5, preferably in a mass ratio of 1:10-1: 8 mass ratio, and mixing.
3. The method according to item 1, wherein the organic solvent is acetone, ethanol, chloroform or a mixture thereof.
4. The method according to item 1, wherein the soybean lecithin and cholesterol are mixed in a ratio of 6:1 to 2:1 in a phosphate buffer, preferably 5:1 to 3:1, more preferably 4:1.
5. The method according to item 1, wherein the content of vitamin E in the liposome solution is 0.2 to 2wt%.
6. The method according to item 1, wherein the pH of the phosphate buffer is 5 to 8.
7. The method according to item 1, wherein the ginsenoside Rg5 nanoparticle solution and the liposome solution are mixed at a mass ratio of 1:2 to 1:20, and then homogenized under high pressure, more preferably 1:10.
8. The method of claim 7, wherein the ginsenoside Rg5 nanoparticle solution is mixed with the liposome solution at 50-60 ℃.
9. The method according to item 7, wherein the pressure during the high pressure homogenization is 10-30Mpa, the temperature is 30-60 ℃, and preferably the temperature is 40 ℃.
10. Ginsenoside Rg5 liposome nanoparticle obtained by the preparation method of any one of the items 1 to 9.
11. The application of the ginsenoside Rg5 liposome nanoparticle in the preparation of a ginsenoside Rg5 sustained release preparation in item 10.
ADVANTAGEOUS EFFECTS OF INVENTION
1. The ginsenoside Rg5 lipid nanoparticle provides reference for the preparation of the ginsenoside Rg5 sustained release preparation, has a nano-scale particle size (< 90 nm), is stable in normal-temperature storage state, and has good ginsenoside content stability.
2. As the ginsenoside Rg5 is extremely insoluble in water in a common preparation, the bioavailability is low after oral administration, and the ginsenoside Rg5 can hardly reach a focus area through a blood brain barrier, but after the ginsenoside Rg5 liposome nano particles are prepared, the nano particles easily pass through blood vessels and enter blood circulation due to small particle size, and due to the slow release effect of the liposome, in vivo experiments of rats show that the lipid can maintain the concentration of the ginsenoside Rg5 in the body for a long time, so that the in vivo elimination speed of the ginsenoside Rg5 is reduced, and the curative effect of the medicament is improved.
3. The ginsenoside Rg5 lipid nanoparticle has high drug loading amount and small particle size, can be prepared into stable solution, has certain targeting property and high biocompatibility, so that the ginsenoside intravenous injection formulation can be developed, the dosage and the dosing times of the ginsenoside Rg5 are reduced, and the compliance of patients is improved.
Drawings
FIG. 1 is a process diagram of ginsenoside Rg5 lipid nanoparticle preparation
FIG. 2 is a graph showing the stability of ginsenoside Rg in different dosage forms at 5℃at 60 ℃
FIG. 3 in vitro drug release patterns of ginsenoside Rg5 in different dosage forms
FIG. 4 in vivo drug concentration versus time graph for rats
Detailed Description
The present application will now be described in detail with reference to the embodiments thereof as illustrated in the accompanying drawings, wherein like numerals refer to like features throughout. While specific embodiments of the application are shown in the drawings, it should be understood that the application may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the application to those skilled in the art.
It should be noted that certain terms are used throughout the description and claims to refer to particular components. Those of skill in the art will understand that a person may refer to the same component by different names. The specification and claims do not identify differences in terms of components, but rather differences in terms of the functionality of the components. As referred to throughout the specification and claims, the terms "include" or "comprising" are used in an open-ended fashion, and thus should be interpreted to mean "include, but not limited to. The description hereinafter sets forth a preferred embodiment for practicing the application, but is not intended to limit the scope of the application, as the description proceeds with reference to the general principles of the description. The scope of the application is defined by the appended claims.
The application provides a preparation method of ginsenoside Rg5 liposome nanoparticles, which is characterized by comprising the following steps:
mixing ginsenoside Rg5 and polylactic acid-glycolic acid copolymer (PLGA) according to a certain proportion, dissolving into an organic solution, and performing ultrasonic vibration to form a ginsenoside Rg5 nanoparticle solution;
dissolving soybean lecithin, cholesterol and vitamin E in a phosphate buffer solution, and uniformly mixing to form a liposome solution;
adding the ginsenoside Rg5 nanoparticle solution into the liposome solution, and homogenizing under high pressure to form a lipid nanoparticle solution;
removing the non-entrapped ginsenoside Rg5 in the lipid nanoparticle solution, and concentrating and drying under reduced pressure to obtain the ginsenoside Rg5 liposome nanoparticle.
