CN110859782A - Multifunctional transdermal absorption enhancer and preparation method and application thereof - Google Patents
Multifunctional transdermal absorption enhancer and preparation method and application thereof Download PDFInfo
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- CN110859782A CN110859782A CN201911393809.4A CN201911393809A CN110859782A CN 110859782 A CN110859782 A CN 110859782A CN 201911393809 A CN201911393809 A CN 201911393809A CN 110859782 A CN110859782 A CN 110859782A
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- China
- Prior art keywords
- multifunctional
- absorption enhancer
- reaction
- chitosan
- transdermal absorption
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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Abstract
The invention discloses a multifunctional transdermal absorption enhancer, a preparation method and application thereof, wherein the multifunctional transdermal absorption enhancer is a compound shown as a formula (I). The preparation method comprises the following steps: firstly, the pegylated chitosan reacts with the vitamin E to prepare chitosan linked with the vitamin E, and then the chitosan is added to react with hyaluronic acid to prepare the multifunctional transdermal absorption enhancer. The multifunctional transdermal absorption enhancer can obviously improve the water solubility of the difficult-to-dissolve nutrient in the cosmetics, has good effect of promoting transdermal absorption, has the advantages of low cost, good effect of promoting transdermal absorption, good moisturizing effect, good biocompatibility, biodegradability and the like, is a novel transdermal absorption enhancer, can be applied to the preparation of cosmetics and transdermal administration preparations, and has high use value and good application prospect. The preparation method has the advantages of simple process, convenient operation, easily obtained raw materials, low cost and the like, is suitable for large-scale preparation, and is beneficial to industrial application.
Description
Technical Field
The invention relates to a multifunctional transdermal absorption enhancer and a preparation method and application thereof.
Background
However, the skin care products are burdened by excessive nutrients which cannot be absorbed by the skin, which causes 'skin oxidation', but cannot play a role in delaying aging, and rather accelerates skin aging. Bacteria on the skin surface require a large amount of vitamins, proteins and biological cell nutrients during their growth and reproduction, which are the main components of nutritional cosmetics. If the nutrients of the cosmetic are not completely absorbed by the skin, he becomes a hotbed for the growth and propagation of parasitic bacteria, and the large amount of bacteria also causes skin infections. In addition, in the existing transdermal drug delivery preparation, macromolecular drugs and fat-soluble drugs are difficult to permeate into the skin, so that the related drugs cannot exert the due drug effects. It is thus clear that the development of a percutaneous absorption enhancer in a percutaneous preparation and a cosmetic is of great significance for the development of a percutaneous preparation and a cosmetic.
Currently, the common transdermal absorption enhancers can be divided into: (1) organic solvents: ethanol, propylene glycol, ethyl acetate, dimethyl sulfoxide, and dimethyl imide; (2) surfactants: cationic surfactants, anionic surfactants, nonionic surfactants; (3) laurocapram and its homologs; (4) organic acids, fatty acids: oleic acid, linoleic acid and lauryl alcohol; (5) cutin moisturizing and softening agent: urea, salicylic acid and pyrrolidones; (6) terpenes: menthol, camphor, limonene, and the like. In addition, amino acids, as well as some water-soluble proteins, phospholipids, etc., can also increase the dermal absorption of many drugs. However, the common transdermal absorption enhancers have the defects of irritation to skin after long-term use, toxicity to body organs after systemic absorption, difficult production and high cost. In addition, the existing transdermal enhancers have the following problems: the transdermal efficiency is low, and the absorption amount of the effective substances through pores is not more than 10%; toxic and harmful components exist, and the toxicity is strong; the structure is unstable and the moisture retention is poor. The above problems are not favorable for popularization and application of the transdermal enhancer. Therefore, the obtained multifunctional transdermal absorption enhancer which is low in cost, good in transdermal absorption promoting effect, good in moisturizing effect, good in biocompatibility and biodegradable has very important significance for improving the permeability of cosmetics and transdermal drug delivery preparations and promoting the wide application of the cosmetics and the transdermal drug delivery preparations.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a biodegradable multifunctional transdermal absorption enhancer with low cost, good effect of promoting transdermal absorption, good moisturizing effect and good biocompatibility as well as a preparation method and application thereof.
