Supramolecular arbutin nicotinamide as well as preparation method and daily chemical product thereof

Abstract

The invention provides supramolecular arbutin nicotinamide, a preparation method thereof and a daily chemical product, and relates to the field of skin care products and cosmetic products. The supramolecular arbutin nicotinamide comprises arbutin and nicotinamide, and the arbutin and the nicotinamide are combined through a non-covalent bond. The structural formula of the supramolecular arbutin nicotinamide is # imgabs0 #. The supramolecular arbutin nicotinamide disclosed by the invention has the advantage of high stability, and meanwhile, the supramolecular compound disclosed by the invention also has the effect of arbutin, so that the problem that the stability of arbutin is relatively poor can be remarkably improved.

Description

Technical Field

[0001] The present application relates to the field of skin care products and cosmetic products, and in particular to a supramolecular arbutin nicotinamide and a preparation method thereof and a daily chemical product. Background Art

[0002] Arbutin, also known as arbutin, is a β-D-pyranoglucoside composed of hydroquinone molecules linked to glucose molecules. It is a natural active substance derived from green plants and is widely found in plants such as bearberry leaves, pear leaves, and saxifraga leaves. Its structural formula is as follows: .

[0003] Structurally, arbutin and tyrosine have certain similarities. They compete for binding to the active site of tyrosinase and inhibit the activity of tyrosinase in the body, thereby preventing the production of melanin, reducing skin pigmentation, removing spots and freckles, and also having bactericidal and anti-inflammatory effects.

[0004] However, current studies have shown that arbutin is unstable. In acidic or alkaline conditions and at higher temperatures, it tends to decompose to a certain extent, and is prone to decomposition to produce hydroquinone substances with certain carcinogenicity and cytotoxicity; it is easy to change color under alkaline and high temperature conditions; products containing arbutin on the market basically need to control the pH at 5-7 during the preparation process, and need to add an appropriate amount of antioxidants to prevent discoloration. The above factors limit the application scope of arbutin in the field of skin care products and cosmetics. Therefore, how to enhance the stability of arbutin and expand its application scope is an urgent problem to be solved. Summary of the invention

[0005] The purpose of the present application is to provide a supramolecular arbutin nicotinamide and a preparation method and daily chemical product thereof to solve the above problems.

[0006] To achieve the above objectives, this application adopts the following technical solutions: A supramolecular arbutin nicotinamide, the supramolecular arbutin nicotinamide comprising arbutin and nicotinamide, wherein the arbutin and nicotinamide are bonded together via a non-covalent bond; The structural formula of the supramolecular arbutin nicotinamide is .

[0007] The present application also provides a method for preparing the supramolecular arbutin nicotinamide as described above, comprising: mixing arbutin, nicotinamide and a first solvent, and performing a supramolecular modification reaction under heating conditions to obtain supramolecular arbutin nicotinamide; Wherein, the temperature of the supramolecular modification reaction is less than 100°C.

[0008] According to an embodiment of the present application, the molar ratio of the arbutin to the niacinamide is 1:1.

[0009] According to an embodiment of the present application, the temperature of the supramolecular modification reaction is 50-80°C, preferably 70-80°C; And / or, the supramolecular modification reaction time is 4 to 24 h, preferably 4 to 8 h; And / or, the first solvent includes a first organic solvent or a mixture of the first organic solvent and water, and the first organic solvent includes any one of methanol, ethanol, isopropanol, and acetone; and / or, the mixing of arbutin, nicotinamide and the first solvent is carried out under a stirring condition of 100-200 rpm; And / or, the supramolecular modification reaction is carried out under the protection of an inert gas, wherein the inert gas includes any one of nitrogen, argon, helium and neon.

[0010] According to an embodiment of the present application, after the supramolecular modification reaction is completed, the method further comprises: cooling, stirring and crystallizing to obtain supramolecular arbutin nicotinamide.

[0011] According to an embodiment of the present application, the cooling temperature is 0-5°C; And / or, the stirring speed of the stirring crystallization is 10 to 300 rpm, preferably 50 to 100 rpm; And / or, the stirring crystallization time is 12 to 48 hours.

[0012] According to an embodiment of the present application, the mixing of arbutin, niacinamide and the first solvent comprises: mixing an arbutin extract with niacinamide, wherein the arbutin extract comprises arbutin and the first solvent; The arbutin extract is obtained by the following method: mixing the raw material containing arbutin with the second solvent, extracting under heating conditions, and performing solid-liquid separation after the extraction is completed to obtain the arbutin extract; The second solvent includes a mixture of a second organic solvent and water or a second organic solvent, and the second organic solvent includes any one of methanol, ethanol, isopropanol, and acetone; Preferably, in the mixture of the second organic solvent and water, the volume ratio of the second organic solvent to water is (5-25): (95-75).

[0013] According to an embodiment of the present application, the raw material containing arbutin includes any one of bearberry, bearberry leaf, and pear leaf; And / or, the mass ratio of the second solvent to the arbutin-containing raw material is (5-10):1; And / or, the mixing of the arbutin-containing raw material and the second solvent is carried out under a stirring condition of 150-300 rpm.

[0014] According to an embodiment of the present application, the extraction temperature is 40-50°C; And / or, the extraction time is 2 to 6 hours; And / or, the solid-liquid separation method includes centrifugal separation, and the rotation speed of the centrifugal separation is 8000~10000r / min.

[0015] The present application also provides a daily chemical product, which includes the supramolecular arbutin nicotinamide described above or the supramolecular arbutin nicotinamide prepared by the preparation method of the supramolecular arbutin nicotinamide described above; Preferably, the daily chemical products include skin care products and cosmetics.

[0016] Compared with the prior art, the beneficial effects of this application include: The supramolecular arbutin nicotinamide of the present application has the advantage of high stability. At the same time, the supramolecular compound of the present application also has the efficacy of arbutin, and can significantly improve the problem of poor stability of arbutin.

[0017] The preparation method of supramolecular arbutin nicotinamide of the present application can prepare supramolecular with high stability, and the supramolecular also has the efficacy of arbutin, which can improve the problem of poor stability of arbutin. In addition, the preparation method of the present application also has the advantages of simple operation, high product yield, low production cost, etc., which is conducive to large-scale promotion and application.

[0018] The daily chemical product of the present application includes supramolecular arbutin nicotinamide, wherein the supramolecular arbutin nicotinamide has the effects of arbutin monomer and nicotinamide monomer at the same time. The arbutin and nicotinamide in the supramolecular arbutin nicotinamide support and cooperate with each other in function, can exert a better whitening effect, and can be applied in daily chemical products with whitening effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope of the present application.

