CN113827487B - Shell material, nano carrier and application thereof - Google Patents
Shell material, nano carrier and application thereof Download PDFInfo
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- CN113827487B CN113827487B CN202111115781.5A CN202111115781A CN113827487B CN 113827487 B CN113827487 B CN 113827487B CN 202111115781 A CN202111115781 A CN 202111115781A CN 113827487 B CN113827487 B CN 113827487B
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- 239000002539 nanocarrier Substances 0.000 title claims description 38
- 239000011257 shell material Substances 0.000 title abstract description 57
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- 239000002502 liposome Substances 0.000 claims abstract description 61
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 43
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000000126 substance Substances 0.000 claims abstract description 18
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- 125000003563 glycoside group Chemical group 0.000 claims abstract 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 309
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 106
- 239000008367 deionised water Substances 0.000 claims description 99
- 229910021641 deionized water Inorganic materials 0.000 claims description 99
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- 108010074988 acetyltyrosyl-arginine cetyl ester Proteins 0.000 claims description 75
- JFHZXDZUXGBFAQ-KYJUHHDHSA-N hexadecyl (2s)-2-[[(2s)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoate Chemical compound CCCCCCCCCCCCCCCCOC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](NC(C)=O)CC1=CC=C(O)C=C1 JFHZXDZUXGBFAQ-KYJUHHDHSA-N 0.000 claims description 75
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Abstract
The invention belongs to the field of cosmetics, and discloses a shell material which comprises phospholipid, peptide fatty acid derivatives and triol ginsenoside secondary glycoside; the weight ratio of the phospholipid to the peptide fatty acid derivative to the triol type ginsenoside secondary glycoside is 0.1-100:0.1 to 100:0.1 to 100; the peptide fatty acid derivative comprises a polypeptide unit structure and contains one or more arginine or lysine units; the unit structure of the polypeptide is one of dipeptide to pentapeptide. The shell material can be used as a shell layer of the micelle and the liposome for stably wrapping and stably releasing lipophilic active substances and hydrophilic active substances, has excellent compatibility in a system, obviously weakens the precipitation phenomenon, is easy to regulate and control the positive and negative properties of the surface charge of the shell material, reduces the cytotoxicity and the skin irritation of cosmetics, reduces the adverse proliferation effect of the traditional shell material on harmful flora as nutrient substances, improves the absorption effect of the skin on the active substances, and simultaneously discloses the application of the micelle and the liposome.
Description
Technical Field
The invention relates to the field of cosmetics, in particular to a shell material, a nano carrier and application thereof.
Background
CN2020116376570 discloses a liposome based on ginsenoside secondary glycosides, which contains phospholipid and diol type ginsenoside secondary glycosides as shown in formula (1); disclosed is an active substance-loaded liposome, which is a liposome in which one or more active substances of cosmetics are encapsulated in a diol-type ginsenoside-based secondary glycoside; the preparation method of the liposome loaded with the active substances comprises the steps of mixing phospholipid and ginsenoside secondary glycoside shown as a formula (1) in an alcohol organic solvent, adding the active substances in the cosmetics, carrying out reduced pressure evaporation until the mixture is formed into a film, then using a phosphate buffer solution with the pH value of 7-8 as a hydration medium, hydrating at 40-50 ℃, and homogenizing to obtain a liposome solution.
Wherein R is 1 Any one of: -O-Glc, -O-Xyl, -O-Rha, -O-Ara, -O-Lyx, -O-Glc (2 → 1) Glc, -O-Glc (6 → 1) Glc, -O-Glc (2 → 1) Xyl, -O-Glc (6 → 1) Xyl, -O-Glc (2 → 1) Rha, -O-Glc (6 → 1) Rha, -O-Glc (2 → 1) Ara, -O-Glc (6 → 1) Ara, -O-Glc (2 → 1) Lyx, -O-Glc (6 → 1) Lyx, -O-Glc (2 → 1) Glc-O-Glc (2 → 1) Glc (6 → 1) Glc, -O-Glc (6 → 1) Glc (2 → 1) Glc, -O-Glc (6 → 1) Glc (6 → 1) Glc, -O-Glc (2 → 1) Glc (2 → 1) Xyl, -O-Glc (2 → 1) Glc (6 → 1) Xyl, -O-Glc (6 → 1) Glc (2 → 1) Xyl, -O-Glc (6 → 1) Glc (6 → 1) Xyl, -O-Glc (2 → 1) Glc (2 → 1) Rha, -O-Glc (2 → 1) Glc (6 → 1) Rha, -O-Glc (6 → 1) Glc (2 → 1) Rha, -O-Glc (6 → 1) Rha, -O-Glc (2 → 1) Ara, -O-Glc (2 → 1) Glc (6 → 1) Ara, -O-Glc (6 → 1) Glc (2 → 1) Ara, and-O-Glc (6 → 1) Ara, -O-Glc (2 → 1) Lyx, -O-Glc (2 → 1) Glc (6 → 1) Lyx, -O-Glc (6 → 1) Glc (2 → 1) Lyx, -O-Glc (6 → 1) Lyx
CN201310155639.2 discloses ginsenoside nano-micelles, and preparation methods, applications and pharmaceutical compositions thereof. The ginsenoside nano micelle comprises ginsenoside Rg3, ginsenoside Rg5 and ginsenoside Rk1, wherein the content of Rg3 is 15-45%, the content of Rg5 is 15-45%, the content of Rk1 is 15-45%, the total amount of Rg3, rg5 and Rk1 is more than or equal to 70%, and the percentage by mass is percentage. The preparation method comprises dissolving each component of ginsenoside nano-micelle in organic solvent capable of dissolving ginsenoside, and removing organic solvent.
Therefore, the application of ginsenoside secondary glycoside as a shell material to prepare liposome and micelle has been published in relevant researches.
The problems with the above studies are: CN2020116376570 discloses a structure of liposome for containing water-soluble active substances, and the obtained liposome is a liposome structure based on diol type secondary ginseng glycoside, and the shell structure disclosed by CN201310155639.2 is pure ginsenoside without other chemical components, and the prepared pure ginsenoside nano-micelles are all neutral or weak negative charge nano-materials, and the high-temperature long-term storage stability of the nano-micelles has certain challenges through research, and cannot meet the requirements of encapsulation, storage and release of stable oil-soluble active substances in cosmetics.
Undeniably, the two schemes both pay attention to the fact that the ginsenoside secondary glycoside is taken as a shell structure, and the basic characteristics of the shell material are expressed, and meanwhile, the activity characteristics of the ginsenoside are also expressed.
Aiming at the ginsenoside secondary glycoside as the shell material, the research finds that if the ginsenoside secondary glycoside is not optimized by the shell material, the solubility and compatibility, the skin adsorbability, the irritation, the soothing and anti-allergy effects and the reduction of the proliferation effect of the membrane material as a nutrient on bacteria in a system are all not to an ideal degree.
Therefore, the technical problem that the present scheme was solved is: how to improve the system compatibility, skin adsorbability and the anti-allergy effect of taking ginsenoside secondary glycoside as shell base materials, enhance the surface charge controllability of the shell base materials and reduce the proliferation effect of the traditional membrane material itself as nutrient on bacteria.
Disclosure of Invention
The invention aims to provide a shell material which can be used as a shell layer of micelle and liposome for stably wrapping and stably releasing lipophilic active substances and hydrophilic active substances, has excellent compatibility in a system, obviously weakens the precipitation phenomenon, reduces the irritation of cosmetics, has the effects of relieving and resisting allergy, improves the absorption effect of skin on the active substances, and reduces the proliferation effect of the traditional membrane material as a nutrient on bacteria, and also discloses a nano carrier based on the shell material and the application thereof.
