Triple supramolecular whitening composition as well as preparation method and application thereof

Abstract

The invention discloses a triple supramolecular whitening composition as well as a preparation method and application thereof, and belongs to the technical field of cosmetics. According to the invention, cyclodextrin is used as a main body material, the active ingredients of nicotinamide, glabridin and ferulic acid are wrapped in cyclodextrin through a supramolecular self-assembly technology, and the obtained inclusion compound can improve the solubility, stability and transdermal effect of nicotinamide, ferulic acid and glabridin; cyclodextrin can control slow release of ferulic acid and glabridin, the synergistic skin care effect of the three components is fully exerted, and multi-target coordinated whitening is achieved.

Description

Technical Field

[0001] This invention relates to the field of cosmetic technology, and more specifically, to a triple supramolecular whitening composition, its preparation method, and its application. Background Technology

[0002] With the increasing demand for skin whitening products from consumers, the development of safe and effective whitening active ingredient compositions has become a research hotspot in the cosmetics industry. Traditional whitening agents such as hydroquinone and kojic acid have strict limitations on their application due to cytotoxic or photosensitizing side effects. In recent years, naturally derived whitening ingredients have received considerable attention due to their safety advantages; however, single-ingredient products often suffer from poor stability and low transdermal efficiency, hindering their practical application effectiveness.

[0003] Niacinamide (vitamin B3), a classic skin-whitening ingredient, can inhibit melanin transport and promote keratin metabolism. However, its target is singular, and high concentrations can easily cause skin irritation. Ferulic acid, a natural antioxidant, can reduce melanin production by inhibiting tyrosinase activity, but its photothermal sensitivity makes it easily degraded and inactivated in formulations. Glabridin, a highly effective skin-whitening ingredient extracted from licorice root, has significantly better tyrosinase inhibition than arbutin, but its extremely low water solubility (<0.1 mg / mL) severely limits its bioavailability. Although some studies have attempted to combine these ingredients in pairs (such as the niacinamide-ferulic acid composition disclosed in CN201810235678.X), the significant differences in their physicochemical properties make direct physical mixing prone to phase separation, and the dissolution problem of glabridin remains unresolved, making it difficult to achieve synergistic effects.

[0004] Supramolecular inclusion technology offers a new approach to solving the aforementioned problems. Cyclodextrins, liposomes, and other carriers have been used to improve the solubility of poorly soluble components (e.g., JP2019523157A), but traditional methods have insufficient drug loading efficiency for multi-component complexes and are prone to active ingredient leakage during high-temperature or long-term storage. While the existing patent CN202110543216.8, which uses β-cyclodextrin to encapsulate glycyrrhizin, improves solubility, it does not solve the problems of synergistic drug loading and sustained release of multiple components. Furthermore, existing supramolecular systems mostly focus on the delivery of single active ingredients, lacking composite carrier systems designed for multi-target mechanisms of action in skin whitening.

[0005] Therefore, developing a triple supramolecular composition that can simultaneously achieve efficient loading, improved stability, and synergistic transdermal effects of three active ingredients has become a key technological direction for breaking through the bottleneck in the development of skin whitening products.

[0006] In view of this, the present invention is proposed. Summary of the Invention

[0007] The purpose of this invention is to provide a triple supramolecular whitening composition, its preparation method and application. This composition achieves efficient loading, improved stability and transdermal sustained release of three active ingredients through the encapsulation effect of cyclodextrin, ultimately achieving a synergistic whitening effect by inhibiting melanin production through multiple pathways.

[0008] This invention is implemented as follows: In a first aspect, the present invention provides a triple supramolecular whitening composition, the raw materials of which include nicotinamide, ferulic acid, glycyrrhizin, cyclodextrin and cosolvent.

[0009] Secondly, the present invention provides a method for preparing the above-mentioned triple supramolecular whitening composition, comprising: Glycyrrhizin was dissolved in a solubilizer, heated and stirred for the first time to obtain a glycyrrhizin solution; the glycyrrhizin solution was added to a cyclodextrin aqueous solution, heated and stirred for the second time; Then ferulic acid was added and stirred for the third time; then nicotinamide was added and heated for the fourth time; after the temperature was reduced to room temperature, a triple supramolecular whitening composition was obtained.

[0010] Thirdly, the present invention provides the application of the above-mentioned triple supramolecular whitening composition in the preparation of cosmetics.

[0011] The present invention has the following beneficial effects: (1) This invention uses cyclodextrin as the main material and encapsulates the active ingredients nicotinamide, glycyrrhizin and ferulic acid inside the cyclodextrin through supramolecular self-assembly technology. The resulting inclusion complex can improve the solubility, stability and transdermal effect of nicotinamide, ferulic acid and glycyrrhizin. The cyclodextrin can control the slow release of ferulic acid and glycyrrhizin, give full play to the synergistic skin care effect of these three ingredients, and achieve multi-target coordinated whitening.

[0012] (2) The triple supramolecular whitening composition of the present invention can improve the bioavailability of nicotinamide, ferulic acid and glycyrrhizin, reduce the risk of nicotinamide directly contacting the skin through encapsulation, and is more stable and safer in formulation application.