In order to solve the technical problems, the invention adopts the technical scheme that:
a multifunctional percutaneous absorption enhancer is a compound shown as a formula (I):
wherein in the formula (I), m is an integer of 0-20; x is an integer of 0-10, Y is an integer of 0-10, and X + Y is 3-12; z is an integer of 0 to 1000.
In the above multifunctional transdermal absorption enhancer, further improvement, the multifunctional transdermal absorption enhancer is nanoparticles; the average particle size of the multifunctional transdermal absorption enhancer is 50 nm-150 nm.
As a general technical concept, the present invention also provides a preparation method of the above multifunctional transdermal absorption enhancer, comprising the steps of:
s1, dissolving the pegylated chitosan in N, N-dimethylformamide, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride for activation, adding a vitamin E-containing N, N-dimethylformamide solution for reaction, dialyzing, and freeze-drying to obtain vitamin E linked chitosan;
s2, dissolving the chitosan linked with the vitamin E prepared in the step S1 in tetrahydrofuran, adding hyaluronic acid, 1, 6-diisocyanatohexane and dibutyltin laurate to react, dialyzing, and freeze-drying to obtain the multifunctional transdermal absorption enhancer.
In a further improvement of the above preparation method, in step S1, the preparation method of the pegylated chitosan comprises the following steps:
(1) dissolving chitosan in tetrahydrofuran, dropwise adding methanesulfonic acid chloride for reaction, removing tetrahydrofuran, adding methanesulfonic acid chloride, washing with water, drying, and removing chloroform to obtain a crude product A;
(2) dissolving the crude product A obtained in the step (1) in DMF, adding NaI for reaction, adding chloroform to terminate the reaction, washing with water, and performing suspended evaporation to obtain a crude product B;
(3) and (3) dissolving the crude product B obtained in the step (2) in DMF, adding sodium polyethylene glycol for reaction, adding water for terminating the reaction, dialyzing, and freeze-drying to obtain the pegylated chitosan.
In the preparation method of the pegylated chitosan, the mass ratio of the chitosan, the methanesulfonic acid chloride, the NaI and the polyethylene glycol sodium is 20: 4-8: 4-10: 7-12.
In the above preparation method, further improvement is provided, in the step (1), the reaction is carried out at 0 ℃; the reaction time is 6-24 h;
in the step (2), the reaction is carried out at 80 ℃; the reaction time is 12-48 h;
in the step (3), the reaction time is 6-24 h.
In the above preparation method, further improvement is provided, in the step S1, the mass ratio of the pegylated chitosan, vitamin E in the vitamin E-containing N, N-dimethylformamide solution, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is 5: 2 to 10: 0.5 to 5; the ratio of the pegylated chitosan to the N, N-dimethylformamide is 2 g: 2 mL-10 mL;
in the step S2, the mass ratio of the vitamin E-linked chitosan to hyaluronic acid to the 1, 6-diisocyanatohexane to the dibutyltin laurate is 5: 0.01-0.5: 0.1-2: 0.001-0.1; the ratio of the vitamin E-linked chitosan to tetrahydrofuran is 2 g: 2 mL-10 mL.
In a further improvement of the above preparation method, in step S1, the activation is performed under ice bath conditions; the activation temperature is 0-4 ℃; the activation time is 0.2 h-8 h; the reaction is carried out under stirring conditions; the reaction time is 12-36 h;
in the step S2, the reaction is carried out under a protective atmosphere; the protective atmosphere is nitrogen or argon; the reaction temperature is 60-80 ℃; the reaction time is 6-48 h.
As a general technical concept, the invention also provides an application of the multifunctional percutaneous absorption enhancer or the multifunctional percutaneous absorption enhancer prepared by the preparation method as a water-soluble auxiliary agent in preparing cosmetics.
As a general technical concept, the invention also provides an application of the multifunctional transdermal absorption enhancer or the multifunctional transdermal absorption enhancer prepared by the preparation method as a penetration enhancer in preparing a transdermal drug delivery preparation.
In the present invention, the process for preparing the multifunctional percutaneous absorption enhancer (compound represented by formula (I)) is as follows:
the compound shown in the formula (II) is chitosan, the compound shown in the formula (III) is pegylated chitosan, and the compound shown in the formula (IV) is chitosan linked with vitamin E; n is an integer of 3-12; m is an integer of 0-20; x is an integer of 0-10, Y is an integer of 0-10, and X + Y is 3-12; z is an integer of 0 to 1000.