Ginsenoside is a kind of solid alcohol compound, is a generic name of various saponin components in ginseng, and is regarded as an active component in ginseng. Wherein Rg5 can induce apoptosis and DNA damage of various tumor cells, and a series of in vitro experiments prove that the ginsenoside Rg5 has proliferation inhibition effect on esophageal cancer cells.
The ginsenoside Rg5 is a known compound and can be prepared by a method known in the technical field. In a specific embodiment of the application, ginsenoside Rg5 is prepared from ginsenoside Rb1 or Rd by directional catalytic conversion by glucosidase to obtain ginsenoside Rg5, and high-pressure preparation chromatography to obtain ginsenoside Rg5 powder with purity of > 95%.
Polylactic acid-glycolic acid copolymer (PLGA) is formed by randomly polymerizing two monomers of lactic acid and glycolic acid, is a degradable functional polymer organic compound, has no toxicity, good biocompatibility and good encapsulation and film forming performance, and is widely applied to the fields of pharmacy, medical engineering materials and the like. Different types of PLGA can be prepared by different monomer ratios, and the solubility, degradation speed and the like of the PLGA are different, such as PLGA 75:25 denotes that the polylactic acid-glycolic acid copolymer consists of 75% lactic acid and 25% glycolic acid, PLGA50:50 means that the polylactic acid-glycolic acid copolymer is composed of 50% lactic acid and 50% glycolic acid. In a specific embodiment of the present application, the copolymer composition ratio of PLGA is PLGA20: 80-PLGA 80:20, for example PLGA20: 80. 30: 70. 40: 60. 50: 50. 60: 40. 70: 30. 80:20, in a preferred embodiment, the copolymer of PLGA is PLGA50:50, the molecular weight of which is 3 ten thousand Da.
In one embodiment of the application, the ginsenoside Rg5 powder is mixed with polylactic acid-glycolic acid copolymer (PLGA) in a mass ratio of 1:12 to 1:5, for example, the ginsenoside Rg5 powder is mixed with PLGA in a mass ratio of 1:12,1:11,1:10,1:9,1:8,1:7,1:6,1:5, preferably in a mass ratio of 1:10 to 1:8.
In one embodiment of the present application, ginsenoside Rg5 and polylactic acid-glycolic acid copolymer (PLGA) are mixed in a certain ratio and then dissolved in an organic solution. The organic solvent can be one or a mixture of more than two of acetone, ethanol, chloroform, methylene dichloride and acetonitrile according to a certain proportion. In a specific embodiment, the organic solvent is a mixture of ethanol and acetone. In a preferred embodiment, the organic solvent is a mixed solvent of ethanol and acetone in a ratio of 1:2.
In one embodiment of the present application, the above-mentioned mixture of ginsenoside Rg5 and PLGA dissolved in an organic solvent is subjected to ultrasonic vibration treatment to obtain the ginsenoside Rg5 nanoparticle solution. In a specific embodiment, the sonication time is 30 minutes and the temperature is controlled between 30 and 60 ℃, for example 30, 35, 40, 45, 50, 55, 60 ℃, preferably 40 ℃. The nano particles obtained by the method have uniform particle size, smaller size and high drug loading and encapsulation efficiency.
In one embodiment of the present application, a liposome solution may be formed by dissolving phospholipid and cholesterol in a certain ratio.
In a specific embodiment of the present application, the phospholipid may be a natural phospholipid, a synthetic phospholipid or a derivative thereof, etc., for example, soybean lecithin, egg yolk lecithin, phosphatidylcholine, phosphatidylglycerol, sodium salt thereof, etc.
In a preferred embodiment, soy lecithin and cholesterol may be used in a ratio dissolved in phosphate buffer to form a liposome solution.
In a specific embodiment of the present application, the soybean lecithin and cholesterol are mixed in a ratio of 6:1-2: 1 in a phosphate buffer, for example, soybean lecithin and cholesterol are mixed in a ratio of 6:1, 5:1, 4:1, 3:1, 2:1, preferably soybean lecithin and cholesterol are mixed in a ratio of 5:1 to 3:1, more preferably soybean lecithin and cholesterol are mixed in a ratio of 4:1.
In a specific embodiment, the liposome solution further comprises vitamin E. Preferably, the content of vitamin E in the liposome solution is 0.2-2 wt%, for example, may be 0.2, 0.5, 0.8, 1.0, 1.2, 1.5, 1.8, 2.0wt%. The vitamin E with proper amount can obviously inhibit the oxidation of phospholipid liposome, protect the ginsenoside Rg5 and improve the stability of the ginsenoside Rg 5.