[0020] Figure 1 is the X-ray powder diffraction pattern of the supramolecular arbutin nicotinamide in Example 1; Figure 2 is a comparison diagram of XRD diffraction of supramolecular arbutin nicotinamide prepared in Example 1 and arbutin and nicotinamide powders; Figure 3 is the H NMR spectrum of the supramolecular arbutin nicotinamide in Example 1; Figure 4is the NMR carbon spectrum of the supramolecular arbutin nicotinamide in Example 1; Figure 5 This is the ESP distribution diagram of supramolecular arbutin nicotinamide; Figure 6 This is a schematic diagram of the weak interactions of the supramolecular arbutin nicotinamide structure; Figure 7 It is the IRI isosurface and scatter plot of the supramolecular arbutin nicotinamide structure; Figure 8 This is a graph showing the effect of supramolecular arbutin nicotinamide on the production of melanin content in human melanocytes; Fig. 9 This is a graph showing the effect of supramolecular arbutin nicotinamide on tyrosinase activity in human melanocytes. DETAILED DESCRIPTION

[0021] As used herein: "Prepared from" is synonymous with "comprising." As used herein, the terms "comprising," "including," "having," "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises the listed elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0022] The conjunction "consisting of excludes any unspecified element, step, or component. If used in a claim, this phrase renders the claim closed-ended so that it does not include materials other than those described, except for conventional impurities associated therewith. When the phrase "consisting of" appears in a clause of the body of a claim rather than immediately following the subject matter, it limits only the elements described in that clause; other elements are not excluded from the claim as a whole.

[0023] When an amount, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper preferred values ​​and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any range upper limit or preferred value with any range lower limit or preferred value, regardless of whether the range is disclosed separately. For example, when a range of "1 to 5" is disclosed, the described range should be interpreted as including ranges "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. When a numerical range is described in this article, unless otherwise stated, the range is intended to include its end values ​​and all integers and fractions within the range.

[0024] In these examples, parts and percentages are by mass unless otherwise indicated.

[0025] "Mass parts" refers to the basic unit of measurement for expressing the mass ratio of multiple components. 1 part can represent any unit mass, such as 1g or 2.689g. If we say that the mass parts of component A are a parts and the mass parts of component B are b parts, it means the ratio of the mass of component A to the mass of component B is a:b. Alternatively, it means that the mass of component A is aK and the mass of component B is bK (K is an arbitrary number, indicating a multiple factor). It should not be misunderstood that, unlike the mass parts, the sum of the mass parts of all components is not limited to 100 parts.

[0026] "And / or" is used to indicate that one or both of the stated situations may occur, for example, A and / or B includes (A and B) and (A or B).

[0027] In order to better explain the technical solution provided by this application, before the embodiments, the technical solution is first described as a whole, as follows: Arbutin has the effects of reducing skin pigmentation, removing spots and freckles, sterilizing, and reducing inflammation, and can be used in skin care products and cosmetics. However, arbutin has the problem of poor stability. It is easy to decompose and produce toxic substances in acidic or alkaline conditions and at high temperatures. Moreover, arbutin also has the problem of harsh preparation conditions. The above problems limit the application scope of arbutin in the field of skin care products and cosmetics.

[0028] Niacinamide, also known as vitamin B3 or vitamin PP, is a whitening active ingredient. Its mechanism includes the following two points: 1) Interfering with the transport of melanin, limiting melanin in melanocytes, preventing melanin from being transferred to the skin surface and darkening the skin, thereby achieving a whitening effect. 2) It has a good anti-glycation effect. The substance produced by skin glycation is brown, which makes the skin look dark. Niacinamide's anti-glycation helps whiten the skin and brighten the skin tone.

[0029] In the present application, arbutin and nicotinamide are combined by non-covalent bonds to form a supramolecular compound. The formed supramolecular compound has the advantage of high stability, and the supramolecular compound also has the efficacy of arbutin, which can significantly improve the problem of poor stability of arbutin.

[0030] The present application provides a supramolecular arbutin nicotinamide, wherein the supramolecular arbutin nicotinamide comprises arbutin and nicotinamide, wherein the arbutin and nicotinamide are combined by a non-covalent bond; The structural formula of supramolecular arbutin nicotinamide is .

[0031] In some embodiments, the molar ratio of arbutin to nicotinamide in the supramolecular arbutin nicotinamide is 1:1.

[0032] The present application also provides a method for preparing the supramolecular arbutin nicotinamide as described above, comprising: mixing arbutin, nicotinamide and a first solvent, and performing a supramolecular modification reaction under heating conditions to obtain supramolecular arbutin nicotinamide; The temperature of the supramolecular modification reaction is less than 100°C.

[0033] According to an embodiment of the present application, the molar ratio of arbutin to niacinamide is 1:1.

[0034] According to the embodiments of the present application, the temperature of the supramolecular modification reaction is 50-80°C, preferably 70-80°C; the above range can provide sufficient heat energy to drive the supramolecular modification reaction in the direction of synthesizing supramolecular arbutin nicotinamide, and can effectively avoid the decomposition of arbutin and nicotinamide under high temperature conditions. When the reaction temperature is too low, the required reaction time increases significantly, and the product yield is relatively low; when the reaction temperature is too high, the reaction raw materials will decompose and the reaction by-products will increase.

[0035] For example, the temperature of the supramolecular modification reaction may be 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, or any value between 50 and 80°C.

[0036] And / or, the time of the supramolecular modification reaction is 4 to 24 hours, preferably 4 to 8 hours; within the above time range, the reactants can have enough time to fully interact with each other, ensuring that the reaction can be completely carried out, which helps to improve the yield of the product. If the reaction time is too short, there will be undesirable problems such as incomplete reaction and low product yield; if the reaction time is too long, the content of by-products will increase, the purity of the product will be reduced, and energy consumption will also increase.

[0037] For example, the time of the supramolecular modification reaction can be 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h, or any value between 4 and 24 h.

[0038] And / or, the first solvent includes a first organic solvent or a mixture of the first organic solvent and water, wherein the first organic solvent includes any one of methanol, ethanol, isopropanol, and acetone; and / or, the mixing of arbutin, nicotinamide and the first solvent is carried out under a stirring condition of 100 to 200 rpm; And / or, the supramolecular modification reaction is carried out under the protection of an inert gas, wherein the inert gas includes any one of nitrogen, argon, helium and neon.

[0039] According to an embodiment of the present application, after the supramolecular modification reaction is completed, the method further comprises: cooling, stirring and crystallizing to obtain supramolecular arbutin nicotinamide.

[0040] According to an embodiment of the present application, the cooling temperature is 0~5°C; for example, the cooling temperature can be 0°C, 1°C, 2°C, 3°C, 4°C, 5°C or any value between 0~5°C.