[0013] (3) The triple supramolecular whitening composition of the present invention can achieve the requirement of high transparency, and therefore can be applied to water-based emulsions and creams in conventional cosmetics, especially water-based formulations. Attached Figure Description

[0014] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0015] Figure 1 This is a schematic diagram of the triple supramolecular whitening composition in Examples 4-8; Figure 2 Photograph of the triple supramolecular whitening composition in Experiment Example 1; Figure 3 The graph shows the tyrosinase activity detection data of the triple supramolecular whitening composition in Experiment Example 3. Figure 4 The graph shows the detection data of DPPH free radical scavenging rate of the triple supramolecular whitening composition in Experiment Example 4; Figure 5 This is a graph showing the particle size distribution data of the triple supramolecular whitening composition in Experiment Example 5; Figure 6 This is a graph showing the transdermal absorption data of the triple supramolecular whitening composition in Experimental Example 6; Figure 7 Photographs showing the stability of the raw materials in the triple supramolecular whitening composition of Experiment Example 7; Figure 8 Photographs showing the stability of the essence water from the triple supramolecular whitening composition in Experiment Example 7; Figure 9 Photographs showing the stability of the face cream made from the triple supramolecular whitening composition in Experiment Example 7. Detailed Implementation

[0016] To make the objectives, 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. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0017] Because the effects of a single whitening ingredient are limited, it is recommended to combine it with other whitening ingredients for a more comprehensive effect. In practical applications, the differences in the physicochemical properties of different whitening ingredients lead to poor stability of the resulting complexes. To address this, the inventors proposed using cyclodextrin to encapsulate multiple whitening ingredients, forming supramolecular structures. However, the following problems were discovered during the assembly process: 1. Differences in molecular size and polarity: The molecular size and polarity of different whitening ingredients vary significantly, leading to cyclodextrin cavity compatibility conflicts and unstable inclusion of active molecules.

[0018] 2. Competitive binding exists when multiple components coexist: Cyclodextrin preferentially includes molecules with high polarity matching (such as the ferulic acid carboxylic acid group and the cyclodextrin hydroxyl group forming a hydrogen bond). However, if the ratio is not set properly, some whitening ingredients may be rejected due to steric hindrance.

[0019] 3. Traditional aqueous solution methods are difficult to dissolve hydrophobic whitening ingredients simultaneously.

[0020] 4. Conventional methods for encapsulating whitening ingredients with different physicochemical properties have a low encapsulation rate.

[0021] To improve the above problems, the inventors have obtained a triple supramolecular whitening composition with high inclusion rate and high stability by screening suitable cyclodextrins and cosolvents, designing ligands, and optimizing the preparation process. The composition includes nicotinamide, ferulic acid, glycyrrhizin, hydroxypropyl-β-cyclodextrin (HP-β-CD), and cosolvent.

[0022] HP-β-CD is specifically 6-hydroxypropyl-β-cyclodextrin, which, as a carrier, can encapsulate nicotinamide, ferulic acid, and glycyrrhizin within HP-β-CD through supramolecular assembly. Compared to other carriers, HP-β-CD exhibits better inclusion stability.

[0023] The combination of niacinamide, glycyrrhizin, and ferulic acid enhances the whitening effect through the multi-pathway synergy of glycyrrhizin (tyrosinase inhibitor) and niacinamide (melanin transport blocker), while improving the stability of the ingredients by utilizing the hydrogen bond co-crystal formed by the two. In the HP-β-CD inclusion process, the size matching between the hydrophobic group of glycyrrhizin and the cyclodextrin cavity is the key to improving the inclusion efficiency, while ferulic acid, as an added antioxidant, further strengthens the whitening pathway.

[0024] Ferulic acid was chosen as one of the whitening ingredients because it has moderate hydrophobicity (containing a hydrophobic benzene ring group and a hydrophilic carboxylic acid group). Its molecular size (molecular weight 194.19) falls between that of hydrophilic small-molecule niacinamide (molecular weight 122.12) and hydrophobic large-molecule glycyrrhizin (molecular weight 324.37), allowing it to both embed in the HP-β-CD cavity and connect to other active ingredients via non-covalent bonds. Its carboxylic acid group can form hydrogen bonds with the hydroxyl groups of HP-β-CD, preferentially occupying the cyclodextrin cavity. In other words, ferulic acid acts as a "bridging ligand," connecting glycyrrhizin via π-π stacking, while simultaneously coordinating the inclusion of niacinamide and cyclodextrin through hydrogen bonds.

[0025] In this supramolecular system, ferulic acid, as the sole ligand, has the following advantages: Spatial adaptation: It resolves the inclusion conflict of HP-β-CD on multi-component active ingredients through size and polarity matching; Dynamic bridging: It tandemly links nicotinamide and glycyrrhizin through hydrogen bonds and π-π stacking to form a stable ternary complex; Synergistic effect: Its own antioxidant activity synergistically inhibits melanin production with glycyrrhizin, while protecting nicotinamide from hydrolysis.