In order to achieve the purpose, the invention provides the following technical scheme: a shell material comprises phospholipid, peptide fatty acid derivatives and triol-type ginsenoside secondary glycoside; the weight ratio of the phospholipid to the peptide fatty acid derivative to the triol type ginsenoside secondary glycoside is 0.1-100:0.1 to 100:0.1 to 100;
the peptide fatty acid derivative comprises a polypeptide unit structure and contains one or more arginine or lysine units; the polypeptide unit structure is one of dipeptide to pentapeptide;
the triol-type ginsenoside secondary glycoside is shown as the following general formula I:
R 1 one selected from the following groups:
-O-Glc、-O-Xyl、-O-Rha、-O-Ara、-O-Lyx、-O-Glc(2→1)Glc、-O-Glc(6→1)Glc、-O-Glc(2→1)Xyl、-O-Glc(6→1)Xyl、-O-Glc(2→1)Rha、-O-Glc(6→1)Rha、-O-Glc(2→1)Ara、-O-Glc(6→1)Ara、-O-Glc(2→1)Lyx、-O-Glc(6→1)Lyx、-O-Glc(2→1)Glc(2→1)Glc、-O-Glc(2→1)Glc(6→1)Glc、-O-Glc(6→1)Glc(2→1)Glc、-O-Glc(6→1)Glc(6→1)Glc、-O-Glc(2→1)Glc(2→1)Xyl、-O-Glc(2→1)Glc(6→1)Xyl、-O-Glc(6→1)Glc(2→1)Xyl、-O-Glc(6→1)Glc(6→1)Xyl、-O-Glc(2→1)Glc(2→1)Rha、-O-Glc(2→1)Glc(6→1)Rha、-O-Glc(6→1)Glc(2→1)Rha、-O-Glc(6→1)Glc(6→1)Rha、-O-Glc(2→1)Glc(2→1)Ara、-O-Glc(2→1)Glc(6→1)Ara、-O-Glc(6→1)Glc(2→1)Ara、-O-Glc(6→1)Glc(6→1)Ara、-O-Glc(2→1)Glc(2→1)Lyx、-O-Glc(2→1)Glc(6→1)Lyx、-O-Glc(6→1)Glc(2→1)Lyx、-O-Glc(6→1)Glc(6→1)Lyx；
R 2 one selected from the following groups:
in the shell material, the peptide fatty acid derivative is one of acetyl dipeptide-1 cetyl ester, palmitoyl dipeptide-7, palmitoyl tripeptide-1, palmitoyl tripeptide-8, palmitoyl tetrapeptide-7, and palmitoyl pentapeptide-4.
In the examples of the present invention, acetyl dipeptide-1 cetyl ester was extensively validated. In the research process of the invention, the derivatives with similar structures with acetyl dipeptide-1 cetyl ester can form stable nano-carriers.
In the shell material, the weight ratio of the phospholipid, the peptide fatty acid derivative and the triol type ginsenoside secondary glycoside is 1-99.9: 0.1 to 40:1 to 99.9.
In the shell material, the phospholipid is one of natural lecithin, soybean lecithin, egg yolk lecithin, hydrogenated lecithin and cephalin.
Meanwhile, the invention also discloses a nano carrier which consists of a core layer and a shell layer, wherein the shell layer is as described in any one of the above, and the core layer is a hydrophobic substance or a hydrophilic substance.
Preferably, the weight ratio of the core layer to the shell layer is 0.01 to 100.
Preferably, the weight ratio of the core layer to the shell layer is 1:1-201:.
It should be noted that, when the nanocarrier is a liposome, there may be no core layer in the shell, that is, the core-shell ratio may reach 0.
The proportion of the core shell layer is very broad in practice in the embodiments of the invention due to space limitations.
In the nano-carrier, the nano-carrier is a micelle or a liposome, and if the nano-carrier is a liposome, the core layer is a hydrophobic substance or a hydrophilic substance; if the nano-carrier is a micelle, the core layer is a hydrophobic substance.
The liposome is defined as a bilayer or a polymolecular layer of a nano carrier material of the membrane material (phospholipid + saponin + peptide), and a coating is a hydrophilic or hydrophobic active matter; the micelle is defined as a nano carrier material of a monomolecular layer of the membrane material (phospholipid + saponin + peptide), and a coating is a hydrophobic active substance;
in the nano-carrier, if the nano-carrier is micelle, the weight ratio of the phospholipid, the peptide fatty acid derivative and the triol type ginsenoside secondary glycoside is 1.1-100;
if the nano-carrier is liposome, the weight ratio of the phospholipid, the peptide fatty acid derivative and the triol ginsenoside secondary glycoside is 10:0.1-10:0.1-10.
Preferably, if the nanocarrier is a micelle, the weight ratio of the phospholipid, the peptide fatty acid derivative and the triol-type ginsenoside secondary glycoside is 1:0.1-50:0.1 to 50;
if the nano-carrier is liposome, the weight ratio of the phospholipid, the peptide fatty acid derivative and the triol ginsenoside secondary glycoside is 10:0.2-8:0.2-8.
Preferably, if the nanocarrier is a micelle, the weight ratio of the phospholipid, the peptide fatty acid derivative and the triol-type ginsenoside secondary glycoside is 1:0.2-30:0.2 to 30;
if the nano-carrier is liposome, the weight ratio of the phospholipid, the peptide fatty acid derivative and the triol ginsenoside secondary glycoside is 10:0.5-5:0.5-5.
Preferably, if the nanocarrier is a micelle, the weight ratio of the phospholipid, the peptide fatty acid derivative and the triol-type ginsenoside secondary glycoside is 1:0.3-6:0.3 to 2;
if the nano-carrier is liposome, the weight ratio of the phospholipid, the peptide fatty acid derivative and the triol ginsenoside secondary glycoside is 10:1-2:0.5-1.
It can be seen that the use of more phospholipids favors the liposome, and the use of less phospholipids favors the micelle.
It should be noted that, as the dosage of the phospholipid increases from a small dosage to a large dosage, the dosage limit of the conversion between the micelle and the liposome is not obvious, and the dosage limit is related to the selection of the phospholipid, the selection of the peptide fatty acid derivative and the selection of the secondary glycoside of the triol ginsenoside.
In the nano-carrier, the hydrophobic active substance is one or more of natural or synthetic oil and fat compounds, phospholipid compounds, vitamins, carotenes, carotenoid compounds, essential oil compounds and fat-soluble small molecule active substances, and the fat-soluble small molecule active substances are one or more of coenzyme Q-10, resveratrol and astaxanthin;
the hydrophilic active substance is one or more of hydrolyzed protein compounds, water-soluble small molecule polypeptide compounds and water-soluble small molecule compounds;
the hydrolyzed protein compound is one or more of hydrolyzed fibroin polypeptide, hydrolyzed collagen polypeptide, hydrolyzed milk protein polypeptide, hydrolyzed rice protein polypeptide and hydrolyzed wool protein polypeptide;
the water-soluble small molecule polypeptide compound is one or more of biotin tripeptide-1, acetyl hexapeptide-8, snake venom tripeptide and nonapeptide-1;
the water-soluble micromolecule compound is one or more of water-soluble ascorbic acid and derivatives, fruit acid, plant extracts, retinol/acid, nicotinamide, phenethyl resorcinol, alpha-arbutin, bioactive oligosaccharide and polysaccharide.
In the above-mentioned nano-carrier, the particle size of the nano-carrier is 10nm to 500nm, preferably 20nm to 200nm, more preferably 40nm to 100nm.
Finally, the invention also discloses the application of any nano-carrier in cosmetics and foods.
The preparation method of the micelle and the liposome comprises but is not limited to: multi-channel rapid mixing method: mixing phospholipid, acetyl dipeptide-1 cetyl ester and rare ginsenoside secondary glycoside shown as general formula I in alcohol organic solvent, stirring at room temperature to dissolve completely to form good solvent solution of the raw materials for preparing nano liposome and micelle such as rare ginseng secondary glycoside, acetyl dipeptide-1 cetyl ester, phospholipid, etc.; introducing a good solvent solution into one or more channels of the multi-channel mixer, and introducing an anti-solvent or an anti-solvent mixed solution containing a hydrophilic active substance and a hydrophobic active substance into the other channels, so that the anti-solvent or the anti-solvent mixed solution can be rapidly self-assembled into a nano liposome and micelle solution based on rare ginseng secondary glycoside in a mixing cavity of the multi-channel mixer.