Compared with the prior art, the invention has the advantages that:
(1) the invention provides a multifunctional transdermal absorption enhancer, which takes vitamin E as an adhesive group and a skin penetrating agent, chitosan as a functional group for moisturizing, conditioning and bacteriostasis and an opening agent of skin keratinocytes, and hyaluronic acid as a functional group for moisturizing. On one hand, the multifunctional transdermal absorption enhancer has a hydrophilic and hydrophobic structure, and fat-soluble substances and chitosan-vitamin E-sodium hyaluronate can form nano particles through hydrophilic and hydrophobic effects to promote the absorption of the fat-soluble substances; on the other hand, as the nano-particles have hydrophilic and hydrophobic structures, the nano-particles can be assembled into nano-structures in aqueous solution, and can enter the interior of the skin through gaps in the stratum corneum, so that the transdermal efficiency is increased; finally, because the specific cationic property of chitosan can be combined with negative charge effective substances such as protein, polypeptide and the like to form a compound, thereby promoting the effective substances such as protein, polypeptide and the like to enter the skin to play a role, the multifunctional transdermal absorption enhancer not only can obviously improve the water solubility of the difficult-to-dissolve nutrient in the cosmetics, but also has good effect of promoting transdermal absorption, has the advantages of low cost, good effect of promoting transdermal absorption, good moisturizing effect, good biocompatibility, biodegradability and the like, is a novel transdermal absorption enhancer, can be applied to the preparation of cosmetics and transdermal drug delivery preparations, and has high use value and good application prospect.
(2) The invention provides a preparation method of a multifunctional transdermal absorption enhancer, which comprises the steps of firstly mixing pegylated chitosan and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride for activation, increasing the reaction activity of the chitosan through activation to enable the chitosan to be more easily combined with vitamin E, adding N, N-dimethylformamide solution containing vitamin E for reaction, enabling phenolic hydroxyl groups on the vitamin E to be linked with hydroxyl groups on polyethylene glycol on the chitosan to form chitosan linked with vitamin E, then dissolving the chitosan linked with vitamin E in tetrahydrofuran, adding hyaluronic acid, 1, 6-diisocynate hexane and dibutyltin laurate (the effect of the 1, 6-diisocynate hexane and the dibutyltin laurate is to enable the hyaluronic acid to be more easily combined with the chitosan linked with the vitamin E for reaction), the chitosan and hyaluronic acid are polymerized to form the novel multifunctional transdermal absorption enhancer. The preparation method has the advantages of simple process, convenient operation, easily obtained raw materials, low cost and the like, is suitable for large-scale preparation, and is beneficial to industrial application.
Drawings
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, 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.
FIG. 1 is an infrared spectrum of the multifunctional skin penetration enhancer (CS-VE-HA) and chitosan monomer (CS) prepared in example 1 of the present invention.
FIG. 2 is a dynamic light scattering diagram of the multifunctional transdermal absorption enhancer (CS-VE-HA) and the chitosan monomer (CS) prepared in example 1 of the present invention.
FIG. 3 is a TEM image of the multifunctional skin absorption enhancer prepared in example 1 of the present invention.
Detailed Description
The invention is further described below with reference to the drawings and specific preferred embodiments of the description, without thereby limiting the scope of protection of the invention.
The materials and equipment used in the following examples are commercially available. In the examples of the present invention, unless otherwise specified, the processes used were conventional processes, the equipment used were conventional equipment, and the data obtained were average values of three or more experiments.
Example 1
A multifunctional percutaneous absorption enhancer is a compound represented by the formula (I):
in the present example, in the compound represented by the formula (I), m is 3, X is 3, Y is 6, and Z is 500.
In this embodiment, the multifunctional skin penetration enhancer is nanoparticles with an average particle size of 150 nm.
