Dual supramolecular vc nicotinamide@aa2g package and preparation method and application thereof

Abstract

The present application relates to the technical field of medical and cosmetic compounds, and particularly relates to a double supramolecular VC nicotinamide@AA2G package and a preparation method and application thereof, the preparation method of the double supramolecular VC nicotinamide@AA2G package uses vitamin C and nicotinamide as precursors, synthesizes a supramolecular VC nicotinamide co-crystal through a supramolecular modification reaction, and uses hydroxypropyl-beta-cyclodextrin to wrap the supramolecular VC nicotinamide co-crystal and ascorbic acid glucoside, so as to obtain the double supramolecular VC nicotinamide@AA2G package. The double supramolecular package prepared by the method can improve the stability of vitamin C, improve the skin permeability, ensure the original whitening effect of vitamin C and nicotinamide, and fully play the role of inhibiting melanin. Meanwhile, the double supramolecular package has good antioxidant property, greatly improves the bioavailability, and enhances the stability and application effect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medical and cosmetic compounds, in particular to a double supramolecular VC nicotinamide@AA2G package and a preparation method and application thereof. BACKGROUND

[0002] Vitamin C (VC) is also known as L-ascorbic acid. The two hydroxyl groups on the double bond are easily affected by the environment and change into carbonyl groups, thereby having strong reducing properties and strong effects on removing melanin deposition and scavenging active free radicals. Nicotinamide is a B vitamin that can effectively reduce the deposited melanin, block its transfer to the surface cells, accelerate cell metabolism, and speed up the exfoliation of melanin keratinocytes.

[0003] However, Vitamin C is easily affected by the external environment and deteriorates, thereby losing the original efficacy, such as transition metal ions, light, pH, temperature, high concentration of oxygen, etc. Nicotinamide alone has poor permeability, resulting in low bioavailability.

[0004] Therefore, the prior art still needs to be improved and developed. SUMMARY

[0005] In view of the above problems of the prior art, the present application aims to provide a double supramolecular VC nicotinamide@AA2G package and a preparation method and application thereof, which aims to solve the problems that Vitamin C and nicotinamide are easily affected by the external environment and have poor permeability.

[0006] The technical scheme of the present application is as follows:

[0007] A preparation method of a double supramolecular VC nicotinamide@AA2G package, comprising the steps of:

[0008] adding Vitamin C and nicotinamide into an organic solvent, performing first stirring treatment and ultrasonic treatment at a first predetermined temperature, filtering and vacuum drying after reacting for a first predetermined time, to obtain a supramolecular VC nicotinamide co-crystal;

[0009] adding ascorbic acid glucoside, hydroxypropyl-beta-cyclodextrin and the supramolecular VC nicotinamide co-crystal into deionized water, performing second stirring treatment and dialysis treatment at a second predetermined temperature, and freeze-drying after reacting for a second predetermined time, to obtain a double supramolecular VC nicotinamide@AA2G package.

[0010] The preparation method of the double supramolecular VC nicotinamide@AA2G package, wherein the molar ratio of the Vitamin C to the nicotinamide is (1:3)-(3:1).

[0011] The preparation method of the dual supramolecular VC nicotinamide@AA2G package, wherein the mass ratio of the supramolecular VC nicotinamide co-crystal, the ascorbyl glucoside and the hydroxypropyl-beta-cyclodextrin is (2-5):(1-4):(3-7).

[0012] The preparation method of the dual supramolecular VC nicotinamide@AA2G package, wherein the first predetermined time is 24-48h; and the second predetermined time is 24-48h.

[0013] The preparation method of the dual supramolecular VC nicotinamide@AA2G package, wherein the first predetermined temperature is 40-80℃; the rotation speed of the first stirring treatment is 30-350rad / min, the time of the first stirring treatment is 24-48h; the frequency of the ultrasonic treatment is 20~50kHz, the power of the ultrasonic treatment is 1000~2000W, the time of the ultrasonic treatment is 4~12h, and the intermittent time of the ultrasonic treatment is 2~10s per interval of 1~5s.

[0014] The preparation method of the dual supramolecular VC nicotinamide@AA2G package, wherein the second predetermined temperature is 30-70℃; the rotation speed of the second stirring treatment is 50-450rad / min, the time of the second stirring treatment is 24-48h; the dialysis treatment adopts a cellulose dialysis bag, the molecular weight of the cellulose dialysis bag is 2000, the time of the dialysis treatment is 2~6h, and the dialysis frequency is 1~3 times.

[0015] The preparation method of the dual supramolecular VC nicotinamide@AA2G package, wherein the temperature of the vacuum drying treatment is 50-80℃; and the temperature of the freeze-drying treatment is -80℃±5℃.

[0016] The preparation method of the dual supramolecular VC nicotinamide@AA2G package, wherein the preparation method of the dual supramolecular VC nicotinamide@AA2G package is carried out in an inert gas atmosphere.

[0017] A dual supramolecular VC nicotinamide@AA2G package is prepared by using the preparation method of the dual supramolecular VC nicotinamide@AA2G package.

[0018] The dual supramolecular VC nicotinamide@AA2G package is used in the preparation of a cosmetic product.

