Supramolecular arbutin nicotinamide, preparation method thereof, and daily chemical product

Abstract

This application provides a supramolecular arbutin nicotinamide, its preparation method, and daily chemical products, relating to the fields of skin care and cosmetics. The supramolecular arbutin nicotinamide comprises arbutin and nicotinamide, which are bound together by a non-covalent bond. The structural formula of the supramolecular arbutin nicotinamide is #imgabs0#. The supramolecular arbutin nicotinamide of this application has the advantage of high stability. Furthermore, the supramolecular compound of this application also possesses the efficacy of arbutin, significantly improving the poor stability of arbutin.

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, a preparation method thereof, and a daily chemical product. Background Art

[0002] Arbutin, also known as arbutin, is a β-D-pyranoside 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 saxifrage leaves. Its structural formula is as follows:

[0003] .

[0004] Structurally, arbutin and tyrosine have certain similarities, competing to bind to the active site of tyrosinase. By inhibiting the activity of tyrosinase in the body, it prevents the production of melanin, reduces skin pigmentation, removes spots and freckles, and also has bactericidal and anti-inflammatory effects.

[0005] However, current research indicates that arbutin is unstable and tends to decompose to a certain extent in acidic or alkaline conditions and at higher temperatures, producing hydroquinone, a substance with certain carcinogenicity and cytotoxicity. Furthermore, it is prone to discoloration in alkaline conditions and at higher temperatures. Products containing arbutin on the market generally require a pH control of 5-7 during the preparation process and the addition of an appropriate amount of antioxidants to prevent discoloration. These factors limit the application of arbutin in skincare and cosmetics. Therefore, enhancing the stability of arbutin and expanding its application are currently urgent issues to be addressed. Summary of the Invention

[0006] The purpose of this application is to provide a supramolecular arbutin nicotinamide and its preparation method and daily chemical product to solve the above problems.

[0007] To achieve the above objectives, this application adopts the following technical solutions:

[0008] A supramolecular arbutin nicotinamide, comprising arbutin and nicotinamide, wherein the arbutin and nicotinamide are bound together by a non-covalent bond;

[0009] The structural formula of the supramolecular arbutin nicotinamide is .

[0010] 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;

[0011] Wherein, the temperature of the supramolecular modification reaction is less than 100°C.

[0012] According to an embodiment of the present application, the molar ratio of the arbutin to the niacinamide is 1:1.

[0013] According to an embodiment of the present application, the temperature of the supramolecular modification reaction is 50-80° C., preferably 70-80° C.;

[0014] And / or, the supramolecular modification reaction time is 4 to 24 h, preferably 4 to 8 h;

[0015] 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;

[0016] and / or, the mixing of arbutin, nicotinamide, and the first solvent is performed under stirring conditions of 100 to 200 rpm;

[0017] 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.

[0018] 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.

[0019] According to an embodiment of the present application, the cooling temperature is 0-5°C;

[0020] And / or, the stirring speed of the stirred crystallization is 10 to 300 rpm, preferably 50 to 100 rpm;

[0021] And / or, the stirring crystallization time is 12 to 48 hours.

[0022] 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;

[0023] The arbutin extract is obtained by: mixing a raw material containing arbutin with a second solvent, extracting the mixture under heating conditions, and performing solid-liquid separation after the extraction is completed to obtain the arbutin extract;

[0024] 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;

[0025] 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).

[0026] According to an embodiment of the present application, the raw material containing arbutin includes any one of bearberry, bearberry leaf, and pear leaf;

[0027] and / or, the mass ratio of the second solvent to the arbutin-containing raw material is (5-10):1;

[0028] 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.

[0029] According to an embodiment of the present application, the extraction temperature is 40-50°C;

[0030] And / or, the extraction time is 2 to 6 hours;

[0031] And / or, the solid-liquid separation method includes centrifugal separation, and the rotation speed of the centrifugal separation is 8000~10000r / min.

[0032] The present application also provides a daily chemical product, which comprises the supramolecular arbutin nicotinamide described above or the supramolecular arbutin nicotinamide prepared by the preparation method of the supramolecular arbutin nicotinamide described above;

[0033] Preferably, the daily chemical products include skin care products and cosmetics.

[0034] Compared with the prior art, the advantages of this application include:

[0035] 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, which can significantly improve the problem of poor stability of arbutin.

[0036] The present invention's supramolecular arbutin nicotinamide preparation method can produce a highly stable supramolecular compound that also possesses the efficacy of arbutin, thereby improving arbutin's poor stability. Furthermore, the present invention's preparation method offers advantages such as simple operation, high product yield, and low production cost, facilitating large-scale application.