[0026] In some embodiments, the co-solvent is 1,3-butanediol. Experiments have shown that 1,3-butanediol is more beneficial in enhancing the stability of the assembly compared to other co-solvents.

[0027] In some embodiments, the above-mentioned triple supramolecular whitening composition further contains a preservative, namely p-hydroxyacetophenone and hexanediol, wherein the mass ratio of p-hydroxyacetophenone to hexanediol in the preservative is 0.5-1:2-5. The above two preservatives do not affect the stability of the supramolecular complex system while providing preservation.

[0028] In some embodiments, the above-described triple supramolecular whitening composition further contains a stabilizer, which is glycerin.

[0029] In some embodiments, the above-mentioned triple supramolecular whitening composition comprises the following raw materials in weight percentage: nicotinamide 0.2%-10%, ferulic acid 0.1%-5%, glycyrrhizin 0.1%-3%, 6-hydroxypropyl-β-cyclodextrin 1%-10%, cosolvent 20%-70%, preservative 1%-5%, stabilizer 3%-5%, and the balance being deionized water.

[0030] In some embodiments, the pH of the above-described triple supramolecular whitening composition is 4-5.

[0031] This invention enhances assembly stability by selecting specific solvent systems and controlling pH, while simultaneously utilizing dynamic covalent bonds (such as pH-sensitive hydrogen bonds). Specifically, under weakly acidic conditions, the ferulic acid carboxyl group remains protonated (-COOH), and the phenolic hydroxyl group (-OH) remains undissociated, serving as a hydrogen bond donor. 1,3-Butanediol possesses a bifunctional group; its hydroxyl group (hydrophilic) forms hydrogen bonds with ferulic acid COO⁻, while the methyl group (hydrophobic) promotes the encapsulation of glycyrrhizin and reduces water molecule interference. Furthermore, in a butanediol-water mixed solvent, the number of intermolecular hydrogen bonds in ferulic acid increases threefold. Therefore, maintaining the pH in the system at approximately 4-5 reduces electrostatic repulsion and increases assembly order.

[0032] The present invention provides the following method for preparing the above-mentioned triple supramolecular whitening composition: S1. Add a solubilizing agent to glycyrrhizin, heat and stir until dissolved to obtain a glycyrrhizin solution; S2. Add deionized water to cyclodextrin and stir until dissolved to obtain an aqueous solution of cyclodextrin; S3. Pour the glycyrrhizin solution into the cyclodextrin aqueous solution, heat and stir for the first time, add ferulic acid, stir for the second time, add nicotinamide, heat and stir for the third time, and then cool to room temperature to obtain the triple supramolecular whitening composition.

[0033] To improve inclusion efficiency and the stability of the inclusion complex, this invention employs a stepwise inclusion strategy: first, glycyrrhizin is included with HP-β-CD; then, by controlling temperature, rotation speed, and stirring time, ferulic acid and nicotinamide are gradually introduced to achieve layered loading. This method increases the inclusion efficiency from 55% in a single step to 92%.

[0034] In some embodiments, the above-mentioned triple supramolecular whitening composition also contains preservatives and stabilizers. During preparation, the preservatives and stabilizers are added after the temperature is lowered to room temperature in S3.

[0035] In some embodiments, the heating temperature in steps S1 and S3 is 45-80°C.

[0036] In some embodiments, in steps S1-S3, the stirring speed is 120 rpm and the time is 10-40 min.

[0037] In this invention, glycyrrhiza glabra is a pale yellow powder with a content of not less than 90% as determined by HPLC; nicotinamide is a white crystalline powder with a content of not less than 98% as determined by HPLC; ferulic acid is a white or off-white powder with a content of not less than 98% as determined by HPLC; and cyclodextrin is a white powder with a content of not less than 97% as determined by HPLC.

[0038] The above preparation method can obtain a complex containing nicotinamide, ferulic acid and glycyrrhizin encapsulated within cyclodextrin. The triple supramolecular whitening composition obtained by combining this complex with other ingredients can not only improve the stability of the three main active ingredients and improve the bioavailability of glycyrrhizin, but also synergistically enhance the whitening effect of the three main active ingredients. Therefore, this composition can be used as a new and efficient raw material for whitening products and has broad application prospects.

[0039] Therefore, the present invention also provides the application of the above-mentioned triple supramolecular whitening composition in the preparation of whitening cosmetics.

[0040] Specifically, the cosmetic is formed directly from the above-mentioned triple supramolecular whitening composition (i.e., the above-mentioned triple supramolecular whitening composition is directly used), or the above-mentioned triple supramolecular whitening composition is added to the carrier of different dosage form cosmetics to form different dosage form cosmetics.

[0041] In the cosmetics of this invention, the dosage form used can be cream, lotion, serum, skin care gel, lotion, mask or other beauty products for skin care.

[0042] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0043] Example 1 This embodiment provides a triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition, the raw materials of which are as follows: Nicotinamide 6.77%, ferulic acid 0.54%, glycyrrhizin 0.90%, 1,3-butanediol 55.5%, 6-hydroxypropyl-β-cyclodextrin 8.55%, balance deionized water.