[0019] Beneficial effects: the present application provides a kind of double supramolecular VC nicotinamide @ AA2G package and its preparation method and application, preparation method includes the following steps: vitamin C and nicotinamide are added to organic solvent, first stirring treatment is carried out at first predetermined temperature, ultrasonic treatment, after reacting first predetermined time, filter and vacuum drying treatment, obtain supramolecular VC nicotinamide co-crystal;Nicotinamide is added to deionized water, ascorbic acid glucoside, hydroxypropyl-β-cyclodextrin and the supramolecular VC nicotinamide co-crystal is added, second stirring treatment is carried out at second predetermined temperature, dialysis treatment, after reacting second predetermined time, freeze-drying treatment, obtain double supramolecular VC nicotinamide @ AA2G package.The present application uses vitamin C, nicotinamide as precursor, after supramolecular modification, the hydroxyl of vitamin C and the amino of nicotinamide attract each other, hydrogen is shifted, thereby synthesizing supramolecular VC nicotinamide co-crystal, then using hydroxypropyl-β-cyclodextrin to wrap supramolecular VC nicotinamide co-crystal and ascorbic acid glucoside (AA2G), obtain double supramolecular VC nicotinamide @ AA2G package.Supramolecular VC nicotinamide co-crystal can enhance transdermal transport across cell and acellular, bypass the barrier of stratum corneum (SC), destroy cell integrity, can open the tight junction in stratum corneum, promote the paracellular transport of active substances, has the effect of penetration, can improve the ability of active substances to penetrate the skin.Then using wrapping technology to seal vitamin C and ascorbic acid glucoside (AA2G), avoid its contact with the outside environment and inactivation, thereby enhancing the stability of vitamin C.When acting on the skin, due to the concentration difference between the package and the skin, hydroxypropyl-β-cyclodextrin will slowly release active substances, play its slow-release effect, can prolong the action time of vitamin C in human body, improve the utilization rate, and then achieve the effect of prolonging the drug effect.The double supramolecular package prepared by the method can improve the stability of vitamin C and the permeability of skin, ensure the original whitening effect of vitamin C and nicotinamide, thereby fully play the role of inhibiting melanin, and have good antioxidant property, greatly improve the bioavailability, stability and application effect. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 It is the process flow schematic diagram of the preparation method of the double supramolecular VC nicotinamide @ AA2G package of the present application;

[0021] Figure 2 It is the thermogravimetric analysis curve of double supramolecular VC nicotinamide @ AA2G package, supramolecular VC nicotinamide co-crystal, ascorbic acid glucoside and hydroxypropyl-β-cyclodextrin in example 1;

[0022] Figure 3 It is the penetration efficiency statistical chart of test example 1;

[0023] Figure 4Figure for observing the stability of the double supramolecular VC nicotinamide @ AA2G package and the supramolecular VC nicotinamide eutectic in Example 4 at 14D and 28D;

[0024] Figure 5 Figure for observing the DPPH free radical scavenging rate in Example 5;

[0025] Figure 6 Figure for observing the ABTS ＋ free radical scavenging rate in Example 5;

[0026] Figure 7 Figure for observing the relative content of reactive oxygen species (ROS) of keratinocytes in Example 6;

[0027] Figure 8 Figure for observing the ROS inhibition rate of keratinocytes in Example 6. DETAILED DESCRIPTION

[0028] The present application provides a double supramolecular VC nicotinamide @ AA2G package and a preparation method and application thereof. In order to make the purpose, technical scheme and effect of the present application more clear and definite, the present application is further described in detail below. It should be understood that the specific embodiments described herein are only used to explain the present application and do not limit the present application.

[0029] Those skilled in the art can understand that, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as generally understood by those skilled in the art to which the present application belongs. It should also be understood that terms such as those defined in general dictionaries should be understood as having meanings consistent with those in the prior art, and should not be interpreted in an idealized or overly formal sense unless specifically defined as such.

[0030] As Figure 1 shown, the present application provides a preparation method of a double supramolecular VC nicotinamide @ AA2G package, comprising the steps of:

[0031] Step S10: adding vitamin C and nicotinamide into an organic solvent, performing first stirring treatment and ultrasonic treatment at a first predetermined temperature, filtering and vacuum drying after reacting for a first predetermined time, to obtain a supramolecular VC nicotinamide eutectic;

[0032] Step S20: adding ascorbic acid glucoside, hydroxypropyl-β-cyclodextrin and the supramolecular VC nicotinamide eutectic into deionized water, performing second stirring treatment and dialysis treatment at a second predetermined temperature, and performing freeze-drying treatment after reacting for a second predetermined time, to obtain a double supramolecular VC nicotinamide @ AA2G package.

[0033] In this embodiment, the supermolecular VC nicotinamide co-crystal is synthesized by taking vitamin C and nicotinamide as precursors. The hydroxyl group of vitamin C and the amino group of nicotinamide attract each other, hydrogen shifts occur, and the two are combined by hydrogen bonds to form a co-crystal, and the structural formula is as follows:

[0034]

[0035] The supermolecular VC nicotinamide co-crystal can enhance transcellular and acellular transport, bypass the barrier of the stratum corneum (SC), destroy cell integrity, and act by opening tight junctions within the SC, mainly by enhancing regional vitamin C fluidization to promote paracellular transport, thereby improving the transdermal penetration ability of vitamin C.