[0037] The daily chemical product of the present application includes supramolecular arbutin nicotinamide, wherein the supramolecular arbutin nicotinamide has the efficacy of both arbutin monomer and niacinamide monomer. The arbutin and niacinamide in the supramolecular arbutin nicotinamide support and cooperate with each other in function, thereby exerting a better whitening effect and can be applied in daily chemical products with whitening effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following is a brief introduction to the drawings required for use in the embodiments. 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.

[0039] Figure 1 is the X-ray powder diffraction pattern of the supramolecular arbutin nicotinamide in Example 1;

[0040] Figure 2 This is a comparison of the XRD diffraction patterns of the supramolecular arbutin nicotinamide prepared in Example 1 and arbutin and nicotinamide powders;

[0041] Figure 3 This is the H NMR spectrum of the supramolecular arbutin nicotinamide in Example 1;

[0042] Figure 4 is the C NMR spectrum of the supramolecular arbutin nicotinamide in Example 1;

[0043] Figure 5 This is the ESP distribution diagram of supramolecular arbutin nicotinamide;

[0044] Figure 6 This is a schematic diagram of the weak interactions of the supramolecular arbutin nicotinamide structure;

[0045] Figure 7 It is the IRI isosurface and scatter plot of the supramolecular arbutin nicotinamide structure;

[0046] Figure 8 This is a graph showing the effect of supramolecular arbutin nicotinamide on melanin production in human melanocytes;

[0047] Figure 9 This is a graph showing the effect of supramolecular arbutin nicotinamide on tyrosinase activity in human melanocytes. DETAILED DESCRIPTION

[0048] As used herein:

[0049] "Prepared from" is synonymous with "comprising." As used herein, the terms "comprising," "including," "having," "containing," or any other variations 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.

[0050] The conjunction "consisting of" excludes any unspecified element, step, or component. If used in a claim, this phrase renders the claim closed, excluding 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.

[0051] 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 alone. For example, when a range of "1 to 5" is disclosed, the described range should be interpreted as including the range "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 herein, unless otherwise stated, the range is intended to include its end values and all integers and fractions within the range.

[0052] In these examples, parts and percentages are by mass unless otherwise indicated.

[0053] "Parts by mass" refers to the basic unit of measurement used to express the mass ratio of multiple components. One part can represent any unit of mass, such as 1g or 2.689g. For example, if we say that the parts by mass of component A are a parts and the parts by mass of component B are b parts, this means the ratio of the mass of component A to the mass of component B is a:b. Alternatively, we could say that the mass of component A is aK and the mass of component B is bK (K is an arbitrary number representing a multiplication factor). It's important to note that, unlike parts by mass, the sum of the parts by mass of all components is not limited to 100 parts.

[0054] "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).

[0055] In order to better illustrate the technical solution provided by this application, before the embodiments, an overall description of the technical solution is first given, as follows:

[0056] Arbutin has the potential to reduce skin pigmentation, remove spots and freckles, and has antibacterial and anti-inflammatory properties, making it suitable for use in skincare and cosmetics. However, arbutin suffers from poor stability and readily decomposes to produce toxic substances in acidic or alkaline environments or at elevated temperatures. Furthermore, arbutin requires stringent preparation conditions. These issues limit its application in skincare and cosmetics.

[0057] Niacinamide, also known as vitamin B3 or vitamin PP, is a skin-whitening active ingredient. Its mechanisms include the following two aspects: 1) It interferes with the transport of melanin, confining it to melanocytes, preventing it from reaching the skin surface and causing darkening, thereby achieving a whitening effect. 2) It has a strong anti-glycation effect. Glycation produces substances that are brown and can make the skin appear darker. Niacinamide's anti-glycation effect helps whiten the skin, thereby brightening the complexion.

[0058] In the present application, arbutin and nicotinamide are combined through non-covalent bonds to form a supramolecular compound. The resulting supramolecular compound has the advantage of high stability and also has the efficacy of arbutin, which can significantly improve the problem of poor stability of arbutin.

[0059] The present application provides a supramolecular arbutin nicotinamide, which comprises arbutin and nicotinamide, wherein arbutin and nicotinamide are bound together by a non-covalent bond;

[0060] The structural formula of supramolecular arbutin nicotinamide is .

[0061] In some embodiments, the molar ratio of arbutin to nicotinamide in the supramolecular arbutin nicotinamide is 1:1.

[0062] 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;

[0063] The temperature of the supramolecular modification reaction is less than 100°C.

[0064] According to an embodiment of the present application, the molar ratio of arbutin to niacinamide is 1:1.

