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

Abstract

Provided in the present disclosure are a supramolecular arbutin nicotinamide and a preparation method therefor, and a daily chemical product, which relate to the field of skin care products and cosmetic products. The supramolecular arbutin nicotinamide comprises arbutin and nicotinamide; the arbutin and the nicotinamide are bound by means of non-covalent bonds. The structural formula of the supramolecular arbutin nicotinamide is formula (I). The supramolecular arbutin nicotinamide of the present disclosure has the advantage of high stability; in addition, the supramolecular compound of the present disclosure also retains the efficacy of arbutin and can significantly alleviate the problem of relatively poor stability of arbutin.

Description

Supramolecular arbutin nicotinamide, its preparation method and daily chemical products

[0001] Cross-reference to related applications

[0002] This disclosure claims priority to Chinese Patent Application No. 2025103231769, filed on March 19, 2025, entitled "Supramolecular Arbutin Nicotinamide and its Preparation Method and Daily Chemical Product", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to the field of skincare and cosmetic products, and in particular to a supramolecular arbutin niacinamide, its preparation method, and daily chemical products thereof. Background Technology

[0004] Arbutin, also known as bearberry extract, is a β-D-glucopyranoside 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:

[0005] Structurally, arbutin and tyrosine have certain similarities. They compete to bind to the active site of tyrosinase, thereby inhibiting the activity of tyrosinase in the body, thus preventing the production of melanin, reducing skin pigmentation, removing age spots and freckles, and also having antibacterial and anti-inflammatory effects.

[0006] However, current research indicates that arbutin is unstable and tends to decompose under acidic or alkaline conditions and at higher temperatures, easily producing hydroquinone, a substance with certain carcinogenic and cytotoxic properties. Furthermore, it is prone to discoloration under alkaline and high-temperature conditions. Commercially available arbutin products generally require pH control between 5 and 7 during preparation and the addition of appropriate antioxidants to prevent discoloration. These factors limit the application of arbutin in skincare and cosmetic products. Therefore, enhancing the stability of arbutin and expanding its application range are urgent issues that need to be addressed. Summary of the Invention

[0007] The purpose of this disclosure is to provide a supramolecular arbutin nicotinamide, its preparation method, and a daily chemical product thereof, in order to solve the above-mentioned problems.

[0008] To achieve the above objectives, the present disclosure adopts the following technical solution:

[0009] A supramolecular arbutin nicotinamide, the supramolecular arbutin nicotinamide comprising arbutin and nicotinamide, wherein the arbutin and nicotinamide are bonded together by a non-covalent bond;

[0010] The structural formula of the supramolecular arbutin nicotinamide is as follows:

[0011] This disclosure also provides a method for preparing supramolecular arbutin nicotinamide as described above, comprising: mixing arbutin, nicotinamide and a first solvent, and carrying out a supramolecular modification reaction under heating conditions to obtain supramolecular arbutin nicotinamide;

[0012] The temperature of the supramolecular modification reaction is less than 100℃.

[0013] According to embodiments of this disclosure, the molar ratio of arbutin to nicotinamide is 1:1.

[0014] According to embodiments of this disclosure, the temperature of the supramolecular modification reaction is 50–80°C, preferably 70–80°C;

[0015] And / or, the duration of the supramolecular modification reaction is 4–24 h, preferably 4–8 h;

[0016] And / or, the first solvent includes a first organic solvent or a mixture of a first organic solvent and water, wherein the first organic solvent includes any one of methanol, ethanol, isopropanol, and acetone;

[0017] And / or, the mixing of arbutin, nicotinamide and the first solvent is carried out under stirring conditions of 100 to 200 rpm;

[0018] And / or, the supramolecular modification reaction is carried out under the protection of an inert gas, which includes any one of nitrogen, argon, helium, and neon.

[0019] According to embodiments of this disclosure, after the supramolecular modification reaction is completed, the method further includes: cooling and stirring to crystallize, thereby obtaining supramolecular arbutin nicotinamide.

[0020] According to embodiments of this disclosure, the cooling temperature is 0–5°C;

[0021] And / or, the stirring speed for the crystallization process is 10 to 300 rpm, preferably 50 to 100 rpm;

[0022] And / or, the stirring crystallization time is 12 to 48 hours.

[0023] According to embodiments of this disclosure, the mixing of arbutin, nicotinamide, and the first solvent includes: mixing an arbutin extract with nicotinamide, wherein the arbutin extract comprises arbutin and the first solvent;

[0024] The arbutin extract is obtained by mixing arbutin-containing raw materials with a second solvent, extracting under heating conditions, and then performing solid-liquid separation after the extraction is completed to obtain the arbutin extract.

[0025] 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;

[0026] 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).

[0027] According to embodiments of this disclosure, the arbutin-containing raw material includes any one of bearberry, bearberry leaf, and pear leaf;

[0028] And / or, the mass ratio of the second solvent to the arbutin-containing raw material is (5-10):1;

[0029] And / or, the arbutin-containing raw material is mixed with the second solvent under stirring conditions of 150 to 300 rpm.