[0036] The supermolecular VC nicotinamide co-crystal and ascorbyl glucoside (AA2G) are wrapped with hydroxypropyl-β-cyclodextrin as a wrapping layer to form a double supermolecular VC nicotinamide@AA2G wrapping. The double supermolecular VC nicotinamide@AA2G wrapping has hydroxypropyl-β-cyclodextrin as a wrapping layer, which not only enhances the stability of vitamin C, but also improves the permeability of the skin, ensures the original whitening effect of vitamin C and nicotinamide, fully plays a role in inhibiting melanin, and has good antioxidant properties, thereby improving the bioavailability of vitamin C, nicotinamide and AA2G, and enhancing the application effect.

[0037] Specifically, the co-crystal of vitamin C and nicotinamide has a penetration-enhancing effect, and the use of hydroxypropyl-β-cyclodextrin to wrap it with AA2G can enhance its stability in the product. When acting on the skin, the slow-release effect can prolong the time of its action on the skin and more effectively inhibit melanin.

[0038] Further, ascorbyl glucoside (AA2G) is a stable chemical structure obtained by chemical modification of vitamin C without changing its efficacy. The embedding technology is used to seal ascorbyl glucoside and supermolecular VC nicotinamide co-crystal to avoid inactivation by contacting the external environment, thereby enhancing the stability of vitamin C. When acting on the skin, the concentration difference between the wrapping and the skin causes the slow release of active substances, which plays a slow-release role, prolongs the action time of vitamin C in the human body, improves the utilization rate, and further achieves the effect of prolonging the drug effect. Therefore, the double supermolecular wrapping prepared by this method can not only improve the stability of vitamin C, but also improve the permeability of the skin, ensure the original whitening effect of vitamin C and nicotinamide, and fully play a role in inhibiting melanin.

[0039] In some embodiments, the molar ratio of the vitamin C and the nicotinamide is (1:3)-(3:1); controlling the molar ratio of the vitamin C and the nicotinamide in this range can make the reaction of vitamin C and nicotinamide more complete, the yield is higher, and the efficacy of removing melanin deposition and scavenging active radicals is optimal.

[0040] In a preferred embodiment, the molar ratio of the vitamin C and the nicotinamide is 1:1; the VC nicotinamide co-crystal prepared by the vitamin C and the nicotinamide in this molar ratio has a larger yield.

[0041] In some embodiments, the mass ratio of the supramolecular VC nicotinamide co-crystal, the ascorbic acid glucoside, and the hydroxypropyl-β-cyclodextrin is (2-5):(1-4):(3-7); the double supramolecular VC nicotinamide@AA2G package prepared by reacting ascorbic acid glucoside, hydroxypropyl-β-cyclodextrin, and supramolecular VC nicotinamide co-crystal in this mass ratio has a larger wrapping rate.

[0042] In a preferred embodiment, the mass ratio of the supramolecular VC nicotinamide co-crystal, the ascorbic acid glucoside, and the hydroxypropyl-β-cyclodextrin is 2:1:2; reacting the supramolecular VC nicotinamide co-crystal, the ascorbic acid glucoside, and the hydroxypropyl-β-cyclodextrin in this mass ratio can obtain a supramolecular VC nicotinamide@AA2G package with a higher wrapping rate and improve the preparation rate.

[0043] In some embodiments, the organic solvent is selected from, but not limited to, one or more of anhydrous ethanol, methanol, ethyl acetate, isopropanol, and acetone; selecting the above organic solvents as the medium for the reaction of vitamin C and nicotinamide can promote the mutual attraction between the hydroxyl group of vitamin C and the amino group of nicotinamide, so that the hydrogen is shifted, thereby completing the supramolecular modification reaction and synthesizing the supramolecular VC nicotinamide co-crystal.

[0044] In a preferred embodiment, the organic solvent is anhydrous ethanol.

[0045] In some embodiments, the first predetermined time is 24-48h; the second predetermined time is 24-48h; controlling the reaction time of the synthesized VC nicotinamide solution and the synthesized supramolecular VC nicotinamide@AA2G solution in the above range can make the reaction complete and avoid waste of raw materials.

[0046] In some embodiments, the first predetermined temperature is 40-80℃; the rotation speed of the first stirring treatment is 30-350 rad / min, and the time of the first stirring treatment is 24-48 h; the frequency of the ultrasonic treatment is 20-50 kHz, the power of the ultrasonic treatment is 1000-2000 W, the time of the ultrasonic treatment is 4-12 h, and the intermittent time of the ultrasonic treatment is 2-10 s of ultrasonic treatment per 1-5 s interval. Below this temperature range, the activity of vitamin C is low, and it is not easy to react with nicotinamide; above this temperature range, vitamin C is easily inactivated, and the whitening effect is low; within this temperature range, the activity of vitamin C is strong, and its hydroxyl group is easily attracted to the amino group in nicotinamide; within this range, ultrasonic treatment can maximize the reaction speed and more easily form a supermolecular VC nicotinamide co-crystal with a high yield.