[0065] According to the embodiments of the present application, the temperature of the supramolecular modification reaction is 50-80°C, preferably 70-80°C. This range can provide sufficient thermal energy to drive the supramolecular modification reaction toward the synthesis of supramolecular arbutin and nicotinamide, while effectively preventing the decomposition of arbutin and nicotinamide at high temperatures. When the reaction temperature is too low, the required reaction time is significantly increased, and the product yield is relatively low; when the reaction temperature is too high, the reaction raw materials may decompose and the reaction byproducts may increase.

[0066] For example, the temperature of the supramolecular modification reaction can be 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, or any value between 50 and 80°C.

[0067] And / or, the supramolecular modification reaction time is 4 to 24 hours, preferably 4 to 8 hours. Within this time range, the reactants have sufficient time to fully interact with each other, ensuring that the reaction proceeds completely, which helps to improve the product yield. If the reaction time is too short, there may be undesirable problems such as incomplete reaction and low product yield. If the reaction time is too long, the content of byproducts will increase, the purity of the product will be reduced, and energy consumption will be increased.

[0068] For example, the supramolecular modification reaction time 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.

[0069] 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;

[0070] and / or, the mixing of arbutin, nicotinamide, and the first solvent is performed under stirring conditions of 100 to 200 rpm;

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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 explosive phenomenon can be avoided and 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 poor system fluidity, and block crystals of varying sizes will be easily precipitated during crystallization; if the stirring speed of the stirred crystallization is too high, explosive analysis, too small crystals, and easy entrainment of impurities are likely to occur.

[0075] 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.

[0076] And / or, the time of stirring and crystallizing is 12 to 48 h. For example, the time of stirring and crystallizing 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.

[0077] 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 the first solvent;

[0078] The arbutin extract is obtained by the following method: mixing a raw material containing arbutin with a second solvent, extracting under heating conditions, and performing solid-liquid separation after the extraction is completed to obtain the arbutin extract;

[0079] 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.

[0080] 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;

[0081] 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).

[0082] According to the embodiments of the present application, the raw materials containing arbutin include any one of bearberry, bearberry leaves, and pear leaves. These substances are rich in the active ingredient arbutin, and arbutin can be obtained by extracting them.

[0083] 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.

[0084] 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.

[0085] And / or, the mixing of the arbutin-containing raw material and the second solvent is performed 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.

[0086] 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℃.

[0087] And / or, the extraction time is 2 to 6 hours; for example, the extraction time can be 2 hours, 3 hours, 4 hours, 5 hours, 6 hours or any value between 2 and 6 hours.

[0088] And / or, the solid-liquid separation method includes centrifugation, and the centrifugal separation speed is 8000-10000 r / min. For example, the centrifugal separation speed 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 through solid-liquid separation.

[0089] 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;

[0090] Preferably, daily chemical products include skin care products and cosmetics.

[0091] The embodiments of the present application will be described in detail below in conjunction with specific examples, but it will be understood by those skilled in the art that the following examples are merely illustrative of the present application and should not be considered as limiting the scope of the present application. In the examples, if specific conditions are not specified, the conditions are carried out according to conventional conditions or manufacturer recommendations. The reagents or instruments used are not specified by the manufacturer and are conventional products that can be purchased commercially.

[0092] 1. Preparation of supramolecular arbutin nicotinamide

[0093] Example 1

[0094] Example 1 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0095] (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 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0096] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0097] High performance liquid chromatography combined with external standard method was used to accurately detect the content of arbutin in the filtrate.

[0098] The reagents and equipment used were as follows: chromatographic column: Agilent ZORBAX SB-C18 column (4.6×250 mm, 5 μm); column temperature: 30°C; 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.

[0099] Preparation of solutions: a. Preparation of arbutin standard solution: Take approximately 100 mg of arbutin standard, accurately weigh it, place it in a 100 mL volumetric flask, add water to dissolve it and dilute it 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.

[0100] Test steps: a. Drawing of the standard curve: Accurately measure 0.2 mL, 0.5 mL, 1.0 mL, 1.5 mL, 2.0 mL, and 2.5 mL of the arbutin reference solution and place them in 5 mL volumetric flasks, dilute to the mark with ultrapure water, and shake well. These are used as linear standard curve solutions 1 to 6. The standard curve is prepared with the arbutin concentration as the horizontal axis and the peak area as the vertical axis. 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.

[0101] The test results showed that the concentration of arbutin in the filtrate was 1.46 wt%.

[0102] (3) Weigh 3.729 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.46 wt %, 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 the supramolecular modification reaction for 6 hours. After the reaction is completed, set the crystallization temperature to 0°C, the stirring speed to 50 rpm, and the crystallization time to 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0103] The weight of supramolecular arbutin nicotinamide was 59.49 g, and the calculated yield was 75.43%.