Compared with the prior art, the invention has the beneficial effects that:
the shell material can be used as a shell layer of the micelle and the liposome for stably wrapping and stably releasing oil-soluble active substances and water-soluble active substances, so that an excellent daily chemical care effect is achieved, the irritation of cosmetics is reduced, the unique charge controllability improves the affinity with the skin, and the bad proliferation of the traditional membrane material serving as a bacterial nutrient substance is reduced.
The rare ginseng secondary glycoside used in the experiment has definite functional components, stable quality and good skin absorbability; has the advantages of industrialization and commercialization. Ginsenosides are mainly classified into protopanaxadiol type and protopanaxatriol type. The two components have distinct activity and pharmacological action, and the difference in cosmetic efficacy is very significant, so that the two components must be separated and enriched for use in different cosmetics. The triol ginseng secondary glycoside subjected to special conversion used in the experiment not only has a definite component structure, but also has better efficacy and activity. The converted triol-type ginseng secondary glycoside has reduced polarity, belongs to an amphiphilic molecule, is a compound which can be better used for replacing a natural plant source of a chemical synthesis coating material, and has better compatibility when being used as a membrane material with acetyl dipeptide-1 cetyl ester with positive charge.
The triol-type rare ginseng secondary glycoside and the nano micelle and liposome prepared from the triol-type rare ginseng secondary glycoside can greatly reduce cytotoxicity, particularly long-term cytotoxicity. In normal fibroblast cultures, 50ug/mL of the indicated sample was added, and cells were sampled at different times after addition and compared for their effect on cell viability (MTT). The lower the activity of the cells obtained, the more cytotoxic the cells obtained. The test result is shown in figure 1, the cytotoxicity of the triol type rare ginseng secondary glycoside is lower than that of the diol type rare ginseng secondary glycoside and commercial ginsenoside primary glycoside under the same condition, and the triol type rare ginseng secondary glycoside has more excellent cell compatibility particularly with long-term action; in addition, after the nano-micelle is wrapped, the cytotoxicity of the used rare ginseng secondary glycoside can be further reduced, and the nano-micelle of the triol type secondary glycoside has higher cell compatibility than the nano-micelle of the diol type under the same condition.
The shell structure formed by phospholipid, ginsenoside secondary glycoside and acetyl dipeptide-1 cetyl ester has unique advantages:
1) The peptide fatty acid derivative can change the surface charge performance of the micelle, so that the membrane material combination can more effectively and conveniently adjust the surface charge performance of the nano-carrier, and the original negative charge ginseng lecithin micelle and liposome are changed into the stable positive charge ginseng micelle and liposome.
2) The prepared positive charge carrier material on the surface can better adsorb skin with negative charges, and the peptide fatty acid derivatives exist in the shell layer, so that the anti-allergy and relieving effects of the prepared nano carrier material are improved, and the skin irritation of the material is reduced.
3) The peptide fatty acid derivative has cationic performance on a shell layer, so that the peptide fatty acid derivative has certain bacteriostatic performance, and can be used as a co-membrane material, so that the utilization rate of the traditional shell material component and the active compound (such as lecithin and the like) wrapped by the traditional shell material component as a nutrient substance for harmful bacteria proliferation is reduced. However, it should be noted that the peptide fatty acid derivative must be in the presence of phospholipids and triol ginsenoside secondary glycosides to precipitate less alcohol solutions of the shell material mixture, and the compatibility is good, so that the preparation of stable micelles and liposomes by the multichannel mixing method disclosed by the invention can be realized, and the skin adsorption performance and other performances are very excellent.
Through the optimization, the positive charge ginseng micelle or liposome can be combined with the skin of a human body more stably, and compared with a shell material without peptide fatty acid derivatives and a shell material adopting diol type ginsenoside secondary glycosides as a substitute, the system can be used for preparing stable shell material alcohol solutions, nano-micelle and liposome more easily, and has good affinity and small irritation to the human body.
Drawings
FIG. 1 shows the long-term cytotoxicity comparison of triol-type secondary ginseng glycosides, diol-type secondary ginseng glycosides, and commercial ginseng primary glycosides, and the long-term cytotoxicity comparison of diol-type secondary ginseng glycoside nanomicelles and triol-type nanomicelles according to the present invention;
FIG. 2 is a comparison of solution compatibility of example 9 of the present invention and comparative example 2;
FIG. 3 is a cryo-transmission electron micrograph of nanoliposomes prepared in example 9 of the present invention
FIG. 4 is a comparison of skin-like interfacial adsorption performance of example 9 of the present invention and comparative example 3
FIG. 5 is a comparison of solution compatibility of example 8 of the present invention and comparative example 5;
FIG. 6 is a cryo-TEM image of nano-micelle prepared in example 8 of the present invention
FIG. 7 is a comparison of skin-like interfacial adsorption performance of example 8 of the present invention and comparative example 4
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
First, micelle preparation experiment
< example 1>
Taking egg yolk lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of the coenzyme Q10 is 1:1:1:1 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the solution is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 15mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. And respectively connecting the prepared lecithin ginsenoside ethanol solution and deionized water to two channels of a multi-channel mixer by using a digital injection pump, wherein the introduction speed is preferably 5mL/min, the same deionized water is respectively introduced into the other two channels, the introduction speed is preferably 45mL/min, and the obtained nano micelle liquid flows out of an outlet and is received by a container.
Wherein R1 is-O-Glc and R2 is
< examples 1 to 1>
Taking yolk lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of the coenzyme Q10 is 1:0.1:0.1:1 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the solution is completely dissolved, the total concentration of the prepared ethanol solution phase is 15mg/mL, and then the prepared ethanol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. And respectively connecting the prepared lecithin ginsenoside ethanol solution and deionized water to two channels of a multi-channel mixer by using a digital injection pump, wherein the introduction speed is preferably 5mL/min, the same deionized water is respectively introduced into the other two channels, the introduction speed is preferably 45mL/min, and the obtained nano micelle liquid flows out of an outlet and is received by a container.
Wherein R1 is-O-Glc and R2 is
< examples 1 and 2>
Taking yolk lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of the coenzyme Q10 is 1:0.1:1:1 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the solution is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 15mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. And respectively connecting the prepared lecithin ginsenoside ethanol solution and deionized water to two channels of a multi-channel mixer by using a digital injection pump, wherein the introduction speed is preferably 5mL/min, the same deionized water is respectively introduced into the other two channels, the introduction speed is preferably 45mL/min, and the obtained nano micelle liquid flows out of an outlet and is received by a container.
Wherein, R1 is-O-Glc, R2 is
< examples 1 to 3>
Taking egg yolk lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of coenzyme Q10 is 1:0.1:0.1:10 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the absolute ethyl alcohol is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 15mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. And respectively connecting the prepared lecithin ginsenoside ethanol solution and deionized water to two channels of a multi-channel mixer by using a digital injection pump, wherein the introduction speed is preferably 5mL/min, the same deionized water is respectively introduced into the other two channels, the introduction speed is preferably 45mL/min, and the obtained nano micelle liquid flows out of an outlet and is received by a container.
Wherein, R1 is-O-Glc, R2 is
< examples 1 to 4>
Taking yolk lecithin: a triol-type rare ginseng secondary glycoside represented by a general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of coenzyme Q10 is 1:0.1:100:1 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the solution is completely dissolved, the total concentration of the prepared ethanol solution phase is 15mg/mL, and then the prepared ethanol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. And respectively connecting the prepared lecithin ginsenoside ethanol solution and deionized water to two channels of a multi-channel mixer by using a digital injection pump, wherein the introduction speed is preferably 5mL/min, the same deionized water is respectively introduced into the other two channels, the introduction speed is preferably 45mL/min, and the obtained nano micelle liquid flows out of an outlet and is received by a container.
Wherein, R1 is-O-Glc, R2 is
< examples 1 to 5>
Taking egg yolk lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of coenzyme Q10 is 1:100:0.1:1 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the solution is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 15mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. And respectively connecting the prepared lecithin ginsenoside ethanol solution and deionized water to two channels of a multi-channel mixer by using a digital injection pump, wherein the introduction speed is preferably 5mL/min, the same deionized water is respectively introduced into the other two channels, the introduction speed is preferably 45mL/min, and the obtained nano micelle liquid flows out of an outlet and is received by a container.