[0047] In some embodiments, the second predetermined temperature is 30-70℃; the rotation speed of the second stirring treatment is 50-450 rad / min, and the time of the second stirring treatment is 24-48 h. Within this temperature range, vitamin C and ascorbic acid glucoside are in a strong active state, and within this stirring speed range, the substances can achieve sufficient stirring effect, the reaction is more complete, and the yield of the double supermolecular VC nicotinamide@AA2G package is higher.

[0048] In some embodiments, the dialysis treatment uses a cellulose dialysis bag with a molecular weight of 2000, and the time of the dialysis treatment is 2-6 h, and the number of dialysis is 1-3 times. Using a dialysis bag with a molecular weight of 2000 can effectively remove substances that do not form a double supermolecular VC nicotinamide@AA2G package, thereby achieving a higher packaging rate.

[0049] In some embodiments, the temperature of the vacuum drying treatment is 50-80℃; the temperature of the freeze-drying treatment is -80℃±5℃; by drying the filtered supermolecular VC nicotinamide solution at 50-80℃, the chemical structure of the supermolecular VC nicotinamide co-crystal can be preserved, i.e., the biological activity of the supermolecular VC nicotinamide co-crystal is ensured, making it have super strong antioxidant and whitening effects; and by freeze-drying at -80℃±5℃, the activity of the double supermolecular VC nicotinamide@AA2G package can be maintained.

[0050] In some embodiments, the preparation method of the double supermolecular VC nicotinamide@AA2G package is carried out in an inert gas atmosphere; by preparing the double supermolecular VC nicotinamide@AA2G package in an inert gas atmosphere, vitamin C can be prevented from deteriorating and losing its original efficacy, and the prepared double supermolecular VC nicotinamide@AA2G package has high stability, which delays discoloration while exerting its efficacy.

[0051] In addition, the application further provides a double supermolecular VC nicotinamide@AA2G package prepared by the preparation method.

[0052] In the embodiment, the double supermolecular VC nicotinamide@AA2G package prepared by the preparation method can effectively enhance the stability of vitamin C, improve the penetration effect of vitamin C, nicotinamide and ascorbic acid glucoside, and fully play the role of inhibiting melanin, and has good antioxidant property.

[0053] In addition, the application further provides a double supermolecular VC nicotinamide@AA2G package in the preparation of cosmetics.

[0054] In the embodiment, the double supermolecular VC nicotinamide@AA2G package is used for preparing cosmetics, so that the cosmetics have better whitening effect, good penetration effect, the function of fully inhibiting melanin, and good antioxidant property.

[0055] In some embodiments, the cosmetics include but are not limited to essence, mask, cream.

[0056] The following examples are further used to illustrate the application in detail. It should also be understood that the following examples are only used to further illustrate the application, and cannot be understood as limiting the protection scope of the application. Some non-essential improvements and adjustments made by those skilled in the art according to the above content of the application are within the protection scope of the application. Example

[0057] The embodiment provides a double supermolecular VC nicotinamide@AA2G package, which is specifically as follows:

[0058] 0.10 mol of vitamin C and 0.10 mol of nicotinamide are placed in anhydrous ethanol under an inert gas atmosphere and reacted for 24 h. Ultrasonic and stirring are carried out at 55℃, the stirring time is 24 h, the stirring rate is 300 rad / min, the ultrasonic frequency is 30 kHz, the ultrasonic power is 2000 W, the ultrasonic time is 6 h, the intermittent time is 5 s of ultrasonic every 3 s, and the supermolecular VC nicotinamide solution is obtained after filtration. The supermolecular VC nicotinamide solution is placed in a vacuum drying box and dried for 48 h, and the drying temperature is 60℃, to obtain a supermolecular VC nicotinamide co-crystal.

[0059] Under an inert gas atmosphere, 4g of supramolecular VC nicotinamide cocrystal, 2g of ascorbate glucoside (AA2G), and 4g of hydroxypropyl-β-cyclodextrin were placed in deionized water and reacted for 24h. Simultaneously, the mixture was stirred at 45℃ and a stirring speed of 200 rad / min. After stirring for 24h, the mixture was dialyzed using a cellulose dialysis bag with a molecular weight of 2000 for 6h and 3 times. After dialysis, the mixture was dried in a vacuum freeze-drying oven for 72h at a freeze-drying temperature of -80℃ to obtain a dual supramolecular VC nicotinamide@AA2G encapsulated compound.

[0060] like Figure 2 As shown, the thermal decomposition behavior of the dual supramolecular VC nicotinamide @AA2G encapsulation, supramolecular VC nicotinamide cocrystal, ascorbate glucoside, and hydroxypropyl-β-cyclodextrin at a heating rate of 5.0 (K / min) was investigated using thermogravimetric analysis. The results showed that the dual supramolecular VC nicotinamide @AA2G encapsulation began to undergo thermal decomposition at approximately 63.49 °C, while the thermal decomposition of the supramolecular VC nicotinamide cocrystal, ascorbate glucoside (VC glucoside / AA2G), and hydroxypropyl-β-cyclodextrin occurred at approximately 154.7 °C, 190.65 °C, and 33.4 °C, respectively, indicating that the dual supramolecular VC nicotinamide @AA2G encapsulation is stable at room temperature.