[0104] Example 2

[0105] Example 2 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0106] (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 300 rpm, heat to 50 °C, and extract for 2 h to obtain a suspension solution.

[0107] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 8000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0108] The concentration of arbutin in the filtrate was detected according to the external standard method in Example 1. The detection result showed that the concentration of arbutin in the filtrate was 1.27 wt %.

[0109] (3) Weigh 4.287 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.27 wt %, 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 carry out the supramolecular modification reaction for 6 hours. After the reaction is completed, set the crystallization temperature to 0°C, the stirring speed to 50 rpm, and crystallize for 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0110] The weight of supramolecular arbutin nicotinamide was 55.44 g, and the calculated yield was 70.29%.

[0111] Example 3

[0112] Example 3 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0113] (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.

[0114] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 10,000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0115] The concentration of arbutin in the filtrate was detected according to the external standard method in Example 1. The detection result showed that the concentration of arbutin in the filtrate was 1.34 wt %.

[0116] (3) Weigh 4.063 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.34 wt %, then add 24.42 g of nicotinamide to the filtrate of step (2), start stirring at 100 rpm, start heating at 75°C, and carry out 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.

[0117] The weight of supramolecular arbutin nicotinamide was 55.75 g, and the calculated yield was 70.69%.

[0118] Example 4

[0119] Example 4 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0120] (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 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0121] (2) Place the suspension into a centrifuge, set the speed of the centrifuge 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 in Example 1. The detection result showed that the concentration of arbutin in the filtrate was 1.44 wt %.

[0123] (3) Weigh 3.781 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.44 wt %, 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 carry out a 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.

[0124] The weight of supramolecular arbutin nicotinamide was 59.41 g, and the calculated yield was 75.33%.

[0125] Example 5

[0126] Example 5 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0127] (1) Crush 1 kg of dried bearberry leaves, then add 5 kg of a mixed solvent prepared by 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.

[0128] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0129] The concentration of arbutin in the filtrate was detected according to the external standard method in Example 1. The detection result showed that the concentration of arbutin in the filtrate was 1.73 wt %.

[0130] (3) Weigh 3.147 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.73 wt %, and then add 24.42 g of nicotinamide to the filtrate of step (2). Stirring is started at a stirring speed of 150 rpm. Heating is started at a heating reaction temperature of 80°C for a supramolecular modification reaction for 6 hours. After the reaction is completed, crystallization is carried out at a temperature of 0°C and a stirring speed of 50 rpm for 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0131] The weight of supramolecular arbutin nicotinamide was 55.36 g, and the calculated yield was 70.19%.

[0132] Example 6

[0133] Example 6 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0134] (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. Stir at 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0135] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0136] The concentration of arbutin in the filtrate was detected according to the external standard method in Example 1. The detection result showed that the concentration of arbutin was 1.48 wt %.

[0137] (3) Weigh 3.679 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.48 wt %, and then add 24.42 g of nicotinamide to the filtrate of step (2). Stirring is started at a stirring speed of 150 rpm. Heating is started at a heating reaction temperature of 75°C for a supramolecular modification reaction for 4 hours. After the reaction is completed, crystallization is carried out at a temperature of 0°C and a stirring speed of 50 rpm for 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0138] The weight of supramolecular arbutin nicotinamide was 59.77 g, and the calculated yield was 75.78%.

[0139] Example 7

[0140] Example 7 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0141] (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 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0142] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0143] The concentration of arbutin in the filtrate was detected according to the external standard method in Example 1. The detection result showed that the concentration of arbutin in the filtrate was 1.45 wt %.

[0144] (3) Weigh 3.755 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.45 wt %, 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 the 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.

[0145] The weight of supramolecular arbutin nicotinamide was 58.34 g, and the calculated yield was 73.97%.

[0146] Example 8

[0147] Example 8 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0148] (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 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0149] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0150] The concentration of arbutin in the filtrate was detected according to the external standard method in Example 1. The detection result showed that the concentration of arbutin was 1.47 wt %.

[0151] (3) Weigh 3.704 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.47 wt %, 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 the supramolecular modification reaction for 6 hours. After the reaction is completed, crystallization is carried out at a crystallization temperature of 5°C and a stirring speed of 50 rpm for 24 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0152] The weight of supramolecular arbutin nicotinamide was 59.46 g, and the calculated yield was 75.39%.

[0153] Example 9

[0154] Example 9 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0155] (1) 1 kg of dried bearberry leaves was crushed, and then 10 kg of a mixed solvent prepared by ethanol and water in a volume ratio of 15:85 was added. The mixture was stirred at a speed of 150 rpm, heated to 45 °C, and extracted for 4 h to obtain a suspension solution.