[0041] And / or, the stirring speed of the stirred crystallization is 10 to 300 rpm, preferably 50 to 100 rpm; when the stirring speed of the stirred crystallization is within the above range, it can ensure that the reaction system cools down and the crystallization speed is moderate, the system fluidity is good, and the explosion phenomenon can be avoided and the impurity entrainment is reduced, which is conducive to obtaining high-quality products. If the stirring speed of the stirred crystallization is too low, the cooling rate of the reaction system will be reduced, resulting in slower crystallization, and the system fluidity will also deteriorate, and block crystals of different sizes are easily precipitated during crystallization; if the stirring speed of the stirred crystallization is too high, it is easy to cause explosion, too small crystals, and easy to carry impurities.

[0042] For example, the stirring speed of the stirred crystallization can be 10 rpm, 50 rpm, 60 rpm, 70 rpm, 80 rpm, 90 rpm, 100 rpm, 150 rpm, 200 rpm, 250 rpm, 300 rpm or any value between 10 and 300 rpm.

[0043] And / or, the stirring and crystallizing time is 12 to 48 h. For example, the stirring and crystallizing time can be 12 h, 15 h, 18 h, 20 h, 23 h, 25 h, 28 h, 30 h, 33 h, 35 h, 38 h, 40 h, 43 h, 45 h, 48 h or any value between 12 and 48 h.

[0044] According to an embodiment of the present application, mixing arbutin, niacinamide and a first solvent comprises: mixing an arbutin extract with niacinamide, wherein the arbutin extract comprises arbutin and a first solvent; The arbutin extract is obtained by the following method: mixing the raw material containing arbutin with the second solvent, extracting under heating conditions, and performing solid-liquid separation after the extraction is completed to obtain the arbutin extract; Furthermore, high performance liquid chromatography (HPLC) in conjunction with an external standard method can be used to accurately detect the content of the active ingredient arbutin in the arbutin extract.

[0045] The second solvent includes a mixture of a second organic solvent and water or a second organic solvent, wherein the second organic solvent includes any one of methanol, ethanol, isopropanol, and acetone; Preferably, in the mixture of the second organic solvent and water, the volume ratio of the second organic solvent to water is (5-25):(95-75). For example, the volume ratio of the second organic solvent to water can be 5:95, 15:85, 25:75 or any value between (5-25):(95-75).

[0046] According to the embodiments of the present application, the raw material containing arbutin includes any one of bearberry, bearberry leaf, and pear leaf. These substances are rich in the active ingredient arbutin, and arbutin can be obtained by extracting them.

[0047] Furthermore, before mixing the arbutin-containing raw material with the second solvent, the method further comprises crushing the arbutin-containing raw material, thereby improving the extraction efficiency.

[0048] And / or, the mass ratio of the second solvent to the raw material containing arbutin is (5-10):1; for example, the mass ratio of the second solvent to the raw material containing arbutin can be 5:1, 6:1, 7:1, 8:1, 9:1, 10:1 or any value between (5-10):1.

[0049] And / or, the mixing of the arbutin-containing raw material and the second solvent is carried out under a stirring condition of 150 to 300 rpm. For example, the stirring speed of the arbutin-containing raw material and the second solvent can be 150 rpm, 180 rpm, 200 rpm, 230 rpm, 250 rpm, 280 rpm, 300 rpm or any value between 150 and 300 rpm.

[0050] According to an embodiment of the present application, the extraction temperature is 40~50℃; for example, the extraction temperature can be 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃, 50℃ or any value between 40~50℃.

[0051] And / or, the extraction time is 2 to 6 h; for example, the extraction time can be 2 h, 3 h, 4 h, 5 h, 6 h or any value between 2 and 6 h.

[0052] And / or, the solid-liquid separation method includes centrifugal separation, and the speed of centrifugal separation is 8000-10000 r / min. For example, the speed of centrifugal separation can be 8000 r / min, 8500 r / min, 9000 r / min, 9500 r / min, 10000 r / min or any value between 8000 and 10000 r / min. Insoluble matter can be removed by solid-liquid separation.

[0053] The present application also provides a daily chemical product, which includes the supramolecular arbutin nicotinamide described above or the supramolecular arbutin nicotinamide prepared by the preparation method of the supramolecular arbutin nicotinamide described above; Preferably, the daily chemical products include skin care products and cosmetics.

[0054] The embodiments of the present application will be described in detail below in conjunction with specific examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present application and should not be considered as limiting the scope of the present application. If specific conditions are not specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0055] 1. Preparation of supramolecular arbutin nicotinamide Example 1 Example 1 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Crush 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 15:85, start stirring at a speed of 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0056] (2) Place the suspension into a centrifuge and set the speed to 9000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0057] High performance liquid chromatography combined with external standard method was used to accurately detect the content of arbutin in the filtrate.

[0058] The reagents and equipment used were: chromatographic column: Agilent ZORBAX SB-C18 column (4.6×250 mm, 5 μm); column temperature: 30 ℃; detector: UV detector; wavelength: 280 nm; injection volume: 10.0 μL; mobile phase A: methanol, mobile phase B: ultrapure water; flow rate: 1.0 mL / min.

[0059] Preparation of solution: a. Preparation of arbutin standard solution: Take about 100 mg of arbutin standard, weigh accurately, place in a 100 mL volumetric flask, add water to dissolve and dilute to the mark, shake well, and prepare a reference solution with an arbutin content of 1000 ppm. b. Preparation of test solution: The filtrate collected in step (2) is the test solution.

[0060] Test steps: a. Drawing of standard curve: Accurately measure 0.2 mL, 0.5 mL, 1.0 mL, 1.5 mL, 2.0 mL, and 2.5 mL of arbutin reference solution, place them in 5 mL volumetric flasks, dilute to scale with ultrapure water, shake well, and use them as linear standard curve solutions 1 to 6. Use arbutin concentration as the horizontal axis and peak area as the vertical axis to make a standard curve. b. Take the filtrate collected in step (2) as the test solution. Analyze according to the above chromatographic conditions, and calculate the arbutin concentration of the filtrate collected in step (2) according to the peak area of ​​the external standard method.

[0061] The test results showed that the concentration of arbutin in the filtrate was 1.46 wt%.

[0062] (3) Weigh 3.729 kg of the filtrate with an arbutin concentration of 1.46 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring, set the stirring speed to 150 rpm, start heating, set the reaction temperature to 75°C, and perform supramolecular modification reaction for 6 h. After the reaction is completed, set the crystallization temperature to 0°C, the stirring speed to 50 rpm for crystallization, and the crystallization time is 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0063] The weight of supramolecular arbutin nicotinamide was 59.49 g, and the calculated yield was 75.43%.

[0064] Example 2 Example 2 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Crush 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 5:95, start stirring at a speed of 300 rpm, heat to 50 °C, and extract for 2 h to obtain a suspension solution.

[0065] (2) Place the suspension into a centrifuge and set the speed to 8000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0066] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin in the filtrate was 1.27 wt %.