The preparation method of the multifunctional transdermal absorption enhancer in the embodiment of the invention comprises the following steps:
(1) 20g of chitosan was dissolved in 100mL of tetrahydrofuran, 5g of methanesulfonyl chloride was added dropwise at 0 ℃ to react for 12 hours, the tetrahydrofuran was distilled off in suspension, the obtained product was dissolved again in chloroform, washed with water 3 times (100 mL/time), dried over anhydrous sodium sulfate, and the chloroform was removed in suspension to obtain 21g of crude product A. The crude product A was dissolved in 100mL of DMF, 6g of NaI was added, the reaction was heated at 80 ℃ for 24 hours, cooled, 100mL of chloroform was added to stop the reaction, washed 3 times with water (100mL each), dried over anhydrous sodium sulfate and evaporated to give crude product B. And dissolving the crude product B in DMF, adding 10g of sodium polyethylene glycol at room temperature, reacting for 12 hours, adding 100mL of water to stop the reaction, dialyzing by using a dialysis membrane to remove unreacted substances, and freeze-drying the obtained product to obtain the pegylated chitosan. In the preparation method of the PEGylated chitosan, n in the structural formula of the chitosan is 6.
(2) Weighing 5g of the pegylated chitosan prepared in step (1) and dissolving in 30mLN, N-Dimethylformamide (DMF), adding 2.96g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) under ice bath, activating for 2h under ice bath, dropwise adding 20mL of DMF solution containing vitamin E (containing 6.67g of vitamin E in the solution), and stirring at 25 ℃ (the stirring speed can be within 1000 rpm) for 24 h. Subsequent dialysis, followed by lyophilization, gave 10g of chitosan-linked vitamin E (CS-VE).
(3) 5g of the product in the above step (2) was dissolved in 50mL of tetrahydrofuran, 0.2g of hyaluronic acid was added under nitrogen protection, 1.3g of 1, 6-diisocyanatohexane (HDI) and 10mg of dibutyltin laurate were further added, the reaction was carried out at 80 ℃ for 24 hours under nitrogen protection, excess methanol was added to terminate the reaction, the reaction was continued for 1 hour with stirring, and then the solid was precipitated by adding ether to obtain 5.2g of a multifunctional transdermal absorption enhancer (CS-VE-HA).
FIG. 1 is an infrared spectrum of the multifunctional skin penetration enhancer (CS-VE-HA) and chitosan monomer (CS) prepared in example 1 of the present invention. As can be seen from FIG. 1, the peak value at 2960cm is 2900--1The stretching vibration peak of CH2 was clearly broadened, indicating that vitamin E had been linked to CS-VE-HA; at the same time at 650cm-1There appears a distinct HO in-plane bending vibration peak, indicating that HA HAs been attached to CS-VE-HA.
FIG. 2 is a dynamic light scattering diagram of the multifunctional transdermal absorption enhancer (CS-VE-HA) and the chitosan monomer (CS) prepared in example 1 of the present invention. As can be seen from FIG. 2, the hydrated average particle size of CS-VE-HA prepared by the present invention is 150nm, while the hydrated average particle size of chitosan monomer is 80nm, which indicates that CS-VE-HA HAs become a nanoparticle.
FIG. 3 is a TEM image of the multifunctional skin absorption enhancer prepared in example 1 of the present invention. As can be seen from FIG. 3, CS-VE-HA prepared by the present invention forms stable nanoparticles.
Example 2
A multifunctional skin penetration enhancer, which is substantially the same as the multifunctional skin penetration enhancer of example 1 except that: the multifunctional percutaneous absorption enhancer of example 2 wherein m is 2, X is 2, Y is 7, and Z is 20.
Example 3
A multifunctional skin penetration enhancer, which is substantially the same as the multifunctional skin penetration enhancer of example 1 except that: the multifunctional percutaneous absorption enhancer of example 3 wherein m is 4, X is 6, Y is 4, and Z is 1000.
Example 4
A multifunctional skin penetration enhancer, which is substantially the same as the multifunctional skin penetration enhancer of example 1 except that: the multifunctional percutaneous absorption enhancer of example 4 is one in which m is 3, X is 2, Y is 7, and Z is 2000.
Example 5
An application of a multifunctional percutaneous absorption enhancer as a water-soluble auxiliary agent in preparing cosmetics, in particular to a water-soluble licoflavone solution prepared by mixing the multifunctional percutaneous absorption enhancer prepared in the embodiment 1-4 and licoflavone, which comprises the following steps: weighing 100mg licoflavone, and dissolving in 1g water solution of multifunctional percutaneous absorption enhancer to obtain water soluble licoflavone solution.