[0156] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0157] The concentration of arbutin in the filtrate was detected according to the external standard method in Example 1. The detection result showed that the concentration of arbutin in the filtrate was 1.45 wt %.

[0158] (3) Weigh 3.755 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.45 wt %, 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 the 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 12 hours. The resulting solid is supramolecular arbutin nicotinamide.

[0159] The weight of supramolecular arbutin nicotinamide was 52.94 g, and the calculated yield was 67.12%.

[0160] Example 10

[0161] Example 10 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0162] (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 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0163] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0164] The concentration of arbutin in the filtrate was detected according to the external standard method in Example 1. The detection result showed that the concentration of arbutin in the filtrate was 1.46 wt %.

[0165] (3) Weigh 3.729 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.46 wt %, 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 the 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.

[0166] The weight of supramolecular arbutin nicotinamide was 60.99 g, and the calculated yield was 77.33%.

[0167] Example 11

[0168] Example 11 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0169] (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 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0170] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0171] The concentration of arbutin in the filtrate was detected according to the external standard method in Example 1. The detection result showed that the concentration of arbutin in the filtrate was 1.48 wt %.

[0172] (3) Weigh 3.679 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.48 wt %, 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 the 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.

[0173] The weight of supramolecular arbutin nicotinamide was 54.47 g, and the calculated yield was 69.06%.

[0174] Example 12

[0175] Example 12 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0176] (1) Crush 1 kg of dried bearberry leaves, then add 15 kg of anhydrous ethanol, start stirring at 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0177] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0178] The concentration of arbutin in the filtrate was detected according to the external standard method in Example 1. The detection result showed that the concentration of arbutin in the filtrate was 0.43 wt %.

[0179] (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 carry out a 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.

[0180] The weight of supramolecular arbutin nicotinamide was 9.45 g, and the calculated yield was 11.98%.

[0181] Compared to Example 1, Example 12 changes the extraction solvent for 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 for bearberry leaves results in poor extraction efficiency, resulting in a low concentration of arbutin. This, in turn, leads to a high solvent dosage in the subsequent supramolecular modification reaction, a low concentration of the reaction precursor in the reaction system, poor reaction efficiency, and a low yield. This indicates that the solvent used in this application is preferably a mixed solvent of ethanol and water.

[0182] Example 13

[0183] Example 13 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0184] (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 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0185] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0186] The concentration of arbutin in the filtrate was detected according to the external standard method in Example 1. The detection result showed that the concentration of arbutin in the filtrate was 1.35 wt %.

[0187] (3) Weigh 4.033 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.35 wt %, and then add 24.42 g of nicotinamide to the filtrate of step (2). Stirring is started at a stirring speed of 150 rpm. Heating is started at a heating reaction temperature of 50°C to carry out a supramolecular modification reaction for a reaction time of 24 h. After the reaction is completed, crystallization is carried out 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.

[0188] The weight of supramolecular arbutin nicotinamide was 19.22 g, and the calculated yield was 24.37%.

[0189] 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.

[0190] Example 14

[0191] Example 14 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0192] (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 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0193] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0194] The concentration of arbutin in the filtrate was detected according to the external standard method in Example 1. The detection result showed that the concentration of arbutin in the filtrate was 1.44 wt %.

[0195] (3) Weigh 3.781 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.44 wt %, 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 the 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.

[0196] The weight of supramolecular arbutin nicotinamide was 55.46 g, and the calculated yield was 70.32%.

[0197] 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 size. This indicates that the crystallization stirring speed is preferably 50-100 rpm.

[0198] Example 15

[0199] Example 15 provides a supramolecular arbutin nicotinamide, the preparation method of which comprises:

[0200] (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 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0201] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0202] The concentration of arbutin in the filtrate was detected according to the external standard method in Example 1. The detection result showed that the concentration of arbutin in the filtrate was 1.44 wt %.

[0203] (3) Weigh 3.781 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.44 wt %, 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 the 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.

[0204] The weight of supramolecular arbutin nicotinamide was 65.41 g, and the calculated yield was 82.93%.

[0205] 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.

[0206] Comparative Example 1

[0207] (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 150 rpm, heat to 45 °C, and extract for 4 h to obtain a suspension solution.

[0208] (2) Place the suspension into a centrifuge, set the speed of the centrifuge to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0209] The concentration of arbutin in the filtrate was detected according to the external standard method in Example 1. The detection result showed that the concentration of arbutin in the filtrate was 1.35 wt %.