[0067] (3) Weigh 4.287 kg of the filtrate with an arbutin concentration of 1.27 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring, set the stirring speed to 200 rpm, start heating, set the heating reaction temperature to 75°C, and perform supramolecular modification reaction for 6 h. After the reaction is completed, set the crystallization temperature to 0°C, the stirring speed to 50 rpm for crystallization, and the crystallization time is 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0068] The weight of supramolecular arbutin nicotinamide was 55.44 g, and the calculated yield was 70.29%.

[0069] Example 3 Example 3 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Crush 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 25:75, start stirring at 200 rpm, heat to 40°C, and extract for 6 h to obtain a suspension solution.

[0070] (2) Place the suspension into a centrifuge and set the speed to 10,000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0071] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin in the filtrate was 1.34 wt %.

[0072] (3) Weigh 4.063 kg of the filtrate with an arbutin concentration of 1.34 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring at a stirring speed of 100 rpm, start heating at a heating reaction temperature of 75°C, and perform supramolecular modification reaction for 6 hours. After the reaction is completed, set the temperature to 0°C and the stirring speed to 50 rpm for crystallization for 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0073] The weight of supramolecular arbutin nicotinamide was 55.75 g, and the calculated yield was 70.69%.

[0074] Example 4 Example 4 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Crush 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 15:85, start stirring at a speed of 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0075] (2) Place the suspension into a centrifuge and set the speed to 9000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0076] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin in the filtrate was 1.44 wt %.

[0077] (3) Weigh 3.781 kg of the filtrate with an arbutin concentration of 1.44 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring at a stirring speed of 150 rpm, start heating at a heating reaction temperature of 70°C, and perform supramolecular modification reaction for 6 hours. After the reaction is completed, set the temperature to 0°C and the stirring speed to 50 rpm for crystallization for 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0078] The weight of supramolecular arbutin nicotinamide was 59.41 g, and the calculated yield was 75.33%.

[0079] Example 5 Example 5 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Crush 1 kg of dried bearberry leaves, then add 5 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 15:85, start stirring at a speed of 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0080] (2) Place the suspension into a centrifuge and set the speed to 9000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0081] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin in the filtrate was 1.73 wt %.

[0082] (3) Weigh 3.147 kg of the filtrate with an arbutin concentration of 1.73 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring at a stirring speed of 150 rpm, start heating at a heating reaction temperature of 80°C, and perform supramolecular modification reaction for 6 hours. After the reaction is completed, crystallization is performed at a temperature of 0°C and a stirring speed of 50 rpm for 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0083] The weight of supramolecular arbutin nicotinamide was 55.36 g, and the calculated yield was 70.19%.

[0084] Example 6 Example 6 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Weigh 1 kg of dried bearberry leaves and crush them. Then add 10 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 15:85. Start stirring at a speed of 150 rpm, heat to 45°C, and extract for 4 h to obtain a suspension solution.

[0085] (2) Place the suspension into a centrifuge and set the speed to 9000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0086] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin was 1.48 wt %.

[0087] (3) Weigh 3.679 kg of the filtrate with an arbutin concentration of 1.48 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring at a stirring speed of 150 rpm, start heating at a heating reaction temperature of 75°C, and perform supramolecular modification reaction for 4 hours. After the reaction is completed, crystallization is performed at a temperature of 0°C and a stirring speed of 50 rpm for 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0088] The weight of supramolecular arbutin nicotinamide was 59.77 g, and the calculated yield was 75.78%.

[0089] Example 7 Example 7 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Crush 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 15:85, start stirring at a speed of 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0090] (2) Place the suspension into a centrifuge and set the speed to 9000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0091] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin in the filtrate was 1.45 wt %.

[0092] (3) Weigh 3.755 kg of the filtrate with an arbutin concentration of 1.45 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring, set the stirring speed to 150 rpm, start heating, set the reaction temperature to 75°C, and carry out supramolecular modification reaction for 8 hours. After the reaction is completed, crystallization is carried out under the conditions of a crystallization temperature of 0°C and a stirring speed of 50 rpm for 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0093] The weight of supramolecular arbutin nicotinamide was 58.34 g, and the calculated yield was 73.97%.

[0094] Example 8 Example 8 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Crush 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 15:85, start stirring at a speed of 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0095] (2) Place the suspension into a centrifuge and set the speed to 9000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0096] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin was 1.47 wt %.

[0097] (3) Weigh 3.704 kg of the filtrate with an arbutin concentration of 1.47 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring, set the stirring speed to 150 rpm, start heating, set the reaction temperature to 75°C, and carry out supramolecular modification reaction for 6 hours. After the reaction is completed, crystallization is carried out under the conditions of a crystallization temperature of 5°C and a stirring speed of 50 rpm for 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0098] The weight of supramolecular arbutin nicotinamide was 59.46 g, and the calculated yield was 75.39%.

[0099] Example 9 Example 9 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Crush 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 15:85, start stirring at a speed of 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0100] (2) Place the suspension into a centrifuge and set the speed to 9000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0101] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin in the filtrate was 1.45 wt %.

[0102] (3) Weigh 3.755 kg of the filtrate with an arbutin concentration of 1.45 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring, set the stirring speed to 150 rpm, start heating, set the reaction temperature to 75°C, and carry out supramolecular modification reaction for 6 h. After the reaction is completed, crystallization is carried out under the conditions of a crystallization temperature of 0°C and a stirring speed of 50 rpm for 12 h. The resulting solid is supramolecular arbutin nicotinamide.

[0103] The weight of supramolecular arbutin nicotinamide was 52.94 g, and the calculated yield was 67.12%.

[0104] Example 10 Embodiment 10 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Crush 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 15:85, start stirring at a speed of 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0105] (2) Place the suspension into a centrifuge and set the speed to 9000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0106] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin in the filtrate was 1.46 wt %.

[0107] (3) Weigh 3.729 kg of the filtrate with an arbutin concentration of 1.46 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring, set the stirring speed to 150 rpm, start heating, set the reaction temperature to 75°C, and carry out supramolecular modification reaction for 6 hours. After the reaction is completed, crystallization is carried out under the conditions of a crystallization temperature of 0°C and a stirring speed of 50 rpm for 48 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0108] The weight of supramolecular arbutin nicotinamide was 60.99 g, and the calculated yield was 77.33%.

[0109] Embodiment 11 Example 11 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Crush 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 15:85, start stirring at a speed of 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0110] (2) Place the suspension into a centrifuge and set the speed to 9000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0111] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin in the filtrate was 1.48 wt %.