In a specific embodiment, the pH of the phosphate buffer is 5-8, and may be, for example, pH5, 5.5, 6, 6.5, 7, 7.5, 8.
In a specific embodiment, the soy lecithin and cholesterol are mixed at a temperature of 50-60 ℃, e.g., 50, 52, 55, 58, 60 ℃, preferably 50 ℃.
In a specific embodiment of the application, the ginsenoside Rg5 nanoparticle solution and the liposome solution are mixed and then circularly homogenized by a high-pressure homogenizer to form a lipid nanoparticle solution.
In a specific embodiment, the ginsenoside Rg5 nanoparticle solution and the liposome solution are mixed in a certain mass ratio. Preferably, mixing is performed at a mass ratio of 1:2 to 1:20, for example, mixing is performed at a mass ratio of 1:2, 1:4, 1:6, 1:8, 1:9, 1:10, 1:11, 1:12, 1:14, 1:16, 1:18, 1:20; more preferably, the ginsenoside Rg5 nanoparticle solution is added to the liposome solution in a mass ratio of 1:10 for mixing.
In a specific embodiment, the pressure during the high pressure homogenization is 10-30Mpa, for example 10, 15, 20, 25, 30Mpa, and the temperature is 30-60 ℃, for example 30, 35, 38, 40, 42, 45, 48, 50, 55, 60 ℃. In a preferred embodiment, the pressure during the high pressure homogenization is 20Mpa and the temperature is 50 ℃.
In a specific embodiment, the lipid nanoparticle solution obtained after high-pressure homogenization is treated by centrifugation, reduced-pressure concentration, drying and other methods to obtain the liposome nanoparticle. In a preferred embodiment, the non-entrapped drug is removed by centrifugation (8000 rpm,10 min). In a preferred embodiment, after the centrifugation, the liposome nanoparticles are uniformly obtained by concentrating and drying under reduced pressure at 50 ℃ under 0.9 mpa.
The application also relates to ginsenoside Rg5 liposome nanoparticles obtained by the preparation method. The ginsenoside Rg5 liposome nanoparticle prepared by the method has a nano-scale particle size, can easily enter blood circulation after being orally taken, can reduce the in-vivo elimination speed of the ginsenoside Rg5 due to the slow release effect of the liposome, improves the curative effect of the medicament, and better plays the roles of reducing blood sugar of the ginsenoside Rg5, inducing apoptosis of various tumor cells and the like.
The application also relates to application of the ginsenoside Rg5 liposome nanoparticle in preparation of a ginsenoside Rg5 sustained release preparation. The ginsenoside Rg5 lipid nanoparticle has high drug loading rate and small particle size, can be prepared into stable solution, has certain targeting property and high biocompatibility, and can be developed into slow release preparations, such as ginsenoside intravenous injection and ginsenoside soft capsules. The sustained release preparation can reduce the dosage and the administration times of ginsenoside Rg5, and improve the compliance of patients.
Examples
The experimental methods used in the following examples are conventional methods, if no special requirements are imposed.
The ginsenoside Rg5 used in the following examples was purified by macroporous adsorption resin and high pressure chromatography. Other materials, reagents, etc., unless otherwise specified, are commercially available.
Example 1
Effects of PLGA and drug ratio on lipid nanoparticles
PLGA copolymer (PLGA 50: 50) and ginsenoside Rg5 powder were dissolved in a ratio of 11:1 (183.3 mg ginsenoside Rg5,2.02g PLGA), 10:1 (200 mg ginsenoside Rg5,2g PLGA), 9:1 (220 mg ginsenoside Rg5,1.98g PLGA), 8:1 (244.4 mg ginsenoside Rg5,1.96g PLGA), 7:1 (275 mg ginsenoside Rg5,1.93g PLGA) in 300mL ethanol-acetone solution (1:2), and subjected to ultrasonic oscillation at 40℃for 30min to form a nano solution of different ratios of PLGA to ginsenoside Rg 5; 30g of soybean lecithin and 7.5g of cholesterol are dissolved in 600mL of phosphate buffer solution with pH of 6.5, 4.8g of vitamin E is added, and the mixture is placed at 50 ℃ and stirred uniformly to form liposome solution; then, the nano solution with the proportion is respectively added into the liposome solution drop by drop according to the proportion of the nano solution to the liposome solution of 1:10, and the mixture is stirred uniformly and homogenized under high pressure at the temperature of 40 ℃ under the pressure of 20 Mpa. Centrifuging (8000 rpm,10 min) the homogenized liposome nanoparticle solution to remove non-entrapped drug, concentrating under reduced pressure at 50 deg.C under 0.9mpa, and drying to obtain uniform liposome nanoparticle. The encapsulation efficiency, the average particle diameter and the zeta potential value of each of the above lipid nanoparticles were measured. Wherein the encapsulation efficiency was measured by a high-speed centrifugation-filtration method, the particle size was measured by a laser particle size distribution apparatus (Dendongbaite instruments Co., ltd.), and the potential was measured by a potential measuring apparatus (Markov instruments Co., ltd.), and the results were shown in Table 1.