[0210] (3) Weigh 4.033 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.35 wt %, and then add 24.42 g of nicotinamide to the filtrate of step (2). Stirring was started at a speed of 150 rpm. Heating was started at a heating reaction temperature of 100°C for a supramolecular modification reaction for 6 h. After the reaction was completed, crystallization was carried out at a temperature of 0°C and a stirring speed of 50 rpm for 24 h. No product was precipitated after the crystallization was completed.

[0211] Comparative Example 1 did not produce a supramolecular arbutin nicotinamide product.

[0212] Compared with Example 1, Comparative Example 1 increases the temperature of the supramolecular modification reaction in step (3). 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.

[0213] 2. Structural Characterization of Supramolecular Arbutin Nicotinamide

[0214] (1) Powder X-ray single crystal diffraction test

[0215] Instruments and parameters: X-ray diffractometer model: XRD-MiniFlex600; test target: copper target; scanning range: 5-85°; scanning rate: 5° / min.

[0216] 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°.

[0217] 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 the 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 formed a new co-crystal under the conditions of the present application.

[0218] (2) MRI test

[0219] The supramolecular arbutin nicotinamide was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum.

[0220] Instrument and parameters: Bruker NMR spectrometer; Solvent type: Heavy water; Experimental conditions: Scan times: 1024 (C spectrum), 16 (H spectrum), test environment temperature controlled by liquid nitrogen; Data analysis: Analyzed using MestReNova, a professional nuclear magnetic resonance (NMR) data analysis software.

[0221] Experimental results: The supramolecular arbutin nicotinamide obtained in Example 1 was subjected to nuclear magnetic resonance spectroscopy ( 1 H-NMR) test, nuclear magnetic resonance hydrogen spectrum data is 1H 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 ).

[0222] like Figure 3 As shown in 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 group 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 seen. 1 H-NMR test results showed that arbutin and nicotinamide in the supramolecular arbutin nicotinamide obtained in Example 1 existed in a molar ratio of 1:1.

[0223] 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.

[0224] like Figure 4 As shown in the carbon NMR spectrum, the carbon atoms on arbutin and nicotinamide can be clearly found, and no obvious impurity peaks are observed. 13 C-NMR) test results showed that the arbutin and nicotinamide in the supramolecular arbutin nicotinamide obtained in Example 1 existed in a molar ratio of 1:1.

[0225] (3) Calculation of interaction forces

[0226] Supramolecular structures typically consist of two or more molecules bound together by intermolecular forces, such as hydrogen bonding, van der Waals forces, and π-π stacking, forming complex, organized structures that maintain a certain level of integrity, resulting in well-defined microstructures and macroscopic properties. π-π stacking is a unique spatial arrangement of aromatic compounds, a weak interaction that often occurs between aromatic rings, typically between relatively electron-rich and electron-deficient molecules. It is a non-covalent interaction that is as important as hydrogen bonding.

[0227] Arbutin contains a benzene ring structure, while nicotinamide contains a nitrogen heterocycle. Structurally, arbutin and nicotinamide may form a stable supramolecule through π-π stacking.

[0228] The interaction force between arbutin and nicotinamide 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 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.

[0229] 3. Particle size test of supramolecular arbutin nicotinamide

[0230] Particle size control is crucial for the bioavailability and efficacy of active ingredients. During the preparation process, particle size control facilitates the dissolution of active ingredients and the absorption of poorly soluble active ingredients, thereby improving the efficacy and bioavailability of the active ingredients.

[0231] 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.

[0232] Testing Method: A laser particle size analyzer is used to analyze particle size by measuring the angle and intensity of laser light scattered from the surface of the particles being tested, based on Mie scattering and Freund's diffraction theory. The dry method uses air as the dispersion medium and utilizes the principle of turbulent dispersion to fully disperse the sample particles before introducing them into the optical system for testing.

[0233] Table 1 Summary of supramolecular arbutin nicotinamide particle size test results

[0234]

[0235] As can be seen from Table 1, the particle sizes of Examples 1-15 range from 6 to 40 μm, with the particle sizes of the supramolecular arbutin nicotinamide in Examples 1-13 ranging from 10 to 20 μm. When the particle size of supramolecular arbutin nicotinamide is 10 to 20 μm, the particle size is appropriate, effectively improving the bioavailability of supramolecular arbutin and increasing the specific surface area of the particles. The particle size of the supramolecular arbutin nicotinamide in Example 14 is too large, and the particle size of the supramolecular arbutin nicotinamide in Example 15 is too small, both of which are detrimental to the bioavailability of supramolecular arbutin.

[0236] Compared with Example 12 and Example 13, Example 1-11 has a higher yield of the supramolecular product, indicating that the reaction conditions of Example 1-11 are preferred reaction conditions. The 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 enhancing skin permeability and improving bioavailability.