[0044] The preparation method of the above-mentioned triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition is as follows: S1. Add 1,3-butanediol to glycyrrhizin, heat and stir until dissolved to obtain glycyrrhizin solution; S2. Add deionized water to 6-hydroxypropyl-β-cyclodextrin and stir until dissolved to obtain an aqueous cyclodextrin solution; S3. Pour the glycyrrhizin solution into the cyclodextrin aqueous solution, heat and stir to mix, add ferulic acid and stir to mix, add nicotinamide, heat and stir to mix, and then cool to room temperature to obtain a triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition.

[0045] The heating temperature in steps S1 and S3 is 55°C.

[0046] In steps S1-S3, the mixing is carried out at a stirring speed of 120 rpm for 40 minutes.

[0047] The difference between Comparative Examples 1-5, Examples 2-3, and Example 1 lies in the types of solubilizers and cyclodextrins used in the raw materials of the supramolecular whitening compositions; the amounts of other components added and the preparation methods are the same. The mass ratios of the main active ingredients and the stability results of each composition are shown in Table 1. Table 1 shows the stability results of Comparative Examples 1-5 and Examples 1-3.

[0048] Example 4 This embodiment provides a triple supramolecular whitening composition and its preparation method. The composition consists of the following raw material components in weight percentage: nicotinamide 6.91%, ferulic acid 0.55%, glycyrrhizin 0.92%, 1,3-butanediol 56.60%, 6-hydroxypropyl-β-cyclodextrin 1.74%, glycerol 5%, and the balance being deionized water.

[0049] The preparation method of the above-mentioned triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition is as follows: S1. Add deionized water to 6-hydroxypropyl-β-cyclodextrin and stir until dissolved to obtain an aqueous cyclodextrin solution; S2. Add 1,3-butanediol, glycyrrhizin, ferulic acid and nicotinamide to a cyclodextrin aqueous solution, heat and stir to prepare a triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition.

[0050] The heating temperature in step S2 is 55°C.

[0051] In steps S1-S2, the mixing is carried out at a stirring speed of 120 rpm for 40 minutes.

[0052] The inclusion rate of the triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition prepared according to the method of Example 4 was 55%.

[0053] Example 5 The difference between the triple supramolecular whitening composition in this embodiment and that in Example 4 lies in the preparation method. The specific steps are as follows: S1. Add 1,3-butanediol to glycyrrhizin, heat and stir until dissolved to obtain glycyrrhizin solution; S2. Add ferulic acid to the glycyrrhizin solution, heat and stir until dissolved to obtain a ferulic acid-glycyrrhizin solution; S3. Add deionized water to 6-hydroxypropyl-β-cyclodextrin and stir until dissolved to obtain an aqueous cyclodextrin solution; S4. Pour the ferulic acid glycyrrhizin solution into the cyclodextrin aqueous solution, heat and stir for the first time, add nicotinamide, heat and stir for the second time, cool to room temperature, add glycerol, and stir for the third time to obtain a triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition.

[0054] The heating temperature in steps S1, S2 and S4 is 55°C.

[0055] In steps S1-S4, the mixing is carried out at a stirring speed of 120 rpm for 40 minutes.

[0056] The inclusion rate of the triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition prepared according to the method in Example 5 was 62%.

[0057] Example 6 The difference between the triple supramolecular whitening composition in this embodiment and that in Example 4 lies in the preparation method. The specific steps are as follows: S1. Add 1,3-butanediol to glycyrrhizin, heat and stir until dissolved to obtain glycyrrhizin solution; S2. Add deionized water to 6-hydroxypropyl-β-cyclodextrin and stir until dissolved to obtain an aqueous cyclodextrin solution; S3. Pour the glycyrrhizin solution into the cyclodextrin aqueous solution, heat and stir for the first time, add ferulic acid, stir for the second time, add nicotinamide, heat and stir for the third time, cool to room temperature, add glycerol, and stir for the fourth time to obtain a triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition.

[0058] The heating temperature in steps S1 and S3 is 55°C.

[0059] In steps S1-S3, the mixing is carried out at a stirring speed of 120 rpm for 40 minutes.

[0060] The inclusion rate of the triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition prepared according to the method of Example 6 was 92%.

[0061] Example 7 The difference between the triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition in this embodiment and that in Example 4 lies in the different preparation methods. The specific steps are as follows: S1. Add 1,3-butanediol to glycyrrhizin, heat and stir until dissolved to obtain glycyrrhizin solution; S2. Add deionized water to 6-hydroxypropyl-β-cyclodextrin and stir until dissolved to obtain an aqueous cyclodextrin solution; S3. Nicotinamide was added to a cyclodextrin aqueous solution and stirred for the first time. Glycyrrhizin solution was added, and the mixture was heated and stirred for the second time. Ferulic acid was added, and the mixture was heated and stirred for the third time. The temperature was lowered to room temperature, and glycerol was added. The mixture was stirred for the fourth time to obtain a triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition.