[0112] (3) Weigh 3.679 kg of the filtrate with an arbutin concentration of 1.48 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring, set the stirring speed to 150 rpm, start heating, set the reaction temperature to 75°C, and carry out supramolecular modification reaction for 6 hours. After the reaction is completed, crystallization is carried out under the conditions of a crystallization temperature of 0°C and a stirring speed of 100 rpm for 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0113] The weight of supramolecular arbutin nicotinamide was 54.47 g, and the calculated yield was 69.06%.

[0114] Example 12 Example 12 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Crush 1 kg of dried bearberry leaves, then add 15 kg of anhydrous ethanol and start stirring at 150 rpm. Heat to 45 °C and extract for 4 h to obtain a suspension solution.

[0115] (2) Place the suspension into a centrifuge and set the speed to 9000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0116] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin in the filtrate was 0.43 wt %.

[0117] (3) Weigh 12.663 kg of the filtrate obtained in step (2) with an arbutin concentration of 0.43%, then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring at a stirring speed of 150 rpm, start heating at a heating reaction temperature of 75°C, and perform supramolecular modification reaction for 6 hours. After the reaction is completed, set the temperature to 0°C and the stirring speed to 50 rpm for crystallization for 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0118] The weight of supramolecular arbutin nicotinamide was 9.45 g, and the calculated yield was 11.98%.

[0119] Compared with Example 1, Example 12 changes the extraction solvent of bearberry leaves, replacing the mixed solvent of ethanol and water with a volume ratio of 15:85 with anhydrous ethanol. Using anhydrous ethanol as the extraction solvent of bearberry leaves has a poor extraction effect, resulting in a low concentration of arbutin, which in turn leads to a large amount of solvent in the next supramolecular modification reaction, a low concentration of reaction precursors in the reaction system, poor reaction effect, and low yield. It is explained that the solvent used in this application is preferably a mixed solvent of ethanol and water.

[0120] Embodiment 13 Example 13 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Crush 1 kg of dried pear leaves, then add 10 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 15:85, start stirring at a speed of 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0121] (2) Place the suspension into a centrifuge and set the speed to 9000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0122] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin in the filtrate was 1.35 wt %.

[0123] (3) Weigh 4.033 kg of the filtrate with an arbutin concentration of 1.35 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring at a stirring speed of 150 rpm, start heating at a heating reaction temperature of 50°C, and perform supramolecular modification reaction for a reaction time of 24 h. After the reaction is completed, crystallization is performed at a temperature of 0°C and a stirring speed of 50 rpm for a crystallization time of 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0124] The weight of supramolecular arbutin nicotinamide was 19.22 g, and the calculated yield was 24.37%.

[0125] Compared with Example 1, Example 13 reduces the temperature of the supramolecular modification reaction in step (3) and prolongs the time of the supramolecular modification reaction. The yield of the supramolecular product in Example 13 is lower than that in Example 1, indicating that the temperature for the supramolecular modification reaction is preferably 70-80° C., and the time for the supramolecular modification reaction is preferably 4-8 h.

[0126] Embodiment 14 Example 14 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Crush 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 15:85, start stirring at a speed of 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0127] (2) Place the suspension into a centrifuge and set the speed to 9000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0128] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin in the filtrate was 1.44 wt %.

[0129] (3) Weigh 3.781 kg of the filtrate with an arbutin concentration of 1.44 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring, set the stirring speed to 150 rpm, start heating, set the reaction temperature to 75°C, and carry out supramolecular modification reaction for 6 hours. After the reaction is completed, crystallization is carried out under the conditions of a crystallization temperature of 0°C and a stirring speed of 10 rpm for 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0130] The weight of supramolecular arbutin nicotinamide was 55.46 g, and the calculated yield was 70.32%.

[0131] Compared with Example 1, Example 14 reduces the crystallization stirring speed in step (3). The system fluidity of Example 14 is poor, and crystal aggregation occurs during the crystallization process, resulting in uneven crystals and larger particle sizes. This indicates that the crystallization stirring speed is preferably 50-100 rpm.

[0132] Embodiment 15 Example 15 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises: (1) Crush 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 15:85, start stirring at a speed of 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0133] (2) Place the suspension into a centrifuge and set the speed to 9000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0134] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin in the filtrate was 1.44 wt %.

[0135] (3) Weigh 3.781 kg of the filtrate with an arbutin concentration of 1.44 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring, set the stirring speed to 150 rpm, start heating, set the reaction temperature to 75°C, and carry out supramolecular modification reaction for 6 hours. After the reaction is completed, crystallization is carried out under the conditions of a crystallization temperature of 0°C and a stirring speed of 300 rpm for 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0136] The weight of supramolecular arbutin nicotinamide was 65.41 g, and the calculated yield was 82.93%.

[0137] Compared with Example 1, Example 15 increases the crystallization stirring speed in step (3). In Example 15, the crystallization stirring speed is relatively fast, the system temperature drops too quickly, and crystal explosion occurs. The yield is high and the purity is low. In addition, other impurities are entrained during the precipitation process, indicating that the crystallization stirring speed is preferably 50-100 rpm.

[0138] Comparative Example 1 (1) Crush 1 kg of dried pear leaves, then add 10 kg of a mixed solvent prepared by mixing ethanol and water in a volume ratio of 15:85, start stirring at a speed of 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0139] (2) Place the suspension into a centrifuge and set the speed to 9000 r / min. Centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0140] The concentration of arbutin in the filtrate was detected according to the external standard method of Example 1. The detection result was: the concentration of arbutin in the filtrate was 1.35 wt %.

[0141] (3) Weigh 4.033 kg of the filtrate with an arbutin concentration of 1.35 wt % obtained in step (2), then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring at a stirring speed of 150 rpm, start heating at a heating reaction temperature of 100°C, and perform supramolecular modification reaction for 6 hours. After the reaction is completed, crystallization is performed at a temperature of 0°C and a stirring speed of 50 rpm for 24 hours. No product is precipitated after the crystallization is completed.

[0142] Comparative Example 1 did not obtain the supramolecular arbutin nicotinamide product.

[0143] Compared with Example 1, the temperature of the supramolecular modification reaction in step (3) is increased in Comparative Example 1. The temperature of the supramolecular modification reaction in Comparative Example 1 is 100° C. The reaction temperature is relatively high. Under this condition, the reaction precursor will decompose and generate by-products. This indicates that the temperature for the supramolecular modification reaction needs to be less than 100° C.

[0144] 2. Structural Characterization of Supramolecular Arbutin Nicotinamide (1) Powder X-ray single crystal diffraction test Instruments and parameters: X-ray diffractometer model: XRD-MiniFlex600; test target: copper target; scanning range: 5-85°; scanning rate: 5 ° / min.