[0237] 4. Stability test of supramolecular arbutin nicotinamide

[0238] (1) Arbutin stability test

[0239] Stability test samples: 1. Supramolecular arbutin and nicotinamide aqueous solutions at different concentrations, at 1.0%, 5.0%, and 10%; 2. Supramolecular arbutin and nicotinamide aqueous solutions at different pH values, at a concentration of 5.0% and pH values of 1.0, 7.0, and 13; 3. Arbutin monomer and nicotinamide monomer were prepared in a molar ratio of 1:1 to form corresponding physical mixed aqueous solution samples according to the above conditions.

[0240] Stability test conditions: The above samples were placed in 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.

[0241] 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 performed. Samples were taken regularly to test the content of hydroquinone. The test results are shown in Tables 2, 3, 4 and 5.

[0242] Supramolecular arbutin nicotinamide aqueous solutions and physically mixed arbutin nicotinamide aqueous solutions with concentrations of 1.0%, 5.0% and 10% were placed under sunlight at 50°C for 28 days. Samples were taken on 0 days, 7 days, 14 days and 28 days to test the hydroquinone content. The test results are shown in Tables 2 and 3.

[0243] Table 2 Changes in hydroquinone content in samples of different concentrations placed in a 50°C oven for 28 days

[0244]

[0245] Table 3 Changes in hydroquinone content in samples of different concentrations placed under sunlight for 28 days

[0246]

[0247] As can be seen from Tables 2 and 3, under conditions of equal concentration, the hydroquinone content of the supramolecular arbutin nicotinamide aqueous solution after 28 days of decomposition was much lower than that of the physically mixed arbutin nicotinamide aqueous solution. Furthermore, the physically mixed arbutin nicotinamide aqueous solution sample began to produce hydroquinone on the 7th day, while the supramolecular arbutin nicotinamide aqueous solution under sunlight conditions began to produce a small amount of hydroquinone on the 28th day. This indicates that compared with the physically mixed arbutin nicotinamide, the supramolecular arbutin nicotinamide prepared in this application has a certain improvement in stability.

[0248] A supramolecular arbutin-nicotinamide aqueous solution and a physically mixed arbutin-nicotinamide aqueous solution, both with a concentration of 5.0% and pH values of 1.0, 7.0, and 13, were placed under sunlight at 50°C for 28 days. Samples were taken at 0, 7, 14, and 28 days to test the hydroquinone content. The test results are shown in Tables 4 and 5.

[0249] Table 4 Changes in hydroquinone content in samples with different pH values after being placed in a 50°C oven for 28 days

[0250]

[0251] Table 5 Changes in hydroquinone content of samples with different pH values after being placed under sunlight for 28 days

[0252]

[0253] As can be seen from Tables 4 and 5, 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 was much lower than that at pH 1.0 and 13.0. Under superacidic or superalkaline conditions, hydroquinone was detected in both the supramolecular arbutin nicotinamide aqueous solution and the physically mixed arbutin nicotinamide aqueous solution on day 7, 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 indicates that the stability of the supramolecular arbutin nicotinamide prepared in this application is improved compared to that of the physically mixed arbutin nicotinamide.

[0254] 5. Testing the Whitening Efficacy of Supramolecular Arbutin Nicotinamide

[0255] Melanin production is primarily inhibited through two approaches: inhibiting tyrosinase activity and inhibiting the melanin production signaling pathway. Some whitening agents, such as kojic acid and its derivatives, inhibit melanin production by inhibiting tyrosinase activity. Others target the melanin production signaling pathway, such as inhibitors targeting the α-melanocyte stimulating hormone (-MSH) receptor MCIR protein. Furthermore, products with antioxidant properties can reduce dopaquinone to L-dopa, potentially finding application in the development of whitening products.

[0256] The supramolecular arbutin nicotinamide obtained in Example 1 was used as the experimental material to evaluate the effect of supramolecular arbutin nicotinamide on melanin content and tyrosinase activity in human melanocytes. This test evaluated the efficacy of supramolecular arbutin nicotinamide by inducing melanocytes with α-MSH and detecting the effects of the sample on melanin production and tyrosinase inhibition using a colorimetric assay.

[0257] (1) Human melanocytes - melanin content test

[0258] The supramolecular arbutin nicotinamide obtained in Experimental Example 1 was used as the experimental material.

[0259] Experimental procedures: a. Inoculate cells into a 6-well plate 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 continuously culture for 5 days, changing the medium once in the middle; c. At the end of the exposure, remove the culture solution, wash once with PBS, and collect the cells in each well using a cell scraper; d. Add a solution containing 1 mol / L NaOH (containing 10% DMSO) to dissolve the cells and obtain cell lysate; e. Place the cell lysate at 80 °C and heat for 30 min to lyse melanosomes; f. Take the cell lysate and measure the absorbance value at a wavelength of 490 nm. The data was 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 tabulated in Table 6.