Table 1: effects of PLGA and drug ratio on lipid nanoparticles
| PLGA：Rg5 | 11:1 | 10:1 | 9:1 | 8:1 | 7:1 |
| Encapsulation efficiency | 85.7％ | 93.5％ | 91.3％ | 90.3％ | 92.4％ |
| Average particle diameter (nm) | 103.6 | 82.0 | 83.8 | 76.3 | 110.3 |
| zeta potential (mv) | -58.2 | -61.8 | -59.1 | -54.7 | -57.8 |
According to the results in Table 1, it can be seen that the ratio of PLGA to ginsenoside Rg5 has a large influence on the average particle size of the lipid nanoparticle, has little influence on the encapsulation efficiency and zeta potential, and when the ratio of PLGA to ginsenoside Rg5 is controlled between 10:1 and 8:1, the average particle size of the prepared lipid nanoparticle can be controlled below 100nm, the encapsulation efficiency is controlled above 90%, and the zeta potential is basically stable.
Example 2
Effect of the ratio of Soybean lecithin to Cholesterol on lipid nanoparticles
Dissolving PLGA copolymer (PLGA 50:50) and ginsenoside Rg5 powder in a ratio of 10:1 (200 mg ginsenoside Rg5,2g PLGA) in 300mL ethanol-acetone solution (1:2), and performing ultrasonic oscillation at 40deg.C for 30min to form nanometer solution; soybean lecithin and cholesterol were dissolved in 600mL of phosphate buffer at pH6.5 at a ratio of 6:1 (soybean lecithin 32.14g, cholesterol 5.36 g), 5:1 (soybean lecithin 31.25g, cholesterol 6.25 g), 4:1 (soybean lecithin 30g, cholesterol 7.5 g), 3:1 (soybean lecithin 28.12g, cholesterol 9.38 g), 2:1 (soybean lecithin 15g, cholesterol 12.5 g), and vitamin E was added thereto, and the mixture was stirred uniformly at 50℃to form liposome solutions of various ratios; then the nano solution coated with ginsenoside Rg5 is respectively and dropwise added into the liposome solution according to the ratio of the nano solution to the liposome solution of 1:10, and the mixture is uniformly stirred and homogenized under high pressure at the pressure of 20Mpa and the temperature of 40 ℃. Centrifuging (8000 rpm,10 min) the homogenized lipid nanoparticle solution to remove non-entrapped drug, concentrating under reduced pressure at 50 deg.C under 0.9mpa, and drying to obtain uniform liposome nanoparticle. The encapsulation efficiency, the average particle diameter and the zeta potential value of each of the above lipid nanoparticles were measured by the method of example 1, and the results are shown in table 2.
Table 2: influence of lipid nanoparticles of the ratio of Soybean lecithin to Cholesterol
From the results in Table 2, it can be seen that as the ratio of cholesterol increases, the encapsulation efficiency increases, the average particle size decreases, and when the ratio of soybean lecithin to cholesterol reaches 4:1, the encapsulation efficiency is maximum, while the average particle size is minimum; and then the proportion of cholesterol is increased, the encapsulation efficiency is reduced, and the average particle size of the lipid nanoparticle is also increased. The ratio of soybean lecithin to cholesterol has little effect on zeta potential. Therefore, the mass ratio of soybean lecithin to cholesterol is optimally selected between 5:1 and 3:1.