[0061] Test Example 1

[0062] The dual supramolecular VC nicotinamide@AA2G encapsulation obtained in Example 1 was formulated into a 4% solution, and a 4% VC nicotinamide + AA2G mixed solution was also prepared. The transdermal efficacy of the above solutions was tested using the following method:

[0063] I. Use skin from the back of a piglet, carefully peel off the subcutaneous fat layer and connective tissue, rinse it clean with physiological saline, and place it in physiological saline for later use.

[0064] II. Transdermal experiments were conducted using the Franz cell method. The exposed skin area in the diffusion cell of the Franz diffusion apparatus was 1.13 cm². 2 The volume of the receiving chamber is 15 mL.

[0065] III. Take 1 mL of the aforementioned dual supramolecular VC nicotinamide @ AA2G encapsulated solution and VC nicotinamide + AA2G mixed solution, respectively, and place them on the exposed skin surface in the diffusion cell as the test solutions. Add 15 mL of physiological saline receiving solution to the receiving cell and place it in a constant temperature water bath at 32±1℃ with a stirring speed of 300 rad / min.

[0066] IV. Subcutaneous sample collection: 1 mL of receiving fluid was collected at 3, 6, 21 and 24 h. Immediately after sampling, 1 mL of receiving fluid was added to the receiving chamber, and the sample was collected at 24 h.

[0067] V. After filtration through a 0.22 μm microporous membrane, the sample was detected by high-performance liquid chromatography (HPLC).

[0068] The formula for calculating the permeability per unit area (1) is as follows:

[0069] (1)

[0070] Where: P: permeation volume per unit area; V: volume of receiving liquid in the receiving chamber, 15 mL; V0: volume of each sample taken, 1.0 mL; Ci: drug concentration in the receiving liquid during the first to n-1 samplings; Cn: sample concentration measured at the nth sampling point; S: exposed skin area in the diffusion cell, 1.13 cm². 2 .

[0071] Depend on Figure 3 It was found that, after 24 hours of percutaneous infiltration, the permeation per unit area of ​​the 4% dual supramolecular VC nicotinamide@AA2G encapsulated solution and the 4% VC nicotinamide + AA2G mixed solution, based on vitamin C content, were 545.16 and 333.45 μg / cm², respectively. 2 Based on nicotinamide content, the permeability per unit area of ​​the 4% dual supramolecular VC nicotinamide@AA2G encapsulated solution and the 4% VC nicotinamide + AA2G mixed solution were 4512.21 and 2704.44 μg / cm², respectively. 2 After 24 h of percutaneous penetration, the permeation capacity per unit area of ​​vitamin C and nicotinamide in the 4% dual supramolecular VC nicotinamide@AA2G encapsulated solution was 1.63 times and 1.67 times that of the 4% VC nicotinamide + AA2G mixed solution, respectively. The results indicate that the percutaneous penetration capacity of the dual supramolecular VC nicotinamide@AA2G encapsulated solution is superior to that of its mixture.

[0072] Test Example 2

[0073] The dual supramolecular VC nicotinamide@AA2G encapsulation obtained in Example 1 was formulated into a 4% aqueous solution and subjected to a closed patch test on human skin to test its safety.

[0074] Establishment of a skin irritation model: Thirty-three subjects aged 20-60 years with healthy skin were selected. Using a closed patch test method, 0.020g-0.025g of the test substance was placed in the patch test device, and a hypoallergenic adhesive tape was applied to the flexor side of the subject's forearm. The test substance was removed after 24 hours, and skin reactions were observed at 0.5, 24, and 48 hours after removal. The results were recorded according to the skin reaction grading standard of the "Cosmetic Safety Technical Specifications" (2015 edition).

[0075] The human skin closed patch test results of the double supramolecular VC nicotinamide@AA2G package are shown in Table 1. No adverse reactions occurred in 33 people.

[0076]

[0077] Test Example 3

[0078] The double supramolecular VC nicotinamide@AA2G package obtained in Example 1 was prepared into a 4% aqueous solution, and multiple skin irritation tests were performed to detect safety.

[0079] Test method: About 24 h before the test, the dorsal spine of 4 test animals (ordinary grade female New Zealand rabbits, 2063.82-2143.29 g) was shaved on both sides, without damaging the epidermis, and the shaved area was about 3 cm x 3 cm on both left and right sides. 0.5 mL of the sample was applied to the left side of the shaved skin with an area of 2.5 cm x 2.5 cm, and the other side of the skin was used as a control. Apply 1 time per day for 14 consecutive days. From the second day, shave before each application, remove residual test material with warm water, and observe the local skin reaction and score after 1 h.