[0062] The heating temperature in steps S1 and S3 is 55°C.

[0063] In steps S1-S3, the mixing is carried out at a stirring speed of 120 rpm for 40 minutes.

[0064] The inclusion rate of the triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition prepared according to the method of Example 7 was 76%.

[0065] Example 8 The difference between the triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition in this embodiment and that in Example 4 lies in the different preparation methods. The specific steps are as follows: S1. Add 1,3-butanediol to glycyrrhizin, heat and stir until dissolved to obtain glycyrrhizin solution; S2. Add a co-solvent to ferulic acid, heat and stir until dissolved to obtain a ferulic acid solution; S3. Add deionized water to 6-hydroxypropyl-β-cyclodextrin and stir until dissolved to obtain an aqueous cyclodextrin solution; S4. Pour ferulic acid solution into cyclodextrin aqueous solution, heat and stir for the first time, add glycyrrhizin solution, heat and stir for the second time, add nicotinamide, heat and stir for the third time, cool to room temperature, add glycerol, and stir for the fourth time to obtain a triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition.

[0066] The heating temperature in steps S1, S2 and S4 is 55°C.

[0067] In steps S1-S4, the mixing is carried out at a stirring speed of 120 rpm for 40 minutes.

[0068] The inclusion rate of the triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition prepared according to the method of Example 8 was 80%.

[0069] In Examples 4-8, a triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition was prepared according to different processes, and the results were as follows: Figure 1 As shown.

[0070] In Example 4, the composition was unstable, immediately precipitating a large amount of crystals, and the liquid was yellow. In Example 5, the composition was unstable, slowly precipitating a large amount of crystals, and the liquid was slightly yellow. In Example 6, the composition was relatively stable, a light yellow transparent liquid. In Example 7, the composition was unstable, precipitating a small amount of crystals, and the liquid was yellow. In Example 8, the composition was unstable, precipitating a small amount of crystals, and a light yellow transparent liquid. This indicates that using Example 6 to prepare the triple supramolecular nicotinamide ferulic acid glycyrrhizin whitening composition yielded the best results.

[0071] Experimental Example 1 Based on the effective concentrations of niacinamide, ferulic acid, and glycyrrhizin in cosmetics being 2%, 0.02%, and 0.05%, respectively, to better facilitate their application in formulations, the mass concentrations of niacinamide, ferulic acid, and glycyrrhizin were increased during the preparation of the triple supramolecular whitening composition to achieve their effective concentrations in cosmetics. The formulation was carried out according to the proportions (wt%) in Table 2. Specific experimental results are as follows. Figure 2 As shown in Table 2: Table 2 Stability test results

[0072] From Table 2 and Figure 2 As can be seen, the triple supramolecular whitening compositions of Examples 11, 13, 16, and 17 are relatively stable, with no crystal precipitation, and are almost light yellow transparent liquids; the concentrations of nicotinamide, ferulic acid, and glycyrrhizin are increased to 10.32%, 1.62%, and 2.70%, respectively.

[0073] Experiment Example 2 In Examples 11, 13, 16, and 17, preservatives and stabilizers were added respectively. The preservatives were p-hydroxyacetophenone and hexanediol in a weight ratio of 1:4, and the stabilizer was glycerol. The formulations were prepared according to the proportions (wt%) in Table 3, and the specific experimental results are as follows: Table 3 Stability results for each experimental group

[0074] As can be seen from the results in Table 3, adding the preservatives and stabilizers selected in this invention does not affect the stability of the triple supramolecular whitening composition.

[0075] Experimental Example 3 The determination of the DPPH free radical scavenging rate of the triple supramolecular whitening composition may specifically include the following steps: The DPPH free radical scavenging ability of the triple supramolecular whitening composition (Example 16) was determined by spectrophotometry. Utilizing the characteristic absorption peak of a purple cluster at 517 nm in anhydrous DPPH-ethanol solution, the decrease in absorbance at 517 nm after the addition of an antioxidant was used to represent its DPPH free radical scavenging ability.

[0076] (1) Preparation of DPPH ethanol solution: Weigh 1 mg of DPPH and dissolve it in 12.5 mL of anhydrous ethanol to prepare a DPPH concentration of 2 × 10⁻⁶. -4 mol / L; store at 0-4℃ protected from light; use vitamin C (0.5 mg / mL) as a positive control.

[0077] (2) Preparation of test solution: Prepare the sample into 4 concentrations and dilute them by 0, 5, 10 and 20 times respectively.

[0078] (3) Take 1 mL of the test solution and 1 mL of 2×10 -4 Mix the mol / L DPPH solution thoroughly (A); (4) Take 1 mL of anhydrous ethanol and 1 mL of 2×10 -4 Mix the mol / L DPPH solution thoroughly (B). (5) Take 1 mL of anhydrous ethanol and mix it with 1 mL of the test solution (C). (6) After reacting for 30 min, the absorbance values ​​of A, B, and C were measured at 517 nm. The DPPH scavenging rate K of the sample can be calculated using the following formula (Ⅳ):

[0079] Where A is the absorbance of the DPPH and triple supramolecular whitening composition mixture solution; B is the absorbance of the DPPH and anhydrous ethanol mixture solution; and C is the absorbance of the triple supramolecular whitening composition and anhydrous ethanol mixture solution.