Wherein R1 is-O-Glc and R2 is
< examples 1 to 6>
Taking egg yolk lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of the coenzyme Q10 is 1:100:1:1 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the solution is completely dissolved, the total concentration of the prepared ethanol solution phase is 15mg/mL, and then the prepared ethanol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. And respectively connecting the prepared lecithin ginsenoside ethanol solution and deionized water with two channels of a multi-channel mixer through a digital injection pump, wherein the introduction speed is preferably 5mL/min, the same deionized water is respectively introduced into the other two channels, the introduction speed is preferably 45mL/min, and the obtained nano micelle liquid flows out of an outlet and is received by a container.
Wherein R1 is-O-Glc and R2 is
< examples 1 to 7>
Taking yolk lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of coenzyme Q10 is 1:100:100:1 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the solution is completely dissolved, the total concentration of the prepared ethanol solution phase is 15mg/mL, and then the prepared ethanol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. And respectively connecting the prepared lecithin ginsenoside ethanol solution and deionized water to two channels of a multi-channel mixer by using a digital injection pump, wherein the introduction speed is preferably 5mL/min, the same deionized water is respectively introduced into the other two channels, the introduction speed is preferably 45mL/min, and the obtained nano micelle liquid flows out of an outlet and is received by a container.
Wherein R1 is-O-Glc and R2 is
< examples 1 to 8>
In general, as in example 1, except that acetyl dipeptide-1 cetyl ester was replaced with the same amount of palmitoyl dipeptide-7.
Examples 1-1 to 1-8 investigated the formation of nano-micelles with different proportions of shell material. Experiments prove that the preparation method can obtain the nano-micelle with different shell ratios by adjusting experiment parameters.
< example 2>
Taking lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of the shea butter is 1:2:6:5 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the absolute ethyl alcohol is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 90mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. And respectively connecting the prepared lecithin ginsenoside ethanol solution and deionized water with two channels of a multi-channel mixer through a digital injection pump at the introduction speed of preferably 7mL/min, respectively introducing the same deionized water into the other two channels at the introduction speed of preferably 81mL/min, and allowing the obtained nano-micelle liquid to flow out of an outlet and be received by a container.
Wherein, R1 is-O-Glc, R2 is
< example 3>
Taking soybean lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of astaxanthin is 2:3:2:1 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the solution is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 100mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. And respectively connecting the prepared lecithin ginsenoside ethanol solution and deionized water to two channels of a multi-channel mixer by using a digital injection pump, wherein the introduction speed is preferably 8mL/min, the same deionized water is respectively introduced into the other two channels, the introduction speed is preferably 100mL/min, and the obtained nano micelle liquid flows out of an outlet and is received by a container.
Wherein the R1 group is-O-Glc (6 → 1) Glc (2 → 1) Glc, and R2 is
< example 4>
Taking yolk lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of resveratrol is 2:1:1:3, dissolving the components in absolute ethyl alcohol together, stirring for 1h at room temperature until the components are completely dissolved, wherein the total concentration of a prepared ethyl alcohol solution phase is 45mg/mL, and then respectively sucking the prepared ethyl alcohol solution phase and the anti-solvent deionized water into a syringe. And (3) mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. And respectively connecting the prepared lecithin ethanol solution and deionized water with two channels of a multi-channel mixer by a digital injection pump, wherein the feeding speed is preferably 6mL/min, respectively feeding the same deionized water into the other two channels at the feeding speed of preferably 100mL/min, and allowing the obtained nano micelle liquid to flow out of an outlet and be received by a container.
Wherein the R1 group is-O-Glc (6 → 1) Xyl and R2 is
< example 5>
Taking natural lecithin: a triol-type rare ginseng secondary glycoside represented by a general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of the vitamin C tetraisopalmitate is 1:2:3:4, dissolving the components in absolute ethyl alcohol together, stirring for 1h at room temperature until the components are completely dissolved, wherein the total concentration of the prepared ethyl alcohol solution phase is 160mg/mL, and then respectively sucking the prepared ethyl alcohol solution phase and the anti-solvent deionized water into a syringe. And (3) mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. And respectively connecting the prepared lecithin ethanol solution and deionized water to two channels of a multi-channel mixer through a digital injection pump, wherein the feeding speed is preferably 9mL/min, respectively feeding the same deionized water into the other two channels, the feeding speed is preferably 90mL/min, and the obtained nano micelle liquid flows out of an outlet and is received by a container.
Wherein, the R1 group is-O-Glc (6 → 1) Glc (6 → 1) Lyx, and R2 is
< example 6>
Taking natural lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of lutein is 3:1:1:10 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the absolute ethyl alcohol is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 75mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. And respectively connecting the prepared lecithin ginsenoside ethanol solution and deionized water to two channels of a multi-channel mixer by using a digital injection pump, wherein the introduction speed is preferably 6mL/min, the same deionized water is respectively introduced into the other two channels, the introduction speed is preferably 60mL/min, and the obtained nano micelle liquid flows out of an outlet and is received by a container.
Wherein the R1 group is-O-Glc (6 → 1) Xyl and R2 is
Example 7
Taking hydrogenated lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of the vitamin E acetate is 2:2:1:5 dissolving the components in absolute ethyl alcohol together, stirring for 1h at room temperature until the components are completely dissolved, wherein the total concentration of a prepared ethyl alcohol solution phase is 30mg/mL, and then respectively sucking the prepared ethyl alcohol solution phase and an anti-solvent deionized water into a syringe. And respectively connecting the prepared lecithin ginsenoside ethanol solution and deionized water to two channels of a multi-channel mixer by using a digital injection pump, wherein the introduction speed is preferably 8mL/min, the same deionized water is respectively introduced into the other two channels, the introduction speed is preferably 75mL/min, and the obtained nano micelle liquid flows out of an outlet and is received by a container.
Wherein the R1 group is-O-Glc (6 → 1) Ara, and R2 is
Example 8
Taking hydrogenated lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of the vitamin E acetate is 2:2:2:5 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the absolute ethyl alcohol is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 33mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. And (3) mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. And respectively connecting the prepared lecithin ethanol solution and deionized water to two channels of a multi-channel mixer through a digital injection pump, wherein the introduction speed is preferably 8mL/min, respectively introducing the same deionized water into the other two channels at the introduction speed of preferably 75mL/min, and allowing the obtained nano micelle liquid to flow out of an outlet and be received by a container.
Wherein the R1 group is-O-Glc (6 → 1) Ara, and R2 is
Second part, nanoliposome example
Example 9
Taking yolk lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: the mass ratio of acetyl dipeptide-1 cetyl ester is 10:1:2, dissolving the components in absolute ethyl alcohol together, stirring the mixture for 1 hour at room temperature until the components are completely dissolved, wherein the total concentration of a prepared ethanol solution phase is 91mg/mL, and then respectively sucking the prepared ethanol solution phase and anti-solvent deionized water into a syringe. Mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. The prepared lecithin ethanol solution and deionized water are respectively connected with two channels of a multi-channel mixer through a digital injection pump, the feeding speed is preferably 6mL/min, the same deionized water is respectively fed into the other two channels, the feeding speed is preferably 54mL/min, and the obtained nano liposome liquid flows out from an outlet and is received by a container.
Wherein R is 1 The group is-O-Glc, R 2 Is composed of
It should be noted that the core layer is not an essential component in the liposome preparation process.
Example 10
Taking yolk lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: the mass ratio of acetyl dipeptide-1 cetyl ester is 10:0.5:2, dissolving the two phases in absolute ethyl alcohol together, stirring the mixture for 1 hour at room temperature until the mixture is completely dissolved, wherein the total concentration of a prepared ethyl alcohol solution phase is 87.5mg/mL, and then respectively sucking the prepared ethyl alcohol solution phase and the anti-solvent deionized water into a syringe. Mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. The prepared lecithin ethanol solution and deionized water are respectively connected with two channels of a multi-channel mixer through a digital injection pump, the feeding speed is preferably 6mL/min, the same deionized water is respectively fed into the other two channels, the feeding speed is preferably 54mL/min, and the obtained nano liposome liquid flows out from an outlet and is received by a container.