Example 3
Influence of the ratio of drug nanosolution to Liposome solution on lipid nanoparticles
Dissolving PLGA copolymer (PLGA 50:50) and ginsenoside Rg5 powder in a ratio of 10:1 (200 mg ginsenoside Rg5,2g PLGA) in 300mL ethanol-acetone solution (1:2), and performing ultrasonic oscillation at 40deg.C for 30min to form nanometer solution; 30g of soybean lecithin and 7.5g of cholesterol are dissolved in 600mL of phosphate buffer solution with pH of 6.5, 4.8g of vitamin E is added, and the mixture is placed at 50 ℃ and stirred uniformly to form liposome solution; then the nano solution coated with ginsenoside Rg5 is dropwise added into the liposome solution according to the proportion of the nano solution to the liposome solution of 1:1,1:2,1:5,1:10,1:15,1:20 and 1:22 respectively, and the mixture is stirred uniformly, and is homogenized under high pressure under 20Mpa pressure and 40 ℃. Centrifuging (8000 rpm,10 min) the homogenized liposome nanoparticle solution to remove non-entrapped drug, concentrating under reduced pressure at 50 deg.C under 0.9mpa, and drying to obtain uniform liposome nanoparticle. The encapsulation efficiency, the average particle diameter and the zeta potential value of each of the above lipid nanoparticles were measured by the method of example 1, and the results are shown in table 3.
Table 3: influence of the ratio of drug nanosolution to Liposome solution on lipid nanoparticles
From the results in table 3, it can be seen that as the content of the ginsenoside nano-solution (aqueous phase) in the mixture is reduced, the encapsulation efficiency is gradually increased and the average particle diameter is gradually reduced. When the ratio is reduced to 1:2, the average particle diameter is smaller than 100nm, and the absolute value of zeta potential is also increased significantly, which indicates that the lipid nanoparticle is more stable. When the ratio of the nano solution to the liposome solution reaches 1:10, the encapsulation efficiency is maximum, and then the encapsulation efficiency gradually decreases, and the average particle size and the zeta potential absolute value tend to be stable. However, when the ratio of the nano-solution to the liposome solution is lower than 1:20, the encapsulation efficiency is already lower than 50%, so that the ratio of the ginsenoside nano-solution (aqueous phase) to the liposome solution should be between 1:2 and 1:20.
Example 4
Effect of mixing temperature on lipid nanoparticles
Dissolving PLGA copolymer (PLGA 50:50) and ginsenoside Rg5 powder in a ratio of 10:1 (200 mg ginsenoside Rg5,2g PLGA) in 300mL ethanol-acetone solution (1:2), and performing ultrasonic oscillation at 40deg.C for 30min to form nanometer solution; 30g of soybean lecithin and 7.5g of cholesterol are dissolved in 600mL of phosphate buffer with pH of 6.5, 4.8g of vitamin E is added, and the mixture is respectively placed at 40 ℃,45 ℃,50 ℃,55 ℃,60 ℃,65 ℃ and 70 ℃ and stirred uniformly to form liposome solution; then the nano solution coated with ginsenoside Rg5 is respectively dripped into the liposome solution at the different temperatures according to the ratio of the nano solution to the liposome solution of 1:10, and the mixture is stirred uniformly and homogenized under high pressure at the pressure of 20Mpa and the temperature of 40 ℃. Centrifuging (8000 rpm,10 min) the homogenized lipid nanoparticle solution to remove non-entrapped drug, concentrating under reduced pressure at 50 deg.C under 0.9mpa, and drying to obtain uniform liposome nanoparticle. The encapsulation efficiency, the average particle diameter and the zeta potential value of each of the above lipid nanoparticles were measured by the method of example 1, and the results are shown in table 4.
Table 4: effect of mixing temperature on lipid nanoparticles
| Mixing temperature (. Degree. C.) | 40 | 45 | 50 | 55 | 60 | 65 | 70 |
| Encapsulation efficiency | 57.1％ | 68.5％ | 94.1％ | 92.4％ | 89.2％ | 62.2％ | 50.2％ |
| Average particle diameter (nm) | 117.2 | 103.4 | 81.9 | 80.3 | 78.2 | 88.1 | 83.3 |
| zeta potential (mv) | -45.8 | -47.9 | -58.8 | -57.8 | -48.9 | -30.1 | -23.4 |
As can be seen from the results in table 4, as the mixing temperature of the nano solution and the liposome solution is increased, the encapsulation efficiency is gradually increased, and is remarkably increased at 50 ℃ to more than 90%, and gradually decreased after 60 ℃; when the temperature is higher than 50 ℃, the average grain diameter is stabilized at about 80 nm; zeta potential shows that the mixing temperature is more than 60 ℃, and the stability of the lipid nanoparticle is poor. In summary, the mixing temperature should be controlled between 50℃and 60 ℃.