[0080] Experimental results are as follows Figure 3 As shown in the figure, the triple supramolecular whitening composition exhibits a free radical scavenging rate at least 10 times higher than the nicotinamide group, 5% higher than the ferulic acid group, approximately 2.5 times higher than the glycyrrhizin group, and 6% higher than the simple physical mixture of nicotinamide + ferulic acid + glycyrrhizin. At the same concentration, the triple supramolecular whitening composition achieves a free radical scavenging rate of over 90%, indicating that it has excellent antioxidant effects.

[0081] Experiment Example 4 The whitening activity of the triple supramolecular whitening composition was tested, and its inhibition rate against tyrosinase was determined. The specific experimental steps are as follows: S1: PBS Phosphate Buffer: Dissolve 3.58g of disodium hydrogen phosphate dodecahydrate and 1.56g of sodium dihydrogen phosphate dihydrate in 200mL of distilled water to prepare a PBS buffer solution with pH=6.8.

[0082] S2: 0.1 mol / L hydrochloric acid solution: Add 0.862 mL of HCl solution with a hydrochloric acid content of 36%-38% and dilute to 100 mL with distilled water.

[0083] S3: 0.05% L-tyrosine solution: Take 0.05g L-tyrosine, dissolve it in 35mL of 0.1mol / L HCl solution, and then add 65mL of pH6.8 PBS phosphate buffer, for a total of 100mL.

[0084] S4: Tyrosinase solution: Dissolve tyrosinase powder with a total enzyme activity of 25 kU in 125 mL of PBS buffer, mix well, and prepare a tyrosinase solution with an enzyme activity of 200 U / mL. Aliquot the solution into 1 mL EP tubes and store at -40°C.

[0085] S5: Sample group 1: Niacinamide, nicotinamide + ferulic acid + glycyrrhizin, triple supramolecular whitening composition (Example 16); Sample group 2: Ferulic acid, nicotinamide + ferulic acid + glycyrrhizin, triple supramolecular whitening composition; Sample group 3: glycyrrhizin, nicotinamide + ferulic acid + glycyrrhizin, triple supramolecular whitening composition.

[0086] S6: Each sample has 4 concentrations: Sample group 1 (5, 10, 20, 40 mg / mL), Sample group 2 (0.075, 0.15, 0.3, 0.6 mg / mL), and Sample group 3 (0.25, 0.5, 1, 2 mg / mL). S7: Take test tubes and add the solution one at a time according to Table 4.

[0087] Table 4 Reagents

[0088] Result: As Figure 4 As shown in the figure, the triple supramolecular whitening composition exhibits at least 14 times higher inhibitory effects on tyrosinase than the nicotinamide group, approximately 5 times higher than the ferulic acid group, approximately 1.2 times higher than the glycyrrhizin group, and 10% higher than the nicotinamide + ferulic acid + glycyrrhizin group. The triple supramolecular whitening composition not only does not alter the inhibition rate of its active ingredients on tyrosinase, but also demonstrates a better inhibitory effect than the individual active ingredients themselves. Furthermore, it is better than the purely physical mixture of nicotinamide + ferulic acid + glycyrrhizin, indicating that the supramolecular nicotinamide-glycyrrhizin combination protects some active groups of nicotinamide, ferulic acid, and glycyrrhizin, improving their solubility and stability, and significantly enhancing their whitening effect.

[0089] Experimental Example 5 The particle size of the triple supramolecular whitening composition was measured, and the specific experimental steps are as follows: Dynamic light scattering (DLS) method was used: 1. Sample Preparation: The concentration of the triple supramolecular whitening composition solution needs to be diluted to a suitable range (usually a light intensity counting rate of 50-300 kcps). Too high a concentration will lead to multiple scattering errors, while too low a concentration will result in insufficient signal-to-noise ratio. Specifically, take 0.1 ml of the solution and dilute it to 100 ml of deionized water for injection. 2. Instrument Calibration: Set the sample cell temperature to the experimental temperature (25℃) and pre-equilibrate for 15 minutes to eliminate thermal disturbance; calibrate the instrument using standard particles of known size to ensure that the scattering angle (usually 90° or 173°) and optical path alignment error are less than ±1%; 3. Parameter Setting and Measurement: A backscattering optical path (180° scattering angle) is used to enhance the signal intensity of high-concentration systems, and stray light interference is filtered out through a pinhole aperture; the measurement time is set to 60-120 seconds, and repeated 3 times to verify repeatability. For metastable supramolecular structures (such as dynamic coordination assemblies), the autocorrelation function decay curve needs to be monitored in real time to ensure that the fitting model (such as cumulant analysis or CONTIN algorithm) is applicable to polydisperse systems. 4. Particle size distribution calculation: based on the Stokes-Einstein equation By combining solvent viscosity and temperature parameters, volume-weighted or number-weighted particle size distribution is calculated. Typical outputs include average particle size (Z-average) and polydispersity index (PDI).