Wherein R is 1 The group is-O-Glc, R 2 Is composed of
Example 11
Taking yolk lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: the mass ratio of acetyl dipeptide-1 cetyl ester is 10:2:2, dissolving the two phases in absolute ethyl alcohol together, stirring the mixture for 1 hour at room temperature until the mixture is completely dissolved, wherein the total concentration of a prepared ethyl alcohol solution phase is 98mg/mL, and then respectively sucking the prepared ethyl alcohol solution phase and an anti-solvent deionized water into a syringe. Mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. And respectively connecting the prepared lecithin ethanol solution and deionized water to two channels of a multi-channel mixer by a digital injection pump, wherein the feeding speed is preferably 6mL/min, respectively feeding the same deionized water into the other two channels, the feeding speed is preferably 54mL/min, and the obtained nanoliposome liquid flows out of an outlet and is received by a container.
Wherein R is 1 The group is-O-Glc, R 2 Is composed of
R 3 Is OH.
Example 11-1
Taking egg yolk lecithin: a triol-type rare ginseng secondary glycoside represented by a general formula I: the mass ratio of acetyl dipeptide-1 cetyl ester is 10:0.1:0.1 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the absolute ethyl alcohol is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 98mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. Mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. The prepared lecithin ethanol solution and deionized water are respectively connected with two channels of a multi-channel mixer through a digital injection pump, the feeding speed is preferably 6mL/min, the same deionized water is respectively fed into the other two channels, the feeding speed is preferably 54mL/min, and the obtained nano liposome liquid flows out from an outlet and is received by a container.
Wherein R is 1 The group is-O-Glc, R 2 Is composed of
R 3 Is OH.
Example 11-2
Taking yolk lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: the mass ratio of acetyl dipeptide-1 cetyl ester is 10:0.1:1 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the solution is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 98mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. Mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. The prepared lecithin ethanol solution and deionized water are respectively connected with two channels of a multi-channel mixer through a digital injection pump, the feeding speed is preferably 6mL/min, the same deionized water is respectively fed into the other two channels, the feeding speed is preferably 54mL/min, and the obtained nano liposome liquid flows out from an outlet and is received by a container.
Wherein R is 1 The group is-O-Glc, R 2 Is composed of
R 3 Is OH.
Examples 11 to 3
Taking yolk lecithin: a triol-type rare ginseng secondary glycoside represented by a general formula I: the mass ratio of acetyl dipeptide-1 cetyl ester is 10:0.1:10 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the absolute ethyl alcohol is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 98mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. Mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. And respectively connecting the prepared lecithin ethanol solution and deionized water to two channels of a multi-channel mixer by a digital injection pump, wherein the feeding speed is preferably 6mL/min, respectively feeding the same deionized water into the other two channels, the feeding speed is preferably 54mL/min, and the obtained nanoliposome liquid flows out of an outlet and is received by a container.
Wherein R is 1 The group is-O-Glc, R 2 Is composed of
R 3 Is OH.
Examples 11 to 4
Taking yolk lecithin: a triol-type rare ginseng secondary glycoside represented by a general formula I: the mass ratio of acetyl dipeptide-1 cetyl ester is 10:1:0.1 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the absolute ethyl alcohol is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 98mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. Mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. The prepared lecithin ethanol solution and deionized water are respectively connected with two channels of a multi-channel mixer through a digital injection pump, the feeding speed is preferably 6mL/min, the same deionized water is respectively fed into the other two channels, the feeding speed is preferably 54mL/min, and the obtained nano liposome liquid flows out from an outlet and is received by a container.
Wherein R is 1 The group is-O-Glc, R 2 Is composed of
R 3 Is OH.
Examples 11 to 5
Taking egg yolk lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: the mass ratio of acetyl dipeptide-1 cetyl ester is 10:1:10 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the absolute ethyl alcohol is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 98mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. Mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. And respectively connecting the prepared lecithin ethanol solution and deionized water to two channels of a multi-channel mixer by a digital injection pump, wherein the feeding speed is preferably 6mL/min, respectively feeding the same deionized water into the other two channels, the feeding speed is preferably 54mL/min, and the obtained nanoliposome liquid flows out of an outlet and is received by a container.
Wherein R is 1 The group is-O-Glc, R 2 Is composed of
R 3 Is OH.
Examples 11 to 6
Taking egg yolk lecithin: a triol-type rare ginseng secondary glycoside represented by a general formula I: the mass ratio of acetyl dipeptide-1 cetyl ester is 10:10:0.1 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the absolute ethyl alcohol is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 98mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. Mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. And respectively connecting the prepared lecithin ethanol solution and deionized water to two channels of a multi-channel mixer by a digital injection pump, wherein the feeding speed is preferably 6mL/min, respectively feeding the same deionized water into the other two channels, the feeding speed is preferably 54mL/min, and the obtained nanoliposome liquid flows out of an outlet and is received by a container.
Wherein R is 1 The group is-O-Glc, R 2 Is composed of
R 3 Is OH.
Examples 11 to 7
Taking yolk lecithin: a triol-type rare ginseng secondary glycoside represented by a general formula I: the mass ratio of acetyl dipeptide-1 cetyl ester is 10:10:10 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the absolute ethyl alcohol is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 98mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. Mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. And respectively connecting the prepared lecithin ethanol solution and deionized water to two channels of a multi-channel mixer by a digital injection pump, wherein the feeding speed is preferably 6mL/min, respectively feeding the same deionized water into the other two channels, the feeding speed is preferably 54mL/min, and the obtained nanoliposome liquid flows out of an outlet and is received by a container.
Wherein R is 1 The group is-O-Glc, R 2 Is composed of
R 3 Is OH.
Examples 11 to 8
In general, as in example 11, except that acetyl dipeptide-1 cetyl ester was replaced with the same amount of palmitoyl tetrapeptide-7.
Examples 11-1 to 11-8 examine the formation of nanoliposomes with shell materials of different ratios. Experiments prove that the preparation method can obtain the nano-liposome with different shell ratios by adjusting experiment parameters.
Third, comparative example
Comparative example 1
With reference to example 9 and < example 14> in CN2020116376570, 200mg of acetyl dipeptide-1 cetyl ester are dissolved in 20% by mass aqueous acetic acid; dissolving 1g of egg yolk lecithin and 100mg of diol type ginsenoside secondary glycoside material shown in general formula I in ethanol solution; mixing the two solutions, and placing the mixture in a round-bottom flask; distilling under reduced pressure to remove organic reagent and acetic acid water solution in the bottle to form a uniform lipid film in the bottle; removing excessive acid components and water by using nitrogen to form a dry film; adding 14.3mL of water, and eluting the film in the bottle; homogenizing with a high-pressure homogenizer (400bar, 2min) to obtain liposome (egg yolk lecithin: diol type rare ginseng secondary glycoside: acetyl dipeptide-1 cetyl ester mass ratio 10.
Wherein, R1 is-O-Glc, R 2 Is composed of
It should be noted that: claim 9 in CN2020116376570 states: when the active substance in the cosmetic is one of acetyl dipeptide-1 cetyl esters, palmitoyl tetrapeptide-7 and palmitoyl pentapeptide-4, the active substance is dissolved in an acetic acid aqueous solution.
In contrast to example 9, the difference is that CN2020116376570 acetyl dipeptide-1 cetyl ester is present as an active ingredient rather than as a shell, which must first be dissolved in aqueous acetic acid as the shell active ingredient.
In this case, if acetyl dipeptide-1 cetyl ester is to be present as a shell, it is necessary to blend the three and then prepare them by means of a multi-channel mixer.
Comparative example 2
Referring to example 9, egg yolk lecithin was taken: a diol-type rare ginseng secondary glycoside represented by formula 1 as represented by CN 2020116376570: the mass ratio of acetyl dipeptide-1 cetyl ester is 10:1:2, dissolving the two phases together in absolute ethyl alcohol, preparing an ethanol solution phase with the total concentration of 91mg/mL, stirring for 3 hours at room temperature, and carrying out ultrasonic oscillation to obtain a completely dissolved solution. As shown in fig. 3, the solution precipitates and phase separates, and nanoliposomes cannot be prepared continuously.