[0080] The results of the multiple skin irritation test of the double supramolecular VC nicotinamide@AA2G package are shown in Table 2. The average score of the sample for each animal per day in the New Zealand rabbit multiple skin irritation test was 0, according to the skin irritation intensity classification of the Skin Irritation Test in the Cosmetics Safety Technical Specification (2015 edition), it belongs to non-irritation.

[0081]

[0082] Test Example 4

[0083] The double supramolecular VC nicotinamide@AA2G package obtained in Example 1 was prepared into a solution with a concentration of 4%, and a 1.6% supramolecular VC nicotinamide solution was prepared according to the conversion of an equal mass of VC nicotinamide. The stability of both was investigated after being stored at room temperature, 45°C, 4°C, and -20°C for one month, and observed at 0D, 14D, and 28D. The discoloration is shown in Figure 4 .

[0084] From Figure 4It can be seen that the color of 4% double supermolecular VC nicotinamide@AA2G package solution and 1.6% supermolecular VC nicotinamide solution changes at 14D and 28D, and the longer the time, the greater the color change. At 14D and 28D, the color change of the two samples under the condition of 45℃ is the largest, followed by normal temperature, and the color change under the condition of 4℃ and-20℃ is the smallest. In addition, under the same conditions and for the same number of days, the color change of 4% double supermolecular VC nicotinamide@AA2G package solution is smaller than that of 1.6% supermolecular VC nicotinamide solution. Therefore, under the condition that the content of VC nicotinamide is the same, the discoloration of double supermolecular VC nicotinamide@AA2G package is smaller than that of supermolecular VC nicotinamide, which plays a role in delaying discoloration and achieves the effect of enhancing stability.

[0085] Test Example 5

[0086] The double supermolecular VC nicotinamide@AA2G package obtained in Example 1 was prepared into 10% aqueous solution and sequentially diluted, and the DPPH free radical scavenging rate and ABTS

[0087] free radical scavenging rate were determined, and the test method was as follows: ＋

[0088] DPPH free radical scavenging rate determination: sample tubes (T), sample background (T0), DPPH tubes (C) and solvent background (C0) were set up, and 3 parallel tubes were set up for each sample tube (T) of each test concentration. 1 mL of the same concentration of sample solution was added to each of the sample tube (T) and the sample background (T0). 2 mL was added to the test tube and mixed. 1 mL of DPPH ethanol solution was added to the sample tube (T) and the DPPH tube (C), and gently shaken, and left to stand at room temperature for 5 min. Each reaction solution was added to a 1 cm cuvette, and the absorbance was measured at 517 nm, and the DPPH free radical scavenging rate was calculated by formula (2), and the results are shown in Table 3 and Figure 5 .

[0089] DPPH scavenging rate (%) (2)

[0090] ABTS ＋ scavenging rate determination: according to the characteristics of the sample and the recommended addition amount, the appropriate concentration gradient was set, and the sample solution was prepared with PBS buffer as the solvent. Sample tubes (A s ), sample background (A b ), sample blank tubes (A0) were set up, and 3 parallel tubes were set up for each sample tube (A s ) of each test concentration, and 3 parallel tubes were also set up for the sample blank tube (A0). 1 mL of the same concentration of sample solution was added to each of the sample tube (A s ) and the sample background (A b ​Each of the sample tubes (A s ) and the sample blank tube (A0) was added with 0.8 mL of ABTS + working solution, and the sample blank (A b ) was added with 0.8 mL of PBS buffer. The reaction was carried out in the dark for 6 min. The solution in each reaction tube was moved into a 1 cm cuvette, and the absorbance was measured at 734 nm. The DPPH free radical scavenging rate was calculated according to Formula 3, and the results are shown in Table 4 and Figure 6 .

[0091] ABTS ＋ scavenging rate (%) (3)

[0092]

[0093] The data in the above table are mean ± relative deviation.

[0094] Statistical method: SPSS software was used, and t-test method was used for analysis, with a test level of α = 0.05; P ≥ 0.05, indicating no statistical difference; 0.01 < P < 0.05, having significant difference; P < 0.01, having very significant difference; P < 0.001, having extremely significant difference.

[0095]

[0096] The results of the DPPH free radical scavenging rate of the double supramolecular VC nicotinamide@AA2G package are shown in Table 3 and Figure 5 , and the half scavenging rate concentration IC 50 = 0.108% (95% confidence interval IC 50 : 0.088% ~ 0.134%), which has antioxidant effect at this concentration. The greater the mass concentration, the better the DPPH free radical scavenging effect. This is because the sample can pair with the single electron existing in the DPPH free radical, thereby reducing it, weakening the color of the purple alcohol solution, and measuring the absorbance at 517 nm wavelength. The greater the absorbance change, the stronger the scavenging ability.

[0097] The results of the ABTS ＋ free radical scavenging rate of the double supramolecular VC nicotinamide@AA2G package are shown in Table 4 and Figure 6 , and the half scavenging rate concentration IC 50 = 0.108% (95% confidence interval IC 50 : 0.042% ~ 0.104%), which has antioxidant effect at this concentration. ABTS reacts with oxidants to become ABTS ＋Free radicals (blue-green), the sample will ABTS ＋ reduced to colorless ABTS, and its absorbance was measured at 734 nm. The greater the change in absorbance, the stronger its scavenging ability.