The water-soluble licoflavone solution corresponding to the multifunctional transdermal absorption enhancer prepared in examples 1-4 is sequentially recorded as: CS-VE-HA-1-licoflavone solution, CS-VE-HA-2-licoflavone solution, CS-VE-HA-3-licoflavone solution, and CS-VE-HA-4-licoflavone solution (blue content is modified, please verify).
And (3) investigating the transdermal absorption effect of the licoflavone in the CS-VE-HA-1-licoflavone solution, the CS-VE-HA-2-licoflavone solution, the CS-VE-HA-3-licoflavone solution and the CS-VE-HA-4-licoflavone solution.
Transdermal experiment:
taking a male mouse with the weight of 18-22g, cutting off the neck, killing, shaving off the abdominal hair, and taking the undamaged skin. Subcutaneous fat was removed on a petri dish and the inner surface of the skin was rinsed with physiological saline. Stored at-4 ℃ and used within 48 hours. The skin is fixed between an upper chamber and a lower chamber of a Franz diffusion cell, the horny layer faces upwards, the receiving solution is 0.9% physiological saline solution, the releasing solution is 3mL of sample solution, the device is placed in a constant-temperature water bath at the temperature of 32 +/-0.5 ℃, stirring is started (200r/min), 1mL of samples are taken at 0.5h, 1h, 2h, 4h, 6h, 8h, 10h and 12h respectively, and meanwhile, no equal-volume fresh receiving solution at the same temperature is added. The sample is diluted by a 0.22 mu m microporous filter membrane, 1mL of the sample filtrate is diluted by a mobile phase and then is subjected to ultraviolet quantitative analysis, the cumulative permeation amount (Qn) of the drug is calculated, and the average operation is carried out on three parts to obtain an average value.
Results and data from the experiments
The results of the data on the cumulative transdermal flux of licoflavone at 12 hours using CS-VE-HA as a penetration enhancer are shown in Table 1.
TABLE 1 Effect of different penetration enhancers on the transdermal absorption of licoflavone
| Sample (I) | Qn(μg·cm-2) (12 hours) |
| Glycyrrhiza glabra flavone | 0 |
| CS-VE-HA-1-licorice flavone solution | 2738.63±112.48 |
| CS-VE-HA-2-licorice flavone solution | 2125.82±82.08 |
| CS-VE-HA-3-licorice flavone solution | 1097.58±49.88 |
| CS-VE-HA-4-licorice flavone solution | 821.53±65.13 |
As shown in Table 1, compared with licoflavone monomer (blank), the CS-VE-HA prepared by the invention can greatly improve the transdermal absorption of licoflavone.
Example 6
An application of a multifunctional transdermal absorption enhancer as a penetration enhancer in preparing a transdermal administration preparation, in particular to a water-soluble astaxanthin solution prepared by mixing the multifunctional transdermal absorption enhancer prepared in the embodiment 1-4 and astaxanthin, which comprises the following steps: 100mg of astaxanthin is weighed and dissolved in 1g of the water solution of the multifunctional percutaneous absorption enhancer to obtain a water-soluble astaxanthin solution.
The water-soluble astaxanthin solutions corresponding to the multifunctional percutaneous absorption enhancers obtained in examples 1 to 4 were sequentially recorded as: CS-VE-HA-1-astaxanthin solution, CS-VE-HA-2-astaxanthin solution, CS-VE-HA-3-astaxanthin solution, and CS-VE-HA-4-astaxanthin solution.
The transdermal absorption effect of astaxanthin in the above-mentioned CS-VE-HA-1-astaxanthin solution, CS-VE-HA-2-astaxanthin solution, CS-VE-HA-3-astaxanthin solution and CS-VE-HA-4-astaxanthin solution was examined.