Example 5
Influence of pH value on lipid nanoparticles
Dissolving PLGA copolymer (PLGA 50:50) and ginsenoside Rg5 powder in a ratio of 10:1 (200 mg ginsenoside Rg5,2g PLGA) in 300mL ethanol-acetone solution (1:2), and performing ultrasonic oscillation at 40deg.C for 30min to form nanometer solution; according to the soybean lecithin: 30g of soybean lecithin and 7.5g of cholesterol are respectively dissolved in 600mL of phosphate buffer solution under the conditions of pH4, pH5, pH5.8, pH6.5, pH7, pH7.4 and pH8, 4.8g of vitamin E is added, and the mixture is placed at 50 ℃ and stirred uniformly to form liposome solution; then the nano solution coated with ginsenoside Rg5 is dropwise added into the liposome solution according to the ratio of the nano solution to the liposome solution of 1:10, and the mixture is stirred uniformly and homogenized under high pressure at the pressure of 20Mpa and the temperature of 40 ℃. Centrifuging (8000 rpm,10 min) the homogenized lipid nanoparticle solution to remove non-entrapped drug, concentrating under reduced pressure at 50 deg.C under 0.9mpa, and drying to obtain uniform liposome nanoparticle. The encapsulation efficiency, the average particle diameter and the zeta potential value of each of the above lipid nanoparticles were measured by the method of example 1, and the results are shown in table 5.
Table 5: influence of pH on lipid nanoparticles
| pH | 4 | 5 | 5.8 | 6.5 | 7 | 7.4 | 8 |
| Encapsulation efficiency | 65.4％ | 60.9％ | 82.3％ | 93.5％ | 90.1％ | 76.3％ | 72.7％ |
| Average particle diameter (nm) | 101.3 | 103.7 | 96.4 | 82.5 | 80.4 | 82.4 | 99.6 |
| zeta potential (mv) | -35.2 | -31.4 | -47.6 | -57.8 | -58.6 | -55.4 | -40.1 |
From the results in table 5, it can be seen that as the pH of the buffer increases, the encapsulation efficiency gradually increases, reaches maximum at pH7, and then gradually decreases; the average particle diameter of the lipid nanoparticle is between 6.5 and 7.4, and the lipid nanoparticle reaches a stable state; the pH is increased again, and the particle size is increased; zeta potential suggests that the lipid nanoparticle is stable at pH 5.8-7.4; therefore, in consideration of the above, the pH of the buffer should be preferably controlled to be between 6 and 7.
Example 6
Ginsenoside Rg5 lipid nanoparticle stability detection
Preparation of lipid nanoparticles:
dissolving PLGA copolymer (PLGA 50:50) and ginsenoside Rg5 powder in a ratio of 10:1 (200 mg ginsenoside Rg5,2g PLGA) in 300mL ethanol-acetone solution (1:2), and performing ultrasonic oscillation at 40deg.C for 30min to form nanometer solution; 30g of soybean lecithin and 7.5g of cholesterol are dissolved in 600mL of phosphate buffer solution with pH of 6.5, 4.8g of vitamin E is added, and the mixture is placed at 50 ℃ and stirred uniformly to form liposome solution; then the nano solution coated with ginsenoside Rg5 is dropwise added into the liposome solution according to the ratio of the nano solution to the liposome solution of 1:10, and the mixture is stirred uniformly and homogenized under high pressure at the pressure of 20Mpa and the temperature of 40 ℃. Centrifuging (8000 rpm,10 min) the homogenized liposome nanoparticle solution to remove non-entrapped drug, concentrating under reduced pressure at 50 deg.C under 0.9mpa, and drying to obtain uniform liposome nanoparticle. The encapsulation efficiency was found to be 93%, the average particle diameter was 83.5nm, the zeta potential was 58.9mV
Lipid nanoparticle stability detection:
accurately weighing 30 parts of the obtained ginsenoside Rg5 lipid nanoparticle, and 50mg of the ginsenoside Rg5 lipid nanoparticle per part; meanwhile, 30 parts of 10mg of ginsenoside Rg5 powder are accurately weighed. The 60 samples were placed at 60℃for 0, 5, 10, 15, 20, 25, 30, 35, 40 days, 45 days each three samples (3 parts in parallel) were taken, dissolved in 5mL of ethanol and content detected by HPLC under the following conditions: 4.6X250mm C18 column; the mobile phase is acetonitrile: water (60:40), column temperature: 35 ℃ and the flow rate is 1.5mL/min; detection wavelength: 203nm; the sample injection volume is 20uL; the stability of ginsenoside Rg5 lipid nanoparticle is shown in figure 2.
According to the experimental results of fig. 2, the content of ginsenoside Rg5 lipid nanoparticle is maintained above 90% within 45 days.