[0098] Test Example 6

[0099] Keratinocytes were used as experimental objects, and an in vitro oxidative damage model was established by irradiation with a certain dose of long-wave ultraviolet light (UVB). The antioxidant efficacy of the double supramolecular VC nicotinamide@AA2G package was evaluated by detecting the changes in the content of reactive oxygen species (ROS).

[0100] The cytotoxicity results are shown in Table 5, the relative content of ROS is shown in Table 6, and Figure 7 the ROS inhibition rate results are shown in Table 7 and Figure 8 .

[0101]

[0102]

[0103]

[0104] Under the conditions of this experiment, the ROS content of the model group (M) was statistically different from that of the blank control (BC) group and the positive control (PC) group (P<0.05), the experimental modeling was successful, and the positive response was normal.

[0105] Under the conditions of this experiment, the relative content of ROS in keratinocytes corresponding to the sample at 0.12% (v / v), 0.08% (v / v), and 0.04% (v / v) concentrations was significantly lower than that of the model group (M) (P<0.01). The relative content of ROS in keratinocytes at 0.12% (v / v), 0.08% (v / v), and 0.04% (v / v) concentrations was significantly reduced by 38.70%, 32.51%, and 17.66%, respectively.

[0106] Test Example 7

[0107] The double supramolecular VC nicotinamide@AA2G package was prepared into an essence according to the following formula: water, butylene glycol, 1,3-propanediol, betaine, double supramolecular VC nicotinamide@AA2G package, p-hydroxyphenylacetone, 1,2-hexanediol, sodium hydroxide, xanthan gum, methyl gluceth-20, dipotassium glycyrrhizate, sodium hyaluronate, glycerol, golden yellow chamomile extract, field mint leaf extract, spilanthes extract, rosmarinus officinalis extract, aloe barbadensis miller extract, sophora flavescens root extract, disodium EDTA, PEG-60 hydrogenated castor oil, fragrance, sodium benzoate, and potassium sorbate.

[0108] The difference between the VC nicotinamide + AA2G mixture essence formula and the double supermolecular VC nicotinamide@AA2G package essence formula lies in that: the double supermolecular VC nicotinamide@AA2G package is replaced by physical mixing raw materials of equal mass parts of VC, nicotinamide, hydroxypropyl-β-cyclodextrin and ascorbic acid glucoside, and the rest of the ingredients and the ratio are the same as those of the double supermolecular VC nicotinamide@AA2G package essence formula.

[0109] 31 subjects used the double supermolecular VC nicotinamide@AA2G package essence and the VC nicotinamide + AA2G mixture essence for 28 consecutive days, and skin data was collected at 0D, 14D and 28D, respectively. The normality of skin brightness (L), melanin (MI) and skin (ITA°) was verified, and the statistical results are shown in Tables 8, 9 and 10.

[0110]

[0111] Note: 1. Mean 1 The average value ± standard deviation measured at this time point of the two groups of subjects. Change rate 2 = (value after use - value before use) / value before use × 100%.

[0112] 2. "n.s." (indicates no statistical difference), P≥0.05; "*" (indicates significant difference), 0.01≤P<0.05; "**" (indicates very significant), 0.001≤P<0.01; "***" (indicates extremely significant), P<0.001.

[0113] 3. The sample concentration of VC nicotinamide + AA2G mixture essence and double supermolecular VC nicotinamide@AA2G package essence is 4%.

[0114]

[0115] 2 groups of subjects used VC nicotinamide + AA2G mixture essence and double supermolecular VC nicotinamide@AA2G package essence for 28 days, respectively, and skin data was collected at 0D, 14D and 28D, respectively. The normality of melanin MI, brightness L and ITA° was verified, and the statistical results are shown:

[0116] (1) After using the product for 14 days and 28 days, the melanin MI improvement rates of the VC nicotinamide + AA2G mixture essence of the subjects were 0.80% (P<0.01) and 0.53% (P≥0.05) respectively; the melanin MI improvement rates of the double supramolecular VC nicotinamide@AA2G package essence of the subjects were 3.02% (P<0.001) and 3.33% (P<0.001) respectively, so the double supramolecular VC nicotinamide@AA2G package essence has a significantly better effect of reducing skin melanin than the VC nicotinamide + AA2G mixture essence.

[0117] (2) After using the product for 14 days and 28 days, the brightness L increase rates of the VC nicotinamide + AA2G mixture essence of the subjects were 0.50% (P≥0.05) and 0.05% (P≥0.05) respectively; the brightness L increase rates of the double supramolecular VC nicotinamide@AA2G package essence of the subjects were 2.10% (P<0.01) and 2.96% (P<0.001) respectively, so the double supramolecular VC nicotinamide@AA2G package essence has a significantly better effect of increasing skin brightness than the VC nicotinamide + AA2G mixture essence.