Transdermal experiment:
taking a male mouse with the weight of 18-22g, cutting off the neck, killing, shaving off the abdominal hair, and taking the undamaged skin. Subcutaneous fat was removed on a petri dish and the inner surface of the skin was rinsed with physiological saline. Stored at-4 ℃ and used within 48 hours. The skin is fixed between an upper chamber and a lower chamber of a Franz diffusion cell, the horny layer faces upwards, the receiving solution is 0.9% physiological saline solution, the releasing solution is 3mL of sample solution, the device is placed in a constant-temperature water bath at the temperature of 32 +/-0.5 ℃, stirring is started (200r/min), 1mL of samples are taken at 0.5h, 1h, 2h, 4h, 6h, 8h, 10h and 12h respectively, and meanwhile, no equal-volume fresh receiving solution at the same temperature is added. The sample is diluted by a 0.22 mu m microporous filter membrane, 1mL of the sample filtrate is diluted by a mobile phase and then is subjected to ultraviolet quantitative analysis, the cumulative permeation amount (Qn) of the drug is calculated, and the average operation is carried out on three parts to obtain an average value.
Results and data from the experiments
The results of the cumulative transdermal flux data for 12 hours astaxanthin using CS-VE-HA as a penetration enhancer are shown in Table 2.
TABLE 2 Effect of different penetration enhancers on the transdermal absorption of astaxanthin
| Sample (I) | Qn(μg·cm-2) (12 hours) |
| Blank astaxanthin | 0 |
| CS-VE-HA-1-astaxanthin solution | 2738.63±112.48 |
| CS-VE-HA-2-astaxanthin solution | 2125.82±82.08 |
| CS-VE-HA-3-astaxanthin solution | 1097.58±49.88 |
| CS-VE-HA-4-astaxanthin solution | 821.53±65.13 |
As is clear from Table 2, the CS-VE-HA prepared by the present invention can greatly improve the transdermal absorption of astaxanthin compared to astaxanthin monomer (blank).
Example 7
In vivo experiment of CS-VE-HA for promoting collagen absorption
Kunming mice, 48, weighing 18-22g, were randomly divided into three groups of 16 mice each, and were administered in groups as follows:
model control group: smearing collagen, 0.1 mg/mL.
Water-soluble azone group: collagen (0.1mg/mL) + water-soluble azone (2 wt%).
CS-VE-HA group: collagen (0.1mg/mL) + CS-VE-HA (2 wt%) of examples 1-4 was applied to obtain a CS-VE-HA-1-collagen solution, a CS-VE-HA-2-collagen solution, a CS-VE-HA-3-collagen solution, and a CS-VE-HA-4-collagen solution, in that order.
Dissolving rosin-paraffin wax in boiling water bath at a ratio of 1:1(w/w), mixing, standing to room temperature, and making into depilatory. The depilatory is re-dissolved in boiling water bath immediately before use, and is allowed to stand at room temperature until it is ready to be solidified. One day prior to the experiment, 3 groups of mice were anesthetized with ether and then depilated of abdominal skin with the above depilatory. On the day of the experiment, 3 groups of mice were anesthetized with 0.3% sodium pentobarbital (0.3ml/10g), and then each group of mice was given the corresponding treatment. After 6H, skin samples were taken, sectioned, and H & E stained.
TABLE 3 Effect of different penetration enhancers on the transdermal absorption of collagen
As can be seen from Table 3, compared with collagen monomer (blank), the CS-VE-HA prepared by the invention can greatly improve the transdermal absorption of collagen.
In example 7, the transdermal rates of collagen in the water-soluble azone group and the CS-VE-HA group (CS-VE-HA of examples 1 to 4) were 15.1%, 72.1%, 67.4%, 60.8%, and 56.2% in this order, as compared to the model control group, and it was found that the amide absorption peaks of the stratum corneum proteins of the skin were shifted from the high wave number to the low wave number of the β folded structure and the random curled structure after the CS-VE-HA treatment, which indicates that the ratio of the β folded structure and the random curled structure in the secondary structure was increased, which indicates that the stratum corneum protein cell activity was increased after the treatment, resulting in the stratum corneum stacked structure becoming loose, increasing the freedom of movement of the corresponding carbon, thereby accelerating the movement of the keratin carbon.
Example 8
An anti-aging skin care product comprises the following components in every 100 Kg: humectant 3Kg, preservative 0.1Kg, solubilizer 1.2Kg, thickener 0.15Kg, skin conditioner 5Kg, chelating agent 0.2Kg, antioxidant 8Kg, fragrance 0.1Kg, anti-allergic agent 0.1Kg, multifunctional transdermal absorption enhancer 5Kg prepared in example 1, and balance water.