[0145] Experimental results: The powder X-ray single crystal diffraction test of the supramolecular arbutin nicotinamide prepared in Example 1 was performed. Figure 1 As shown, the X-ray powder diffraction pattern (XRD) of the supramolecular arbutin nicotinamide is about 10.91° ± 0.2°, 12.26° ± 0.2°, 14.24° ± 0.2°, 15.16° ± 0.2°, 16.54° ± 0.2°, 19.30° ± 0.2°, 20.82° ± 0.2°, 21.52° ± 0.2°, 21.78° ± 0.2°, 22.65° ± 0.2°, 22.23° ± 0.2°, 24.46° ± 0.2°, 25.77° ± 0.2°, 26.19° ± 0.2°, 27.63° ± 0.2°, 28.12° ± 0.2°, 28.95° ± 0.2°, and there are characteristic peaks at 31.63° ± 0.2°.

[0146] The X-ray powder diffraction data of the supramolecular arbutin nicotinamide of Example 1 were compared with those of arbutin and nicotinamide monomers. Figure 2 As shown by Figure 2 It can be seen that the peaks in the powder X-ray single crystal diffraction spectrum of supramolecular arbutin nicotinamide are not a simple superposition of the peaks of nicotinamide and arbutin monomers. Therefore, it is proved that nicotinamide and arbutin have generated a new cocrystal under the conditions of the present application.

[0147] (2) MRI test The supramolecular arbutin nicotinamide was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum.

[0148] Instrument and parameters: Bruker NMR spectrometer; Solvent type: heavy water; Experimental conditions: Scan times 1024 times (carbon spectrum), 16 times (hydrogen spectrum), the test environment is temperature controlled by liquid nitrogen; Data analysis: Professional nuclear magnetic resonance (NMR) data analysis software - MestReNova is used for analysis.

[0149] Experimental results: The supramolecular arbutin nicotinamide obtained in Example 1 was subjected to nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR) test, nuclear magnetic resonance hydrogen spectrum data is 1 H NMR (600 MHz, D2O) δ8.90 (d, 1H ), 8.69-8.68 (dd, 1H ), 8.22-8.21 (dt, 1H ), 7.58-7.56 (m, 1H ), 7.07-7.06 (m, 2H ), 6.87-6.85 (m, 2H ),5.48-5.47 (d, 1H ), 3.91-3.90 (t, 1H ), 3.84-3.82 (m, 1H ), 3.80-3.78 (q, 1H ),3.77-3.74 (q, 1H ), 3.71-3.69 (q, 1H ), 3.52-3.49 (t, 1H ).

[0150] like Figure 3 As shown, from the H NMR spectrum, we can clearly find 4 hydrogen atoms on the benzene ring of arbutin, 5 hydrogen atoms on the oxygen heterocycle, 2 hydrogen atoms on the methylene connected to the oxygen heterocycle, and 4 hydrogen atoms on the nitrogen heterocycle of nicotinamide; the rest are deuterated reagent peaks, and no obvious impurity peaks are found. 1 H-NMR test results show that in the supramolecular arbutin nicotinamide obtained in Example 1, arbutin and nicotinamide exist in a molar ratio of 1:1.

[0151] The supramolecular arbutin nicotinamide obtained in Example 1 was subjected to carbon nuclear magnetic resonance spectroscopy ( 13 C-NMR) characterization, D2O was selected as the test solvent, and the C-NMR spectrum data were 13 C NMR (150 MHz, D2O) δ 170.74, 151.77, 151.11,147.58, 136.41, 129.25, 124.15, 116.18, 98.26, 72.96, 72.37, 71.11, 69.34,60.24 ppm.

[0152] like Figure 4 As shown in Figure 2, the carbon atoms on arbutin and nicotinamide can be clearly found from the C NMR spectrum, and no obvious impurity peaks are observed. 13 C-NMR) test results show that the arbutin and nicotinamide of the supramolecular arbutin nicotinamide obtained in Example 1 exist in a molar ratio of 1:1.

[0153] (3) Calculation of interaction forces Supramolecular molecules usually refer to complex and organized supramolecular molecules that are bound together by intermolecular forces such as hydrogen bonds, van der Waals forces, π-π stacking, etc., and maintain a certain degree of integrity so that they have clear microstructures and macroscopic properties. π-π stacking is a special spatial arrangement of aromatic compounds, which refers to a weak interaction that often occurs between aromatic rings, usually between two relatively electron-rich and electron-deficient molecules, and is a non-covalent bond interaction that is as important as hydrogen bonds.

[0154] Arbutin contains a benzene ring structure, while niacinamide contains a nitrogen heterocycle. Structurally, arbutin and niacinamide may form a stable supramolecule through π-π stacking.

[0155] The interaction force between arbutin and niacinamide was calculated and analyzed. Figure 5 , Figure 6 , Figure 7 As shown, from Figure 5 (ESP diagram) It can be observed that electrostatic attraction occurs between areas with positive electrostatic potential (red) and areas with negative electrostatic potential (blue). The blue areas on the IRI contour surface diagram and scatter plot represent attractive forces, such as hydrogen bonds and halogen bonds of normal strength, while the red areas represent repulsive forces and the green areas represent van der Waals forces. Figure 7 (IRI isosurface and scatter plot of supramolecular arbutin and nicotinamide) It can be seen that the isosurface between arbutin and nicotinamide is basically green, indicating that the main interaction between the two is the van der Waals force. Figure 6 (IRI weak interaction) Two obvious hydrogen bonds were observed where there was electrostatic attraction, and a large van der Waals interaction existed between the two rings of the two small molecules. Figure 5 , Figure 6 and Figure 7 It can be seen that there are certain hydrogen bonds and van der Waals forces between arbutin and niacinamide, which promote the formation of supramolecular arbutin niacinamide through self-assembly.

[0156] 3. Particle size test of supramolecular arbutin nicotinamide The control of particle size is of great significance to the bioavailability and effect of active substances. In the preparation process, the control of particle size is conducive to the dissolution of active substances and the absorption of poorly soluble active substances by the human body, thereby improving the application effect and bioavailability of active substances.

[0157] The dry particle size test was performed on the supramolecular arbutin nicotinamide prepared in Examples 1-15 and Comparative Example 1. The test results are shown in Table 1.

[0158] Test method: Use a laser particle size analyzer to test. This method measures the angle and light intensity of laser scattering on the surface of the measured particles, and analyzes the particle size based on Mie scattering and Freund diffraction theory. The dry method uses air as the dispersion medium and uses the turbulent dispersion principle to fully disperse the sample particles, and then introduces them into the optical path system for testing.

[0159] Table 1 Summary of supramolecular arbutin nicotinamide particle size test results

[0160] As can be seen from Table 1, the particle sizes of Examples 1 to 15 are between 6 and 40 μm, among which the particle size of supramolecular arbutin nicotinamide in Examples 1 to 13 is between 10 and 20 μm. When the particle size of supramolecular arbutin nicotinamide is 10 to 20 μm, the particle size is appropriate, which can effectively improve the bioavailability of supramolecular arbutin and increase the specific surface area of ​​the particles. The particle size of supramolecular arbutin nicotinamide in Example 14 is too large, and the particle size of supramolecular arbutin nicotinamide in Example 15 is too small, which is not conducive to the bioavailability of supramolecular arbutin.