Example 7
Ginsenoside Rg5 lipid nanoparticle in vitro drug release test
1. Accurately weighing the ginsenoside Rg5 lipid nanoparticle prepared in example 6, diluting with 5% glucose solution until the concentration of ginsenoside Rg5 is 5mg/mL, taking 2mL, placing in a dialysis bag (MWCO=3500) which is balanced in a release medium in advance for 12h, placing in a beaker containing 100mL of PBS release medium with pH of 7.4 after tightening the two ends, carrying out warm bath at the constant temperature of 37+ -0.5 ℃ at the rotating speed of a water bath oscillator of 80-100rpm, respectively sucking 1mL of release medium outside the dialysis bag and supplementing 1mL of the same release medium at the 2h,4h,6h,8h,10h,12h,24h,2d,3d,4d,5d, and carrying out liquid phase detection analysis on samples taken at each time point by passing through a 0.45 mu m filter membrane.
2. Accurately weighing ginsenoside Rg5 powder (purity > 98%), dissolving with 5% glucose buffer solution to obtain ginsenoside Rg5 concentration of 5mg/mL, taking 2mL, placing into dialysis bag (MWCO=3500) equilibrated in release medium for 12 hr, fastening two ends, placing into beaker containing PBS release medium of pH7.4 for 100mL, performing warm bath at 37+ -0.5deg.C at 80-100rpm/min with water bath constant temperature oscillator, sucking release medium 1mL outside dialysis bag at 2h,4h,6h,8h,10h,12h,24h,2d,3d,4d,5d, supplementing the same release medium 1mL, filtering the sample taken at each time point with 0.45 μm filter membrane, and performing liquid phase detection analysis.
3. Samples (ginsenoside Rg5 lipid nanoparticles, ginsenoside Rg5 powder) at each sampling time point were subjected to HPLC detection for the content of ginsenoside Rg5 (external standard method), and the detection method is as described in example 6.
4. And drawing a drug release curve by taking time as an abscissa and taking the ratio of the detected ginsenoside Rg5 content in the release medium at each time point to the ginsenoside Rg5 content in the release medium after the drug is completely released as an ordinate, wherein the graph is shown in figure 3.
As can be seen from FIG. 3, after the ginsenoside Rg5 lipid nanoparticle is stored in a release medium for 5 days, the accumulated release amount is 83.06%, the release curve in the graph shows that the drug can be slowly released, the time can last for more than 5 days, the release amount of the ginsenoside Rg5 lipid nanoparticle reaches the peak (burst release phenomenon) in unit time at 8 hours, the release amount reaches 34.9%, the released ginsenoside Rg5 can immediately act, the release rate of 8 hours to 12 hours is slowly reduced, the release amount is about 51.07% at 12 hours, and then the release amount is detected to be stable at the level (the release amount is about 10% every day) every time. The ginsenoside Rg5 lipid nanoparticle can achieve the purpose of slow release. The ginsenoside Rg5 powder is completely released within 24 hours, and the release amount reaches 96.75%, which indicates that the unmodified ginsenoside Rg5 has no slow release effect.
Example 8
Ginsenoside Rg5 lipid nanoparticle in-vivo blood concentration and pharmacokinetics
1. And (3) standard curve preparation: dissolving ginsenoside Rg5 with different masses in SD rat blood (blank group, no drug administration), adding ethyl acetate with the same volume, extracting for 3 times, mixing upper organic phases, blow-drying with nitrogen at 37 ℃, dissolving residues with 200ul methanol, detecting ginsenoside Rg5 content according to HPLC detection method of example 6, performing linear regression with ginsenoside Rg5 peak area as ordinate, determining that blank blood has no interference on ginsenoside Rg5 detection, and linear relationship is good within the range of 0.5-500mg/mL, and regression equation is: y=2x10 7 X-2x10 6 (R 2 ＝0.9994)。
2. In vivo blood concentration and kinetic detection: healthy SD rats (supplied by the university of Western An traffic animal center) with a body weight of (200+ -20) g were selected for a total of 12 and observed 3 days prior to the experiment. SD rats were randomly divided into 2 groups of 6. One group is a ginsenoside Rg5 powder control group, and the other group is a ginsenoside Rg5 lipid nanoparticle group (ginsenoside Rg5 lipid nanoparticles are prepared by the method of example 6). Fasted for 12 hours before the experiment, the rats can drink water at will, and the rats containing ginsenoside Rg5 lipid nanoparticle group and ginsenoside Rg5 powder group are respectively perfused with stomach according to the dosage of 25mg/kg of ginsenoside Rg 5. 0.5mL of blood is taken from the eye sockets after the administration of 0.5h,1h,2h,4h,6h,8h,10h,12h,24h,48h and 72h, the mixture is placed in an EP tube containing heparin sodium, ethyl acetate with the same volume is added and mixed uniformly, the mixture is centrifuged at 3000rpm for 20min, an upper organic layer is taken, the mixture is extracted for 2 times according to the method, the upper organic layer is combined, nitrogen is dried at 37 ℃, the residue is dissolved in 200uL of methanol, the ginsenoside Rg5 content in the blood is determined according to the HPLC detection method of example 6, and the graph of the blood concentration-time in the rat is shown in figure 4.