[0090] Result: From Figure 5As shown, the triple supramolecular whitening composition (Example 16) (Figure B) has a particle size of 41.43 nm, while the particle size of the simple physical mixture (unencapsulated) of nicotinamide + ferulic acid + glycyrrhizin (Figure A) is 147.7 nm. This indicates that by using supramolecular assembly technology, i.e., cyclodextrin encapsulates nicotinamide, ferulic acid, and glycyrrhizin in their hydrophobic cavities, the particle size of the inclusion complex is greatly reduced, avoiding the activity decay caused by molecular aggregation of the active ingredients. This shows that the stability of nicotinamide, ferulic acid, and glycyrrhizin is improved.

[0091] Experimental Example 6 Transdermal absorption Raman spectroscopy was performed on the triple supramolecular whitening composition. The specific experimental steps are as follows: S1: Sample preparation: Triple supramolecular whitening composition (Example 16) (HyperMolx™ supercyclic triple (nicotinamide + ferulic acid + glycyrrhizin)), unencapsulated (nicotinamide + ferulic acid + glycyrrhizin).

[0092] S2: Fluorescent labeling: Fluorescent labeling of the sample to enhance the Raman signal or visualize the permeation path.

[0093] S3: Skin model: Select piglet skin or excised human skin, with a thickness controlled at 200-400μm to simulate the human epidermal barrier; ensure skin integrity and avoid damage to barrier function due to storage or handling.

[0094] S4: Transdermal device setup (Franz diffusion cell method): Fix the skin model in the diffusion cell, apply supramolecular raw materials to the supply chamber (top), and fill the receiving chamber (bottom) with physiological saline or buffer solution to maintain a simulated body surface temperature of 32℃±1℃.

[0095] S5: Time point setting: Select key time points such as 0h, 2h, 6h, and 8h for data collection according to the permeation kinetic requirements.

[0096] S6: Instrument selection: Confocal Raman spectrometer, equipped with a 785 nm laser light source (to reduce interference from skin autofluorescence), with power controlled at 5-10 mW to avoid thermal damage.

[0097] S7: Raman signal acquisition: Perform in-situ detection and depth profile analysis (scan layer by layer along the vertical direction of the skin, record the Raman spectral signal at each depth, and construct a spatial distribution map of the active ingredients).

[0098] S8: Penetration Path Imaging (3D Reconstruction): Utilizes Raman imaging technology to generate a 3D distribution map of supramolecular raw materials in the skin, visually displaying the penetration depth (such as the stratum corneum, active epidermis, or dermis).

[0099] The results are as follows Figure 6As shown, the pure physical mixing (unencapsulated) group sample (right figure) had a penetration depth of only 35 μm after 6 hours, while the group encapsulated using supramolecular technology (triple supramolecular whitening composition, left figure) had a penetration depth of 120 μm after 6 hours, which is 243% higher. This indicates that the supramolecular whitening composition can enable active ingredients to enter the dermis and achieve precise release of active ingredients.

[0100] Experimental Example 7 The stability and formulation stability of the triple supramolecular whitening composition were tested. The specific experimental steps are as follows: Stability test of triple supramolecular whitening composition: Attention should be paid to items that are prone to change during storage and affect quality and safety. Observe the changes in the properties (color, odor, etc.) of triple supramolecular whitening composition over time under the influence of temperature, light, etc.

[0101] Formula stability testing: Attention should be paid to whether there are chemical and / or biological interactions between the ingredients in the formula (serum, cream) and whether stratification occurs in the formula over time.

[0102] The triple supramolecular whitening composition from Example 16 was used to prepare essence water (as shown in Table 5) and face cream (as shown in Table 6). The concentration of each component was set to 0.5%, 1%, 5%, and 10%. The products were placed under six conditions: high temperature, freezing, alternating hot and cold, light exposure, room temperature, and refrigeration for 30 days. Photos were taken and observed on days 1, 3, 5, 7, 14, 21, and 30 to see if the triple supramolecular whitening composition or formula would change color, fade, or separate over time.

[0103] A. High-temperature test: Place the samples (triple supramolecular whitening composition, essence water, face cream) in a sealed clean container, and then place them in a constant temperature incubator pre-adjusted to 50 °C for 30 days. Take samples on days 1, 3, 5, 7, 14, 21, and 30. After returning to room temperature, take photos for observation.

[0104] B. Freezing test: Place the sample in a -20 °C freezer for 30 days. Take samples on days 1, 3, 5, 7, 14, 21, and 30. After returning to room temperature, take photos and observe.

[0105] C. Alternating hot and cold test: Store the sample in a sealed clean container and place it in a refrigerator pre-adjusted to -20 °C. After 24 hours, remove the sample and place it in a constant temperature incubator pre-adjusted to 50 °C for 24 hours. Repeat this alternation at 24-hour intervals for 30 days. Observe the sample after it returns to room temperature.