[0161] Compared with Example 12 and Example 13, Example 1-11 has a higher yield of supramolecular products, indicating that the reaction conditions of Example 1-11 are preferred reaction conditions, supramolecular arbutin nicotinamide has a higher yield, and the crystal form and crystal particle size distribution of the product are more uniform, which is beneficial to enhance skin permeability and improve bioavailability.

[0162] 4. Stability test of supramolecular arbutin nicotinamide (1) Arbutin stability test Samples for stability test: 1. Supramolecular arbutin nicotinamide aqueous solutions with different concentrations, which are 1.0%, 5.0% and 10% respectively; 2. Supramolecular arbutin nicotinamide aqueous solutions with different pH values, which are all 5.0% in concentration and have pH values ​​of 1.0, 7.0 and 13 respectively; 3. Arbutin monomer and nicotinamide monomer are prepared into corresponding physical mixed aqueous solution samples in a molar ratio of 1:1 according to the above conditions.

[0163] Stability test conditions: The above samples were placed under sunlight and 50°C, and samples were taken at 0 days, 7 days, 14 days, and 28 days to test the content of hydroquinone in the samples.

[0164] The corresponding aqueous solution was prepared according to the above method using the supramolecular arbutin nicotinamide prepared in Example 1, and a stability test was carried out. Samples were taken on time to test the content of hydroquinone. The test results are shown in Tables 2, 3, 4 and 5.

[0165] The supramolecular arbutin nicotinamide aqueous solution and the physically mixed arbutin nicotinamide aqueous solution with concentrations of 1.0%, 5.0% and 10% were placed under sunlight and 50°C for 28 days, and samples were taken at 0 days, 7 days, 14 days and 28 days to test the content of hydroquinone. The test results are shown in Tables 2 and 3.

[0166] Table 2 The changes in hydroquinone content of samples with different concentrations placed in a 50℃ oven for 28 days

[0167] Table 3 Changes in hydroquinone content of samples with different concentrations placed under sunlight for 28 days

[0168] It can be seen from Table 2 and Table 3 that under the condition of equal concentration, the hydroquinone content of the supramolecular arbutin nicotinamide aqueous solution decomposed at 28 days is much lower than that of the physically mixed-arbutin nicotinamide aqueous solution. In addition, the physically mixed-arbutin nicotinamide aqueous solution sample began to produce hydroquinone on the 7th day, while the supramolecular arbutin nicotinamide aqueous solution began to produce a small amount of hydroquinone on the 28th day under sunlight conditions. This shows that compared with the physically mixed-arbutin nicotinamide, the stability of the supramolecular arbutin nicotinamide prepared in the present application is improved to a certain extent.

[0169] The supramolecular arbutin nicotinamide aqueous solution and the physical mixed arbutin nicotinamide aqueous solution with a concentration of 5.0% and pH values ​​of 1.0, 7.0, and 13 were placed under sunlight and 50°C for 28 days, and samples were taken at 0 days, 7 days, 14 days, and 28 days to test the content of hydroquinone. The test results are shown in Tables 4 and 5.

[0170] Table 4 The changes in hydroquinone content of samples with different pH values ​​placed in a 50℃ oven for 28 days

[0171] Table 5 Changes in hydroquinone content of samples with different pH values ​​placed under sunlight for 28 days

[0172] It can be seen from Tables 4 and 5 that at pH = 7.0, the hydroquinone content produced by the decomposition of the supramolecular arbutin nicotinamide aqueous solution and the physically mixed-arbutin nicotinamide aqueous solution is much lower than that of pH = 1.0 and 13.0. Under the conditions of excessive acid or alkalinity, hydroquinone was detected in both the supramolecular arbutin nicotinamide aqueous solution and the physically mixed-arbutin nicotinamide aqueous solution on the 7th day, but the hydroquinone content detected in the supramolecular arbutin nicotinamide aqueous solution was much lower than that in the physically mixed-arbutin nicotinamide aqueous solution. This shows that the stability of the supramolecular arbutin nicotinamide prepared in this application is improved to a certain extent compared with the physically mixed-arbutin nicotinamide.

[0173] 5. Testing of the whitening effect of supramolecular arbutin nicotinamide The inhibition of melanin production is mainly achieved in two directions, one is to inhibit the activity of tyrosinase, and the other is to inhibit the signal pathway of melanin production. Some whitening agents, such as kojic acid and its derivatives, inhibit the production of melanin by inhibiting the activity of tyrosinase. There are also inhibitors that act on the melanin production signal pathway, such as inhibitors of α-melanocyte stimulating hormone (-MSH) receptor MCIR protein. In addition, products with antioxidant effects can reduce dopaquinone to levodopa, which can be used in the development of whitening products to a certain extent.

[0174] The experimental material used was the supramolecular arbutin nicotinamide obtained in Example 1, and the purpose was to evaluate the effect of supramolecular arbutin nicotinamide on the melanin content and tyrosinase activity of human melanocytes. This test used α-MSH to induce melanocytes, and used colorimetry to detect the effect of the sample on melanin production and tyrosinase inhibition to evaluate the efficacy of supramolecular arbutin nicotinamide.

[0175] (1) Human melanocytes - melanin content test The supramolecular arbutin nicotinamide obtained in Experimental Example 1 was used as the experimental material.

[0176] Experimental steps: a. Inoculate cells into 6-well plates and culture them in DMEM medium containing 10% FBS (fetal bovine serum) for 20 h; b. Remove the original medium, add medium containing different concentrations of the test substance and α-MSH, and culture for 5 consecutive days, changing the medium once in the middle; c. At the end of exposure, remove the culture medium, wash once with PBS, and collect cells in each well with a cell scraper; d. Add 1 mol / L NaOH solution (containing 10% DMSO) to dissolve the cells and obtain cell fluid; e. Heat the cell fluid at 80℃ for 30min to lyse the melanosomes; f. Take the cell fluid and measure the absorbance value at a wavelength of 490 nm. The data were analyzed using SPSS and expressed as mean ± standard deviation. If p < 0.05, the difference was considered statistically significant, and then the test results were statistically reported in Table 6.

[0177]

[0178] The detection results of the melanin content in human melanocytes by supramolecular arbutin and nicotinamide are shown in Table 6.

[0179] Table 6 Detection results of the melanin content in human melanocytes by supramolecular arbutin and nicotinamide

[0180] Compared with the NC group, 0.01 < P < 0.05 is indicated as *, P < 0.01 is indicated as **, and P < 0.001 is indicated as ***. When compared with the blank control group (NC), p < 0.05 is indicated as #.