[0260]

[0261] The detection results of the melanin content in human melanocytes by supramolecular arbutin nicotinamide are shown in Table 6.

[0262] Table 6 Detection results of the melanin content in human melanocytes by supramolecular arbutin nicotinamide

[0263] <着

[0264] 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 ***. Compared with the blank control group (NC), p < 0.05 is denoted as #.

[0265] From Table 6 and Figure 8 it can be seen that in the experiment on the melanin content of human melanocytes, when the concentrations of supramolecular arbutin nicotinamide are 0.34 mg / mL, 0.1\着 mg / mL, and 0.085 mg / mL respectively, the corresponding relative melanin content is reduced by 37.97%, 26.99%, and 21.94% compared with the model control group (M). This result indicates that supramolecular arbutin nicotinamide has the effect of inhibiting melanin production.

[0266] (2) Inhibition experiment on tyrosinase activity in human melanocytes

[0267] Use the supramolecular arbutin nicotinamide obtained in Experimental Example 1 as the experimental material.

[0268] Experimental procedures: a. Inoculate 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 media 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 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 statistically recorded in Table 7.

[0269]

[0270] The detection results of the inhibition test of supramolecular arbutin nicotinamide on the tyrosinase activity of human melanocytes are shown in Table 7.

[0271] Table 7 Detection results of the test of supramolecular arbutin nicotinamide on the tyrosinase activity of human melanocytes

[0272]

[0273] 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 ***. Compared with the blank control group (NC), p < 0.05 is denoted as #.

[0274] From Table 7 and Figure 9 it can be seen that in the inhibition experiment of the tyrosinase activity of human melanocytes, when the concentrations of supramolecular arbutin nicotinamide are 0.34 mg / mL, 0.17 mg / mL, and 0.085 mg / mL respectively, the corresponding relative tyrosinase activities are reduced by 19.26%, 13.81%, and 12.62% compared with the model control group (M), indicating that supramolecular arbutin nicotinamide has the effect of inhibiting tyrosinase activity.

[0275] 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 recorded in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

[0276] Furthermore, those skilled in the art will appreciate that although some embodiments herein include certain features included in other embodiments but not others, combinations of features from different embodiments are intended to be within the scope of this application and to form distinct embodiments. For example, in the claims above, any of the claimed embodiments may be used in any combination. The information disclosed in this background section is intended solely to enhance understanding of the overall background of this application and should not be construed as an admission or any implication that such information constitutes prior art known to those skilled in the art.

Claims

1. A method for preparing supramolecular arbutin nicotinamide, characterized in that: The supramolecular arbutin nicotinamide comprises arbutin and nicotinamide, and the arbutin and nicotinamide are combined via a non-covalent bond; The structural formula of the supramolecular arbutin nicotinamide is ; The preparation method comprises: mixing arbutin, nicotinamide and a first solvent, performing a supramolecular modification reaction under heating conditions, cooling, stirring and crystallizing to obtain supramolecular arbutin nicotinamide; The molar ratio of the arbutin to the niacinamide is 1:1; The temperature of the supramolecular modification reaction is 50-80°C; The supramolecular modification reaction time is 4 to 24 h; 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; The cooling temperature is 0~5℃; The stirring speed of the stirred crystallization is 10-300 rpm; The stirring crystallization time is 12 to 48 hours; The X-ray powder diffraction pattern of the supramolecular arbutin nicotinamide shows that the 2θ angles are 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°.

2. The method for preparing supramolecular arbutin nicotinamide according to claim 1, characterized in that: The mixing of the arbutin, nicotinamide and the first solvent is carried out under stirring conditions 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.

3. The method for preparing supramolecular arbutin nicotinamide according to claim 1, characterized in that: The mixing of arbutin, nicotinamide and the first solvent comprises: mixing an arbutin extract with nicotinamide, wherein the arbutin extract comprises arbutin and the first solvent; The arbutin extract is obtained by: mixing a raw material containing arbutin with a second solvent, extracting the mixture 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).

4. The method for preparing supramolecular arbutin nicotinamide according to claim 3, 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.

5. The method for preparing supramolecular arbutin nicotinamide according to claim 3 or 4, 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.

6. A daily chemical product, characterized in that: The daily chemical product comprises the supramolecular arbutin nicotinamide prepared by the preparation method of supramolecular arbutin nicotinamide according to any one of claims 1 to 5; The daily chemical products include skin care products and cosmetics.

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