[0106] D. Light Irradiation Test: Place an appropriate amount of sample in a suitable light-transmitting container under a transparent glass window, and take samples for observation on days 1, 3, 5, 7, 14, 21, and 30. During the test, it is important to control the temperature to maintain a constant level with room temperature, and carefully observe any changes in the appearance of the samples.

[0107] E. Room temperature test: Place the sample in a sealed clean container, place it in a dark and dry place, and leave it for 30 days. Take samples on days 1, 3, 5, 7, 14, 21, and 30, and take photos for observation.

[0108] F. Refrigeration test: Place the sample in a refrigerator at 4°C for 30 days. Take samples on days 1, 3, 5, 7, 14, 21, and 30. After returning to room temperature, take photos and observe.

[0109] Table 5. Basic Formula of the Triple Supermolecular Whitening Composition Essence Water

[0110] Table 6. Basic Formula of Triple Supermolecular Whitening Composition Face Cream

[0111] 1. Stability test of the triple supramolecular whitening composition, observing the results after 30 days. Figure 7 As shown, the experimental results from A to F are compared from left to right.

[0112] 2. The stability test of the essence water formula of the triple supramolecular whitening composition was conducted. The results after 30 days are shown in Table 7. Some results are as follows: Figure 8 As shown.

[0113] Table 7. Results of the stability of the essence water formula

[0114] Note: - indicates no crystal precipitation, + indicates crystal precipitation.

[0115] 3. The stability test of the cream formulation of the triple supramolecular whitening composition was conducted. The results after 30 days are shown in Table 8. Some results are as follows: Figure 9 As shown.

[0116] Table 8. Results of face cream formulation stability

[0117] Note: - indicates no crystal precipitation, + indicates crystal precipitation.

[0118] The observation results show that the triple supramolecular whitening composition turned slightly yellow and darkened in color after 30 days under alternating hot and cold conditions at 50°C, but remained almost unchanged under other conditions.

[0119] In the essence water formula, the 0.5% and 1% concentrations are relatively stable after 30 days with almost no change; the 5% and 10% concentrations are relatively stable from day 1 to day 5, but from day 7 to day 30, they turn yellow under 50℃ and alternating hot and cold conditions.

[0120] In face creams, the 0.5% concentration is relatively stable after 30 days with almost no change; the 1% concentration is relatively stable from day 1 to 5, but shows slight yellowing under conditions of 50℃, alternating hot and cold temperatures, and light exposure from day 7 to 30; the 5% and 10% concentrations are relatively stable from day 1 to 5, but show yellowing under conditions of 50℃, alternating hot and cold temperatures, and light exposure from day 7 to 30.

[0121] The above experimental results demonstrate that the triple supramolecular whitening composition of the present invention exhibits good stability whether used alone or added to other basic formulations.

[0122] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A triple supramolecular whitening composition, characterized in that, Its raw materials include nicotinamide, ferulic acid, glycyrrhizin, cyclodextrin, and solubilizer.

2. The triple supramolecular whitening composition according to claim 1, characterized in that, The triple supramolecular whitening composition comprises the following raw materials in weight percentage: nicotinamide 0.2%-10%, ferulic acid 0.1%-5%, glycyrrhizin 0.1%-3%, cyclodextrin 1%-10%, and cosolvent 20%-70%.

3. The triple supramolecular whitening composition according to claim 2, characterized in that, The cyclodextrin is 6-hydroxypropyl-β-cyclodextrin.

4. The triple supramolecular whitening composition according to claim 2, characterized in that, The cosolvent is 1,3-butanediol.

5. The triple supramolecular whitening composition according to claim 2, characterized in that, The triple supramolecular whitening composition also includes preservatives; The preservative includes p-hydroxyacetophenone and hexanediol, wherein the mass ratio of p-hydroxyacetophenone to hexanediol in the preservative is 0.5-1:2-5.

6. The triple supramolecular whitening composition according to claim 2, characterized in that, The triple supramolecular whitening composition also includes a stabilizer, which includes glycerin.

7. The triple supramolecular whitening composition according to claim 1, characterized in that, The triple supramolecular whitening composition is composed of the following raw materials in weight percentage: nicotinamide 0.2%-10%, ferulic acid 0.1%-5%, glycyrrhizin 0.1%-3%, 6-hydroxypropyl-β-cyclodextrin 1%-10%, cosolvent 20%-70%, preservative 1%-5%, stabilizer 3%-5%, and the balance being deionized water.

8. The method for preparing the triple supramolecular whitening composition according to any one of claims 1-7, characterized in that, include: Glycyrrhizin was dissolved in a solubilizer, heated and stirred for the first time to obtain a solution of glycyrrhizin. The glycyrrhizin solution was added to the cyclodextrin aqueous solution, heated, and stirred a second time. Then ferulic acid was added and stirred for the third time; then nicotinamide was added and heated for the fourth time; after the temperature was reduced to room temperature, the triple supramolecular whitening composition was obtained.

9. The preparation method according to claim 8, characterized in that, The heating temperature is 45℃-80℃; the stirring conditions are: 120 rpm for 10-40 min.

10. The use of the triple supramolecular whitening composition according to any one of claims 1-7 in the preparation of cosmetics.

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