The R1 group is-O-Glc and R2 is
Through the experiments of this comparative example we can conclude that: the diol-type rare ginseng secondary glycosides do not support the stable presence of liposomes containing the shell material of acetyl dipeptide-1 cetyl ester.
Comparative example 3
Taking yolk lecithin: the mass ratio of the triol type rare ginseng secondary glycoside shown as the general formula I is 10:1 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the solution is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 77mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. Mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. And respectively connecting the prepared lecithin ethanol solution and deionized water to two channels of a multi-channel mixer by a digital injection pump, wherein the feeding speed is preferably 6mL/min, respectively feeding the same deionized water into the other two channels, the feeding speed is preferably 54mL/min, and the obtained nanoliposome liquid flows out of an outlet and is received by a container.
Wherein R is 1 The group is-O-Glc, R 2 Is composed of
Comparative example 4
Referring to example 8, hydrogenated lecithin was taken: triol-type rare ginseng secondary glycoside represented by general formula I: the mass ratio of the vitamin E acetate is 2:2:5 are dissolved in absolute ethyl alcohol together, stirred for 1h at room temperature until the absolute ethyl alcohol is completely dissolved, the total concentration of the prepared ethyl alcohol solution phase is 27mg/mL, and then the prepared ethyl alcohol solution phase and the anti-solvent deionized water are respectively sucked into a syringe. And (3) mixing the prepared lecithin ginsenoside ethanol solution and deionized water by a digital injection pump. And respectively connecting the prepared lecithin ethanol solution and deionized water to two channels of a multi-channel mixer through a digital injection pump, wherein the feeding speed is preferably 8mL/min, respectively feeding the same deionized water into the other two channels, the feeding speed is preferably 75mL/min, and the obtained nano micelle liquid flows out of an outlet and is received by a container.
Wherein R is 1 The group is-O-Glc (6 → 1) Ara, R 2 Is composed of
Comparative example 5
Taking hydrogenated lecithin: triol-type rare ginseng secondary glycoside represented by general formula I: acetyl dipeptide-1 cetyl ester: the mass ratio of the vitamin E acetate is 2:2:1:5 dissolving in absolute ethyl alcohol together, preparing an ethanol solution phase with the total concentration of 30mg/mL, stirring for 3hr at room temperature, and ultrasonically shaking to obtain a completely dissolved solution. As shown in fig. 4, the solution precipitates the phase separation and the nanomicelle preparation cannot be continued.
The R1 group is-O-Glc and R2 is
This comparative example can demonstrate that: the stable nano micelle containing the shell material can not be obtained by adopting a common ultrasonic mode.
Fifth, performance test
5.1 comparison of Performance advantages as Liposome membranes
5.1.1 nanometer liposome morphology, particle size, monodispersity and shell charge controllability
As shown in Table 1, the liposome comparative example 1 prepared by the high pressure homogenization method described in < example 14> in CN2020116376570 using the same concentration (concentration and ratio of phospholipid, secondary ginseng glycoside and acetyl dipeptide-1 cetyl ester) has a surface charge Zeta positive potential of 12.4mV much lower than the Zeta positive potential of 41mV in example 9 prepared by the present invention. It is demonstrated that the method described in < example 14> in CN2020116376570 does not make most of acetyl dipeptide-1 cetyl ester with positive charge enter the shell layer, and the size of the positive and negative charges on the surface of the shell layer of the nano material can not be freely adjusted by the concentration of acetyl dipeptide-1.
Referring to the multi-channel mixing preparation method of example 9 of the present invention, using the same concentrations and ratios of phospholipids, diol-type secondary ginsenosides and acetyl dipeptide-1 cetyl ester as in comparative example 1, as shown in fig. 2, when acetyl dipeptide-1 cetyl ester is contained, the diol-type ginsenosides (comparative example 2) cannot form a stable and uniform alcohol phase solution with phospholipids and acetyl dipeptide-1 cetyl ester (right in fig. 2), and significant precipitation occurs, so that stable, positively charged nanoliposomes cannot be further prepared.
Compared with the comparative example 2, the triol-type ginseng secondary glycoside, phospholipid and acetyl dipeptide-1 disclosed by the invention show very good compatibility, and as shown in figure 2, the three substances can form stable and homogeneous ethanol phase solution (figure 2 left), and further, the nano liposome with uniform particle size and high positive charges on the surface can be obtained by the multichannel mixing preparation method disclosed by the invention. As shown in FIG. 3, the imaging analysis of the aqueous nanoliposome solution of example 9 was performed by using a cryo-electron microscope (Talos F200C 200 kV), and first using PELCO easygow TM Glow Discharge hydrophilizes copper mesh (Ted Pella inc., u.s.a.). Then using Vitrobot FEI TM Low temperature tem samples were prepared with the following parameters: the block times are 4.5s, the block force is 3, the wait time is 3.0s, the bolt total is 1, and the drain time is 0s. The sample liquid is first frozen in liquid ethane and then cooled in liquid nitrogen. Then transferred to a cryoelectron microscope for imaging using a Gatan 698cryo-transfer holder. The imaging result of example 9 is shown in fig. 3, which shows the rare ginseng secondary glycoside nanoliposome structure.
Furthermore, as shown in the examples 9-11 of Table 1, by adjusting the concentration of acetyl dipeptide-1 cetyl esters, stable, positively charged nanoliposomes with adjustable surface charge number can be obtained by the membrane material complex and multi-channel mixing preparation method.
TABLE 1
5.1.2 irritation and anti-allergic effects of skin patch containing nanometer liposome
The skin irritation of the human body was tested by comparing 3% of the aqueous solution of example 9 and 3% of comparative example 1 using a 48-hour human patch test, and 30 volunteers, all 20-40 years old. The patch was removed 48 hours after application and the skin condition was observed. The results showed that comparative example 1 was highly irritating, positive in the patch test, and 10-15 volunteers showed slight redness and tingling sensation. In example 9 of the present invention, the stimulation was small, none of the 30 cases was positive, and the anti-allergy and soothing effects were exhibited. The results show that the liposome membrane material prepared by the liposome, namely the acetyl dipeptide-1 cetyl ester, the triol type ginseng secondary glycoside and the lecithin, has better skin mildness and lower irritation.
The soothing anti-allergy effect on irritants of the samples of example 9 and comparative example 3 with the addition of 5ul were tested using SLS stimulation model at low concentration 2% and high concentration 10%. 3 volunteers were tested, all aged 20-25 years. The front ends of the arms of three volunteers were washed with clear water and the residual water was gently wiped off. The corresponding example sample was lightly smeared with a cotton swab at the designated numbered position (blank and pure stimulus positions were lightly smeared with equal amounts of deionized water) and allowed to wait for 5 minutes. Add 15. Mu.L of SLS solution (2% or 10%) and 5. Mu.L of the solution of the example specified in the corresponding position of the patch tester, and place the prepared patch in the corresponding numbered arm position and seal it. The reaction was allowed to proceed under occlusive conditions for up to 24 hours, and the skin response was observed and evaluated after removal of the patch. Since the test stimulus SLS did not produce a significant erythematous or scaly response to the subject's skin, the skin was organoleptically evaluated and scored for stinging after the patch was removed (0 for completely no stinging, 5 for strong stinging). The scores of the three evaluators were averaged and recorded in table 2. The results in Table 2 show that compared with the comparative example 3 of triol anionic liposome without acetyl dipeptide-1 cetyl ester, the cationic liposome based on triol secondary ginseng glycoside, lecithin and acetyl dipeptide-1 cetyl ester, which is disclosed by the invention, in example 9, the stimulation of SLS at high and low concentrations can be better reduced, and the effect of improving the soothing and anti-allergy effects is achieved.