In the embodiment, the humectant consists of 1Kg of sodium hyaluronate and 2Kg of polyglutamic acid.
In this example, the preservative is composed of 0.05Kg of propyl hydroxybenzoate and 0.05Kg of 2-phenoxyethanol.
In the embodiment, the solubilizer comprises 0.3Kg of PEG60 hydrogenated castor oil, 0.3Kg of PEG60 glycerol isostearate, 0.3Kg of polyglycerol-10 stearate and 0.3Kg of PEG/PPG-17/6 copolymer.
In this example, the thickener is hydroxypropyl guar.
In the embodiment, the skin conditioner consists of 2Kg of wheat ceramide, 1Kg of propolis extract, 1Kg of yeast extract and 1Kg of ginseng root extract.
In this example, the chelating agent is disodium EDTA.
In the embodiment, the antioxidant consists of 1Kg of licoflavone, 1Kg of resveratrol, 1Kg of astaxanthin, 2Kg of tea polyphenol, 1Kg of safflower extract, 1Kg of cranberry extract and 1Kg of pteroceltis tatarinowii extract
In this embodiment, the anti-allergic agent is dipotassium glycyrrhizinate.
In this example, the fragrance is an aqueous rose extract.
The preparation method of the anti-aging skin care product in the embodiment of the invention comprises the following steps:
(1) dissolving PEG60 hydrogenated castor oil, PEG60 glyceryl isostearate, polyglycerol-10 stearate, and PEG/PPG-17/6 copolymer in 20Kg water, adding ethanol solution of licoflavone, resveratrol, and astaxanthin, dissolving, and removing ethanol under reduced pressure to obtain mixture A.
(2) And (3) putting the sodium hyaluronate and the polyglutamic acid into a stirring pot, stirring and dissolving to obtain a mixture B.
(3) Adding EDTA disodium and hydroxypropyl guar gum into a stirring pot, heating to 90 ℃ while stirring to fully dissolve the EDTA disodium and the hydroxypropyl guar gum, and preserving the temperature for 20 minutes to obtain a mixture C.
(4) Cooling the mixture C to 42 ℃, sequentially adding the multifunctional transdermal absorption enhancer prepared in the example 1, wheat ceramide, propolis extract, yeast extract, ginseng extract, tea polyphenol, safflower extract, cranberry extract, pteroceltis tatarinowii extract, dipotassium glycyrrhizinate and rose water extract, stirring and dissolving to obtain a mixture D.
(5) And (3) keeping the temperature at 40 ℃, adding propyl hydroxybenzoate, 2-phenoxyethanol, the mixture A prepared in the step (1) and the mixture B prepared in the step (2) into the mixture D, adding water to 100kg, fully stirring, cooling to room temperature, discharging, and standing to obtain the anti-aging skin care product.
The moisturizing and hydrating abilities of the anti-aging skin care product prepared in example 8 are shown in table 4.
TABLE 4 comparative data for consumer versus skin care product usage
| Test items | Anti-aging skin care product without adding multifunctional transdermal absorption enhancer | Example 8 |
| Water content | Increase by 42 percent | The improvement is 52 percent |
| Texture | The improvement is 47 percent | Increase by 57 percent |
| Skin tone | Increase by 53 percent | Increase by 59 percent |
| 3D | The improvement is 61 percent | The improvement is 66 percent |
| Pigment | The reduction is 58 percent | The reduction is 65 percent |
| Elasticity | Increase by 56 percent | Increase by 68 percent |
In table 4, the anti-aging skin care product using water as a blank control and without the multifunctional skin penetration enhancer is the same as the anti-aging skin care product of example 8 except that the multifunctional skin penetration enhancer is not added.
As can be seen from table 4, the anti-aging skin care product prepared by the present invention can improve the skin condition and restore the skin condition more significantly.
The above examples are merely preferred embodiments of the present invention, and the scope of the present invention is not limited to the above examples. All technical schemes belonging to the idea of the invention belong to the protection scope of the invention. It should be noted that modifications and embellishments within the scope of the invention may be made by those skilled in the art without departing from the principle of the invention, and such modifications and embellishments should also be considered as within the scope of the invention.