[0118] (3) After using the product for 14 days and 28 days, the ITA° increase rates of the VC nicotinamide + AA2G mixture essence of the subjects were 6.31% (P<0.001) and 1.88% (P≥0.05) respectively; the ITA° increase rates of the double supramolecular VC nicotinamide@AA2G package essence of the subjects were 10.94% (P<0.01) and 12.87% (P<0.001) respectively, so the double supramolecular VC nicotinamide@AA2G package essence has a significantly better effect of increasing skin ITA° than the VC nicotinamide + AA2G mixture essence.

[0119] In summary, the whitening effect of the double supramolecular VC nicotinamide@AA2G package essence is significantly better than that of the VC nicotinamide + AA2G mixture essence.

[0120] In summary, the application provides a double supramolecular VC nicotinamide@AA2G package and a preparation method and application thereof, the preparation method comprising the steps of: adding vitamin C and nicotinamide into an organic solvent, performing first stirring treatment and ultrasonic treatment at a first predetermined temperature, filtering and performing vacuum drying treatment after reacting for a first predetermined time, to obtain a supramolecular VC nicotinamide co-crystal; adding ascorbic acid glucoside, hydroxypropyl-beta-cyclodextrin and the supramolecular VC nicotinamide co-crystal into deionized water, performing second stirring treatment and dialysis treatment at a second predetermined temperature, and performing freeze-drying treatment after reacting for a second predetermined time, to obtain the double supramolecular VC nicotinamide@AA2G package. The application takes vitamin C and nicotinamide as precursors, synthesizes a supramolecular VC nicotinamide co-crystal through a supramolecular modification reaction, and uses hydroxypropyl-beta-cyclodextrin to wrap the supramolecular VC nicotinamide co-crystal and ascorbic acid glucoside (AA2G), to obtain the double supramolecular VC nicotinamide@AA2G package. The double supramolecular package prepared by the method can improve the stability of vitamin C and the permeability of skin, ensure the original whitening effect of vitamin C and nicotinamide, fully play the role of inhibiting melanin, has good antioxidant property, greatly improves the bioavailability, and enhances the stability and application effect.

[0121] It should be understood that the application is not limited to the above examples, and can be improved or changed according to the above description by those skilled in the art, and all these improvements and changes shall belong to the protection scope of the appended claims of the application.

Claims

1. A method for preparing a dual supramolecular VC nicotinamide@AA2G package, characterized in that, The method comprises the steps of: adding vitamin C and nicotinamide into an organic solvent, performing a first stirring treatment and an ultrasonic treatment at a first predetermined temperature for a first predetermined time, filtering and vacuum drying to obtain a supramolecular VC-nicotinamide co-crystal; adding ascorbic acid glucoside, hydroxypropyl-beta-cyclodextrin and the supramolecular VC-nicotinamide co-crystal into deionized water, performing a second stirring treatment and a dialysis treatment at a second predetermined temperature for a second predetermined time, and freeze-drying to obtain a double supramolecular VC-nicotinamide@AA2G package.

2. The process for the preparation of dual supramolecular VC nicotinamide@AA2G package as claimed in claim 1, wherein, The molar ratio of the vitamin C to the nicotinamide is (1:3)-(3:1).

3. The process for the preparation of dual supramolecular VC nicotinamide@AA2G package as claimed in claim 1, wherein, The mass ratio of the supramolecular VC-nicotinamide co-crystal, the ascorbic acid glucoside and the hydroxypropyl-beta-cyclodextrin is (2-5):(1-4):(3-7).

4. The process for the preparation of dual supramolecular VC nicotinamide@AA2G package as claimed in claim 1, wherein, The first predetermined time is 24-48h, and the second predetermined time is 24-48h.

5. The method of preparing a dual supramolecular VC nicotinamide@AA2G package according to claim 1, characterized in that, The first predetermined temperature is 40-80℃, the stirring speed of the first stirring treatment is 30-350rad / min, the stirring time of the first stirring treatment is 24-48h, the ultrasonic frequency is 20-50kHz, the ultrasonic power is 1000-2000W, the ultrasonic time is 4-12h, and the ultrasonic interval time is 2-10s per 1-5s.

6. The method of preparing a dual supramolecular VC nicotinamide@AA2G package according to claim 1, characterized in that, The second predetermined temperature is 30-70℃, the stirring speed of the second stirring treatment is 50-450rad / min, the stirring time of the second stirring treatment is 24-48h, the dialysis bag is made of cellulose, the molecular weight of the dialysis bag is 2000, the dialysis time is 2-6h, and the dialysis frequency is 1-3 times.

7. The method of claim 1, wherein the dual supramolecular VC nicotinamide@AA2G package is prepared by the steps of: The vacuum drying temperature is 50-80℃, and the freeze-drying temperature is -80℃±5℃.

8. The method of claim 1, wherein the dual supramolecular VC nicotinamide@AA2G package is prepared by, The preparation method of the double supramolecular VC-nicotinamide@AA2G package is performed in an inert gas atmosphere.

9. A dual supramolecular VC nicotinamide@AA2G wrap, characterized in that, The double supramolecular VC-nicotinamide@AA2G package is prepared by the method of any one of claims 1-8.

10. Use of the double supramolecular VC-nicotinamide@AA2G package of claim 9 in the preparation of a cosmetic product.

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