[0181] From Table 6 and Figure 8 it can be seen that in the experiment of the melanin content in human melanocytes, when the concentrations of supramolecular arbutin and nicotinamide are 0.34 mg / mL, 0.17 mg / mL, and 0.085 mg / mL respectively, the corresponding relative melanin contents are reduced by 37.97%, 26.99%, and 21.94% compared with the model control group (M). This result indicates that supramolecular arbutin and nicotinamide have the effect of inhibiting melanin production.

[0182] (2) Inhibition experiment of human melanocytes - tyrosinase activity Use the supramolecular arbutin and nicotinamide obtained in Experimental Example 1 as the experimental material.

[0183] Experimental steps: a. Inoculate the cells into a 96-well plate and culture them in DMEM medium containing 10% FBS (fetal bovine serum) for 20 h; b. Remove the original medium, add the medium containing different concentrations of the test substance and α-MSH, and culture continuously for 3 days; c. At the end of the exposure, remove the culture solution, wash twice with PBS, add 90 μL of cell lysate, and treat by repeated freezing and thawing to lyse the cells; e. Pre-warm the well plate at 37 °C for 5 min, quickly add 10 μL of L-DOPA solution, measure the absorbance value at a wavelength of 405 nm after oscillation, and measure the absorbance value again after reacting at 37 °C for 30 min. The data is analyzed using SPSS and expressed as mean ± standard deviation. If p < 0.05, the difference is considered statistically significant, and then the test results are tabulated in Table 7.

[0184]

[0185] The detection results of the inhibition test of supramolecular arbutin and nicotinamide on the tyrosinase activity of human melanocytes are shown in Table 7.

[0186] Table 7 Detection results of the inhibition test of supramolecular arbutin and nicotinamide on the tyrosinase activity of human melanocytes

[0187] Compared with the NC group, 0.01 < P < 0.05 is denoted as *, P < 0.01 is denoted as **, and P < 0.001 is denoted as ***. When compared with the blank control group (NC), p < 0.05 is denoted as #.

[0188] As can be seen from Table 7 and Fig. 9 In the experiment of inhibiting the activity of human melanocyte tyrosinase, when the concentrations of supramolecular arbutin and nicotinamide are 0.34 mg / mL, 0.17 mg / mL, and 0.085 mg / mL respectively, the corresponding relative activities of tyrosinase are reduced by 19.26%, 13.81%, and 12.62% respectively compared with the model control group (M), indicating that supramolecular arbutin and nicotinamide have the effect of inhibiting tyrosinase activity.

[0189] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, and are not intended to limit them; although the present application has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application.

[0190] In addition, those skilled in the art can understand that although some of the embodiments herein include certain features included in other embodiments rather than other features, the combination of the features of different embodiments means that it is within the scope of the present application and forms different embodiments. For example, in the above claims, any one of the claimed embodiments can be used in any combination. The information disclosed in this background section is only intended to deepen the understanding of the overall background technology of the present application, and should not be regarded as an admission or any form of suggestion that this information constitutes prior art known to those skilled in the art.

Claims

1. A supramolecular arbutin nicotinamide, characterized in that: The supramolecular arbutin nicotinamide comprises arbutin and nicotinamide, and the arbutin and nicotinamide are combined by a non-covalent bond; The structural formula of the supramolecular arbutin nicotinamide is .

2. A method for preparing supramolecular arbutin nicotinamide as claimed in claim 1, characterized in that: include: The arbutin, nicotinamide and the first solvent are mixed, and a supramolecular modification reaction is performed under heating conditions to obtain supramolecular arbutin nicotinamide; Wherein, the temperature of the supramolecular modification reaction is less than 100°C.

3. The method for preparing supramolecular arbutin nicotinamide according to claim 2, characterized in that: The molar ratio of the arbutin to the niacinamide is 1:

1.

4. The method for preparing supramolecular arbutin nicotinamide according to claim 2, characterized in that: The temperature of the supramolecular modification reaction is 50-80°C; And / or, the supramolecular modification reaction time is 4 to 24 h; And / or, the first solvent includes a first organic solvent or a mixture of the first organic solvent and water, and the first organic solvent includes any one of methanol, ethanol, isopropanol, and acetone; and / or, the mixing of arbutin, nicotinamide and the first solvent is carried out under a stirring condition of 100-200 rpm; And / or, the supramolecular modification reaction is carried out under the protection of an inert gas, wherein the inert gas includes any one of nitrogen, argon, helium and neon.

5. The method for preparing supramolecular arbutin nicotinamide according to claim 2, characterized in that: After the supramolecular modification reaction is completed, the method further comprises: cooling, stirring and crystallizing to obtain supramolecular arbutin nicotinamide.

6. The method for preparing supramolecular arbutin nicotinamide according to claim 5, characterized in that: The cooling temperature is 0~5℃; And / or, the stirring speed of the stirred crystallization is 10 to 300 rpm; And / or, the stirring crystallization time is 12 to 48 hours.

7. The method for preparing supramolecular arbutin nicotinamide according to claim 2, characterized in that: The mixing of arbutin, niacinamide and the first solvent comprises: mixing an arbutin extract with niacinamide, wherein the arbutin extract comprises arbutin and the first solvent; The arbutin extract is obtained by the following method: mixing the raw material containing arbutin with the second solvent, extracting under heating conditions, and performing solid-liquid separation after the extraction is completed to obtain the arbutin extract; The second solvent includes a mixture of a second organic solvent and water or a second organic solvent, and the second organic solvent includes any one of methanol, ethanol, isopropanol, and acetone; In the mixture of the second organic solvent and water, the volume ratio of the second organic solvent to water is (5-25): (95-75).

8. The method for preparing supramolecular arbutin nicotinamide according to claim 7, characterized in that: The arbutin-containing raw material includes any one of bearberry, bearberry leaf, and pear leaf; And / or, the mass ratio of the second solvent to the arbutin-containing raw material is (5-10):1; And / or, the mixing of the arbutin-containing raw material and the second solvent is carried out under a stirring condition of 150-300 rpm.

9. The method for preparing supramolecular arbutin nicotinamide according to claim 7 or 8, characterized in that: The extraction temperature is 40-50°C; And / or, the extraction time is 2 to 6 hours; And / or, the solid-liquid separation method includes centrifugal separation, and the rotation speed of the centrifugal separation is 8000~10000 r / min.

10. A daily chemical product, characterized in that: The daily chemical product comprises the supramolecular arbutin nicotinamide according to claim 1 or the supramolecular arbutin nicotinamide prepared by the preparation method of the supramolecular arbutin nicotinamide according to any one of claims 2 to 9; The daily chemical products include skin care products and cosmetics.

Images