Claims (10)
1. A multifunctional percutaneous absorption enhancer is characterized in that the multifunctional percutaneous absorption enhancer is a compound shown as a formula (I):
2. The multifunctional transdermal absorption enhancer according to claim 1, wherein the multifunctional transdermal absorption enhancer is a nanoparticle; the average particle size of the multifunctional transdermal absorption enhancer is 50 nm-150 nm.
3. A method for preparing the multifunctional percutaneous absorption enhancer as claimed in claim 1 or 2, comprising the steps of:
s1, dissolving the pegylated chitosan in N, N-dimethylformamide, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride for activation, adding a vitamin E-containing N, N-dimethylformamide solution for reaction, dialyzing, and freeze-drying to obtain vitamin E linked chitosan;
s2, dissolving the chitosan linked with the vitamin E prepared in the step S1 in tetrahydrofuran, adding hyaluronic acid, 1, 6-diisocyanatohexane and dibutyltin laurate to react, dialyzing, and freeze-drying to obtain the multifunctional transdermal absorption enhancer.
4. The method according to claim 3, wherein the step S1, the method for preparing the pegylated chitosan comprises the steps of:
(1) dissolving chitosan in tetrahydrofuran, dropwise adding methanesulfonic acid chloride for reaction, removing tetrahydrofuran, adding methanesulfonic acid chloride, washing with water, drying, and removing chloroform to obtain a crude product A;
(2) dissolving the crude product A obtained in the step (1) in DMF, adding NaI for reaction, adding chloroform to terminate the reaction, washing with water, and performing suspended evaporation to obtain a crude product B;
(3) and (3) dissolving the crude product B obtained in the step (2) in DMF, adding sodium polyethylene glycol for reaction, adding water for terminating the reaction, dialyzing, and freeze-drying to obtain the pegylated chitosan.
5. The method according to claim 4, wherein the mass ratio of the chitosan, the methanesulfonic acid chloride, the NaI and the sodium polyethylene glycol is 20: 4-8: 4-10: 7-12.
6. The production method according to claim 5, wherein in the step (1), the reaction is carried out at 0 ℃; the reaction time is 6-24 h;
in the step (2), the reaction is carried out at 80 ℃; the reaction time is 12-48 h;
in the step (3), the reaction time is 6-24 h.
7. The method according to any one of claims 3 to 6, wherein in step S1, the mass ratio of the pegylated chitosan, vitamin E in the vitamin E-containing N, N-dimethylformamide solution, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is 5: 2 to 10: 0.5 to 5; the ratio of the pegylated chitosan to the N, N-dimethylformamide is 1 g: 2 mL-10 mL;
in the step S2, the mass ratio of the vitamin E-linked chitosan to hyaluronic acid to the 1, 6-diisocyanatohexane to the dibutyltin laurate is 5: 0.01-0.5: 0.1-2: 0.001-0.1; the ratio of the vitamin E-linked chitosan to tetrahydrofuran is 1 g: 2 mL-10 mL.
8. The method according to any one of claims 3 to 6, wherein in step S1, the activation is performed under ice bath conditions; the activation temperature is 0-4 ℃; the activation time is 0.2 h-8 h; the reaction is carried out under stirring conditions; the reaction time is 12-36 h;
in the step S2, the reaction is carried out under a protective atmosphere; the protective atmosphere is nitrogen or argon; the reaction temperature is 60-80 ℃; the reaction time is 6-48 h.
9. The use of the multifunctional skin penetration enhancer according to claim 1 or 2 or the multifunctional skin penetration enhancer prepared by the preparation method according to any one of claims 3 to 8 as a water-soluble auxiliary agent in the preparation of cosmetics.
10. Use of the multifunctional transdermal absorption enhancer of claim 1 or 2 or the multifunctional transdermal absorption enhancer prepared by the preparation method of any one of claims 4 to 8 as a penetration enhancer in the preparation of a transdermal drug delivery preparation.
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| CN102558391A (en) * | 2011-12-31 | 2012-07-11 | 沈阳药科大学 | Vitamin E succinate-chitosan graft and preparation method and application thereof |
| CN106883404A (en) * | 2017-01-17 | 2017-06-23 | 沈阳药科大学 | TPGS derivative and its preparation method and application |
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