TABLE 2
5.1.3 stability of nanoliposomes
The nanoliposome solutions prepared in comparative example 1 and example 9 were taken for long-term high temperature stability comparison. And (3) diluting the nanoliposome solution by 250 times, introducing the nanoliposome solution into a Nanosight NS300 particle tracking analyzer, and determining the particle size and Zeta charge of the nanoliposome solution to be detected. The examples were stored in a high-temperature 48 ℃ incubator for 4 weeks, and the particle size and Zeta potential of the nanoliposomes shown in Table 2 were followed with time. The measurement results are shown in Table 3.
TABLE 3
As can be seen from table 2, in example 9, nanoliposomes obtained using the triol-type secondary ginseng glycoside, lecithin, and acetyl dipeptide-1 cetyl ester of the present invention have small particle size (all below 100 nm), good monodispersity (PDI < 0.3), and surface charge controllability, and are very stable in that both the particle size and the surface potential do not change much with time under high temperature storage.
The diol-type ginsenoside secondary glycoside nanoliposome of comparative example 2 showed an unstable state due to the aggregation phenomenon, in which the particle size increased with time and the surface charge decreased with time.
5.1.4 skin adsorption Properties of nanoliposomes
As shown in FIG. 4, the skin-friendly advantages of using acetyl dipeptide-1 cetyl ester for the shell layer (example 9 containing acetyl dipeptide-1 cetyl ester, comparative example 4 not) were compared, and equilibrium adsorption amounts on the interface of simulated skin were determined for the same concentration of examples and comparative examples using a dissipative quartz crystal microbalance. The higher the adsorption quantity, the stronger the affinity of the sample and the skin, and the better adsorption effect. As can be seen from the results in FIG. 4, the adsorption performance of example 9 of the present invention (1070 ng/cm) 2 ) Is far superior to that of comparative example 3 (320 ng/cm) 2 ) Example 9 had a much higher amount of adsorption at the skin interface than comparative example 3.
Through the comparison, it can be found that: in order to form a uniform and stable nanoliposome solution with positive charges, and simultaneously have low skin irritation, a soothing and anti-allergy effect and excellent skin adsorption performance, acetyl dipeptide-1 cetyl ester with a positive point charge tendency is adopted to be matched with phospholipid, and triol type ginsenoside secondary glycoside with better compatibility is necessary and none of the three components is necessary.
5.2 comparison of Performance advantages as Nano-micelle Membrane Material
5.2.1. Nano micelle appearance, particle size, monodispersity and shell charge controllability
As shown in Table 4, comparative example 4, which used the same concentrations (same concentrations and ratios of phospholipid, ginseng secondary glycoside and tocopherol acetate), did not contain acetyl dipeptide-1 cetyl ester and had a surface charge of Zeta negative-38.2 mV, and example 8, prepared according to the present invention, had a Zeta potential of 72.3mV, which is a positive charge. And further comparing example 7 with example 8 shows that the positive charge on the surface of the nano-micelle can be regulated and controlled by adjusting the concentration of acetyl dipeptide-1 cetyl ester, and the fact that the acetyl dipeptide-1 cetyl ester with positive charge enters the shell layer is proved again, and the positive charge on the surface of the shell layer of the nano-micelle can be freely regulated by the concentration of the acetyl dipeptide-1.
Comparative example 5 using the same concentrations and ratios of phospholipid, diol-type secondary ginseng glycoside, tocopherol acetate and acetyl dipeptide-1 cetyl ester as in example 8, as shown in fig. 5, in the case of acetyl dipeptide-1 cetyl ester, diol-type ginsenoside (comparative example 2) could not form a stable and uniform alcohol phase solution with phospholipid, tocopherol acetate and acetyl dipeptide-1 cetyl ester (fig. 5 right), resulting in significant precipitation, and thus stable, positively charged nanomicelles could not be further prepared. In contrast, example 8 (triol-type secondary ginseng glycoside, tocopherol acetate, phospholipid and acetyl dipeptide-1) described in the present invention shows very good compatibility compared to comparative example 5, as shown in fig. 5 (left), the above three substances can form a stable and homogeneous ethanol phase solution, and further, through the multichannel mixing preparation method described in the present invention, a nano micelle having a uniform particle size and a high positive charge on the surface can be obtained.
Imaging analysis of aqueous Nanmicellar solution Using cryoelectron microscope (Talos F200C 200 kV), PELCO easiGlow was first used TM Glow Discharge hydrophilizes copper mesh (Ted Pella inc., u.s.a.). Then using Vitrobot FEI TM Low temperature tem samples were prepared with the following parameters: the block time is 4.5s, the block force is 3, the wait time is 3.0s, the bolt total is 1, and the drain time is 0s. The sample liquid is quickly frozen in liquid ethane and then cooled in liquid nitrogen. Then transferred to a cryo-electron microscope for imaging using a Gatan 698cryo-transfer holder. The imaging result of example 8 is shown in fig. 6, and the rare ginseng secondary glycoside nano-micelle structure is presented.
TABLE 4
5.2.2 comparison of stability of Nanomicelle solution
The stability of the nano-micelle solutions prepared in comparative example 4, comparative example 5 and example 8 was compared. And (3) diluting the nano-micelle solution by 250 times, introducing the diluted nano-micelle solution into a Nanosight NS300 particle tracking analyzer, and determining the particle size of the nano-micelle solution to be detected. The examples were stored in a high temperature 48 ℃ incubator for 4 weeks, and the change of the particle size of the obtained nano-micelle containing ginsenoside secondary glycosides or ginsenoside primary glycosides with time was followed.
The measurement results are shown in Table 5.
TABLE 5
As can be seen from table 5, in example 8, the nanomicelle particle size obtained using the triol-type secondary ginseng glycoside, lecithin and acetyl dipeptide-1 cetyl ester of the present invention is very small (100 nm or less), has good monodispersity (PDI < 0.2), and has no significant change in particle size and Zeta potential with time (< 15%) when stored at high temperature.
In contrast, in comparative example 4, the triol-type ginsenoside secondary glycoside nanomicelles without acetyl dipeptide-1 cetyl ester were relatively stable, but the particle size increased with time to a greater extent than in example 8 (about 40%), indicating that comparative example 4 may have partial aggregation or fusion phenomena.
Comparative example 5, in the case of using the diol-type secondary ginseng glycoside, a good micellar solution could not be prepared under most conditions, and stability monitoring could not be performed.
Through the comparison, it can be found that: in order to form a uniform and stable nano-micelle solution with positive charges, acetyl dipeptide-1 cetyl ester with positive point charge tendency is adopted to be matched with phospholipid, and triol type ginsenoside secondary glycoside with better compatibility is necessary and none of the three is available.
6.2.3 encapsulation efficiency of hydrophobic substance in Nano micelle
For example, in example 8, since the hydrophobic substance is insoluble in water and hardly dissolved in the final aqueous-alcoholic (5% v/v ethanol) solution, the solution prepared was not found to precipitate or separate oil of vitamin E acetate, which is a hydrophobic active substance, even after long-term storage at high temperature, and the particle size and surface potential were stable, it was found that the nano-micelle based on rare ginseng secondary glycoside prepared according to the present invention can encapsulate the hydrophobic active substance at 100%.
5.2.4 skin adsorption Effect test of Nano-micelles
As shown in FIG. 7, comparing the skin-friendly advantages of nanomicelles using acetyl dipeptide-1 cetyl ester for the shell layer (example 8 containing acetyl dipeptide-1 cetyl ester and comparative example 4 not containing acetyl dipeptide-1 cetyl ester), the equilibrium adsorption amounts on the interface of the simulated skin of the same concentration of the examples and comparative examples were measured using a dissipative quartz crystal microbalance. The higher the adsorption quantity, the stronger the affinity of the sample and the skin, and the better adsorption effect. As can be seen from the results in FIG. 4, the adsorption performance of the nano-micelle example 8 (380 ng/cm) is illustrated by the invention 2 ) Is superior to that of comparative example 4 (330 ng/cm) 2 ) Example 8 has a higher adsorption at the skin interface than comparative example 4.