The experimental results of fig. 4 show that the peak of the blood concentration of the ginsenoside Rg5 lipid nanoparticle group and the peak of the blood concentration of the ginsenoside Rg5 powder control group occur at the same time, namely, the peak of the highest drug concentration occurs at 6 hours, but the blood concentration of the ginsenoside Rg5 lipid nanoparticle is higher (p < 0.05), and the blood concentration of the ginsenoside Rg5 lipid nanoparticle can be maintained for a longer time and the half-life period is longer under the same administration dosage. Analysis of the above results shows that ginsenoside Rg5 lipid nanoparticles have a sustained release effect in vivo; the concentration of the medicine entering the blood is higher, and the medicine effect is stronger, so that the bioavailability of the ginsenoside Rg5 can be improved by preparing the ginsenoside Rg5 into lipid nanoparticles.
In conclusion, the ginsenoside Rg5 is prepared into liposome nano particles, so that the stability of the ginsenoside Rg5 can be improved, the sustained release effect is achieved, the dosage and the administration times are reduced, and meanwhile, the bioavailability in vivo is relatively improved. The ginsenoside Rg5 lipid nanoparticle has outstanding advantages as a novel administration type, and the novel ginsenoside Rg5 lipid nanoparticle preparation can be used for treating various diseases along with further research and optimization.
The above description is only a preferred embodiment of the present application, and is not intended to limit the application in any way, and any person skilled in the art may make modifications or alterations to the disclosed technical content to the equivalent embodiments. However, any simple modification, equivalent variation and variation of the above embodiments according to the technical substance of the present application still fall within the protection scope of the technical solution of the present application.
Claims (9)
1. The preparation method of the ginsenoside Rg5 liposome nanoparticle is characterized by comprising the following steps of:
ginsenoside Rg5 and polylactic acid-glycolic acid copolymer are mixed according to the proportion of 1: 10-1: 8, mixing and dissolving the materials in the mass ratio into an organic solution, and carrying out ultrasonic vibration to form a ginsenoside Rg5 nanoparticle solution;
dissolving soybean lecithin, cholesterol and vitamin E in a phosphate buffer solution, and uniformly mixing to form a liposome solution, wherein the mass ratio of the soybean lecithin to the cholesterol is 5: 1-3: 1, wherein the pH value of the phosphate buffer solution is 6-7;
mixing the ginsenoside Rg5 nanoparticle solution and the liposome solution at 50-60 ℃, and homogenizing under high pressure to form a lipid nanoparticle solution, wherein the mass ratio of the ginsenoside Rg5 nanoparticle solution to the liposome solution is 1:2-1:20;
removing the non-entrapped ginsenoside Rg5 in the lipid nanoparticle solution, and concentrating and drying under reduced pressure to obtain the ginsenoside Rg5 liposome nanoparticle.
2. The method of claim 1, wherein the organic solvent is acetone, ethanol, chloroform or a mixture thereof.
3. The method according to claim 1, wherein the soybean lecithin and cholesterol are dissolved in a phosphate buffer at a mass ratio of 4:1.
4. The method according to claim 1, wherein the content of vitamin E in the liposome solution is 0.2-2wt%.
5. The preparation method according to claim 1, wherein the ginsenoside Rg5 nanoparticle solution and the liposome solution are mixed at a mass ratio of 1:10 and then subjected to high-pressure homogenization.
6. The method according to claim 5, wherein the pressure during the high-pressure homogenization is 10-30Mpa and the temperature is 30-60 ℃.
7. The method according to claim 6, wherein the temperature during the high-pressure homogenization is 40 ℃.
8. Ginsenoside Rg5 liposome nanoparticle obtained by the preparation method of any one of claims 1-7.
9. The use of the ginsenoside Rg5 liposome nanoparticle of claim 8 in the preparation of a ginsenoside Rg5 sustained release preparation.
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