5.2.5 evaluation of anti-allergic and soothing Effect of Nano-micelle
The soothing anti-allergy effect of the comparative addition of 5ul of the samples of example 8 and comparative example 4 on the irritants was tested using SLS stimulation models at low concentration 2% and high concentration 10%. 3 volunteers were tested, all aged 20-25 years. The front ends of the arms of three volunteers were washed with clear water and the residual water was gently wiped off. The corresponding example sample was lightly smeared with a cotton swab at the designated numbered position (blank and pure stimulus positions were lightly smeared with equal amounts of deionized water) and allowed to wait for 5 minutes. mu.L of SLS solution (2% or 10%) and 5. Mu.L of the solution of the specified example were added to the corresponding sites of the plaque tester, and the prepared plaques were placed on the corresponding numbered arm sites and sealed. The reaction was allowed to proceed under occlusive conditions for up to 24 hours, and the skin response was observed and evaluated after removal of the patch. Since the test stimulus SLS did not produce a significant erythematous or scaly response to the subject's skin, the skin was organoleptically evaluated and scored for stinging after the patch was removed (0 for completely no stinging, 5 for strong stinging). The scores of the three evaluators were averaged and recorded in table 2. The results in table 6 show that compared with the triol-type anionic nanomicelle comparative example 4 without acetyl dipeptide-1 cetyl ester, the cation nanomicelle example 8 based on triol-type ginseng secondary glycoside, lecithin and acetyl dipeptide-1 cetyl ester, which is disclosed by the invention, can better reduce the stimulation of SLS at high and low concentrations and has the effect of improving the effects of relieving and resisting allergy. Further, by comparing example 7 with example 8, it was shown that the anti-allergy relieving effect can be improved by increasing acetyl dipeptide-1 cetyl ester used for the shell layer.
The test results can be found in Table 6 below
TABLE 6 evaluation results of anti-allergy relief Effect of different nanomicelles
| Sample (I) | Description of the applied sample | Scoring | |
| Blank | Blank space | 0 | |
| 2％SLS | Low concentration of irritants | 5 | |
| 2% SLS + comparative example 4 | Low-concentration stimulant + triol type anion nano micelle | 4 | |
| 2% SLS + comparative example 7 | Low-concentration stimulant + triol type cation nano micelle | 1 | |
| 2% SLS + example 8 | Low-concentration stimulant + triol type |
0 |
5.2.6 Effect of Nanoglemons on inhibition of bacterial colonization
Bacterial qualification refers to the property of adding a substance that can be utilized as a nutrient source for a particular bacterium. The composition has flexibility on putrefying bacteria and can accelerate putrefying and deterioration; harmful bacteria, which are irritating to the skin, exhibit financing properties and induce skin irritation and other related skin diseases. Qualitative performance comparison of harmful flora was performed on the cationic triol-type ginseng nanomicelles and the anionic triol-type ginseng nanomicelles described in example 8 and comparative example 4. Escherichia coli or Staphylococcus aureus (S.aureus) was added to the semi-solid medium, and cultured under anaerobic conditions at 37 ℃ for 24 hours. After 24 hours of culture, the optical concentration (OD value 600) was measured. The higher the OD value, the more serious the material acts as a nutrient for the harmful flora, leading to hyperproliferation (funding).
The test results can be found in Table 7.
The results of the experiments in table 7 show that the cationic property brought by acetyl dipeptide-1 cetyl ester enables example 8, which is illustrated in the present invention, to effectively reduce the proliferation of harmful bacteria by conventional membrane materials and core materials (such as lecithin, vitamin E, and oil) compared to comparative example 4 under the same conditions of other materials, thereby avoiding the negative effects of bacterial qualification.
TABLE 7 evaluation results of bacterial colonization inhibitory effect of different nanomicelles
In summary, we can conclude the following by the above tests:
1. the triol type ginsenoside secondary glycoside can improve the system compatibility of micelles or liposomes when phospholipid and acetyl dipeptide-1 cetyl ester are used as blended membrane materials, but the diol type ginsenoside secondary glycoside has poor system compatibility to the micelles of the phospholipid and the acetyl dipeptide-1 cetyl ester.
2. The storage stability, especially the high-temperature storage stability of the micelle formed by acetyl dipeptide-1 cetyl ester, phospholipid and triol type ginsenoside secondary glycoside is obviously superior to that of a comparative example.
3. Acetyl dipeptide-1 cetyl ester can change the surface charging performance of micelle, and change original negative charge ginseng lecithin liposome and micelle into stable positive charge ginseng liposome and micelle, so that the adsorption performance or skin-friendly effect of the liposome and the micelle with skin is better
4. The acetyl dipeptide-1 has the functions of relieving and resisting allergy, and compared with the comparative proportion, the nano liposome or micelle has better anti-allergy relieving effect.
5. The acetyl dipeptide-1 has a cationic bacteriostatic action, and compared with the comparative ratio, the qualification effect of the nano liposome or micelle on inhibiting harmful bacteria is better.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Claims (4)
1. A nano-carrier is characterized in that the nano-carrier is a micelle or a liposome, and if the nano-carrier is the liposome, a core layer is a hydrophobic substance or a hydrophilic substance; if the nano carrier is micelle, the core layer is hydrophobic substance;
the micelle or liposome is prepared by the following method: mixing phospholipid, acetyl dipeptide-1 cetyl ester and triol type ginsenoside secondary glycoside shown as a general formula I in an alcohol organic solvent, and stirring at room temperature until the mixture is completely dissolved to form a good solvent solution; introducing a good solvent solution into one or more channels of the multi-channel mixer, and introducing an anti-solvent into the other channels, so that the good solvent solution and the anti-solvent are self-assembled into a nano liposome or micelle solution based on the rare ginseng secondary glycoside in a mixing cavity of the multi-channel mixer; the anti-solvent is deionized water;
the triol-type ginsenoside secondary glycoside is shown as the following general formula I:
general formula I
R 1 One selected from the following groups:
-O-Glc、-O-Xyl、-O-Rha、-O-Ara、-O-Lyx、-O-Glc(2→1)Glc、-O-Glc(6→1)Glc、-O-Glc(2→1)Xyl、-O-Glc(6→1)Xyl、-O-Glc(2→1)Rha、-O-Glc(6→1)Rha、-O-Glc(2→1)Ara、-O-Glc(6→1)Ara、-O-Glc(2→1)Lyx、-O-Glc(6→1)Lyx、-O-Glc(2→1)Glc(2→1)Glc、-O-Glc(2→1)Glc(6→1)Glc、-O-Glc(6→1)Glc(2→1)Glc、-O-Glc(6→1)Glc(6→1)Glc、-O-Glc(2→1)Glc(2→1)Xyl、-O-Glc(2→1)Glc(6→1) Xyl、-O-Glc(6→1)Glc(2→1) Xyl、-O-Glc(6→1)Glc(6→1) Xyl、-O-Glc(2→1)Glc(2→1)Rha、-O-Glc(2→1)Glc(6→1) Rha、-O-Glc(6→1)Glc(2→1) Rha、-O-Glc(6→1)Glc(6→1) Rha、-O-Glc(2→1)Glc(2→1)Ara、-O-Glc(2→1)Glc(6→1) Ara、-O-Glc(6→1)Glc(2→1) Ara、-O-Glc(6→1)Glc(6→1) Ara、-O-Glc(2→1)Glc(2→1)Lyx、-O-Glc(2→1)Glc(6→1) Lyx、-O-Glc(6→1)Glc(2→1) Lyx、-O-Glc(6→1)Glc(6→1) Lyx；
R 2 one selected from the following groups:
if the nano-carrier is micelle, the weight ratio of the phospholipid, the acetyl dipeptide-1 cetyl ester and the triol type ginsenoside secondary glycoside is 1: (0.3-6): (0.3-2);
if the nano-carrier is liposome, the weight ratio of the phospholipid, the acetyl dipeptide-1 cetyl alcohol ester and the panaxatriol type ginsenoside secondary glycoside is 10: (1-2): (0.5-1).
2. The nanocarrier of claim 1, wherein the phospholipid is one of soy lecithin, egg lecithin, hydrogenated lecithin, and cephalin.
3. The nanocarrier of claim 1 or 2, wherein the nanocarrier has a particle size of from 10nm to 500nm.
4. Use of the nanocarrier of any of claims 1-3 for cosmetics, food.
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