[0030] According to embodiments of this disclosure, the extraction temperature is 40–50°C;

[0031] And / or, the extraction time is 2 to 6 hours;

[0032] And / or, the solid-liquid separation method includes centrifugal separation, wherein the centrifugal separation speed is 8000-10000 r / min.

[0033] This disclosure 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.

[0034] Preferably, the daily chemical products include skin care products and cosmetics.

[0035] Compared with the prior art, the beneficial effects of this disclosure include:

[0036] The supramolecular arbutin nicotinamide disclosed herein has the advantage of high stability. At the same time, the supramolecular compound disclosed herein also has the efficacy of arbutin, which can significantly improve the problem of poor stability of arbutin.

[0037] The disclosed method for preparing supramolecular arbutin nicotinamide can produce a supramolecular compound with high stability, which also possesses the efficacy of arbutin, thus improving the poor stability of arbutin. Furthermore, the preparation method disclosed herein has advantages such as simple operation, high product yield, and low production cost, which is conducive to large-scale promotion and application.

[0038] The disclosed daily chemical products include supramolecular arbutin nicotinamide, which has the effects of both arbutin monomer and nicotinamide monomer. The arbutin and nicotinamide in supramolecular arbutin nicotinamide support and cooperate with each other in terms of function, which can exert a better whitening effect and can be used in daily chemical products with whitening effect. Attached Figure Description

[0039] To more clearly illustrate the technical solutions of the embodiments of this disclosure, the accompanying drawings used in the embodiments will be briefly described below. It should be understood that the following drawings only show some embodiments of this disclosure and should not be regarded as a limitation on the scope of this disclosure.

[0040] Figure 1 is the X-ray powder diffraction pattern of supramolecular arbutin nicotinamide in Example 1;

[0041] Figure 2 is a comparison of XRD diffraction patterns of the supramolecular arbutin nicotinamide prepared in Example 1 with arbutin and nicotinamide powders.

[0042] Figure 3 is the 1H NMR spectrum of supramolecular arbutin nicotinamide in Example 1;

[0043] Figure 4 is the carbon NMR spectrum of supramolecular arbutin nicotinamide in Example 1;

[0044] Figure 5 is the ESP distribution diagram of supramolecular arbutin nicotinamide;

[0045] Figure 6 is a schematic diagram of the weak interactions in the supramolecular arbutin nicotinamide structure;

[0046] Figure 7 shows the IRI isosurface and scatter plot of the supramolecular arbutin nicotinamide structure;

[0047] Figure 8 shows the effect of supramolecular arbutin nicotinamide on melanin production in human melanocytes.

[0048] Figure 9 shows the effect of supramolecular arbutin nicotinamide on the activity of tyrosinase in human melanocytes. Detailed Implementation

[0049] As used in this article:

[0050] "Prepared from" is synonymous with "comprising". The terms "comprising", "including", "having", "containing", or any other variations thereof as used herein are intended to cover non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not necessarily limited to those elements, but may include other elements not expressly listed or elements inherent to such composition, step, method, article, or apparatus.

[0051] The conjunction "composed of..." excludes any unspecified elements, steps, or components. If used in a claim, this phrase makes the claim closed, excluding materials other than those described, except for associated conventional impurities. When the phrase "composed of..." appears in a clause of the body of a claim rather than immediately following it, it limits only the elements described in that clause; other elements are not excluded from the claim as a whole.

[0052] When a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “1–5” is disclosed, the described range should be interpreted as including ranges “1–4”, “1–3”, “1–2”, “1–2 and 4–5”, “1–3 and 5”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range.

[0053] In these embodiments, unless otherwise specified, the portions and percentages are all by weight.

[0054] "Parts by mass" refers to the basic unit of measurement that expresses the mass ratio of multiple components. One part can represent any unit mass, such as 1g or 2.689g. If we say that component A has "a" parts by mass and component B has "b" parts by mass, it means the ratio of the mass of component A to the mass of component B is a:b. Alternatively, it can mean that the mass of component A is aK and the mass of component B is bK (K is any number representing a multiplier). It is important to understand that, unlike the number of parts by mass, the sum of the mass parts of all components is not limited to 100 parts.

[0055] "And / or" is used to indicate that one or both of the described situations may occur, for example, A and / or B includes (A and B) and (A or B).

[0056] To better illustrate the technical solutions provided in this disclosure, a general description of the technical solutions will be given before the embodiments, as follows:

[0057] Arbutin has properties that reduce skin pigmentation, remove age spots and freckles, and has antibacterial and anti-inflammatory effects, making it suitable for use in skincare and cosmetic products. However, arbutin suffers from poor stability; it easily decomposes into toxic substances in acidic or alkaline environments and at high temperatures. Furthermore, arbutin requires stringent preparation conditions. These issues limit its application in skincare and cosmetic products.

[0058] Niacinamide, also known as vitamin B3 or vitamin PP, is a skin-whitening active ingredient. Its mechanism includes the following two points: 1) It interferes with melanin transport, confining melanin within melanocytes and preventing it from reaching the skin surface and causing darkening, thus achieving a whitening effect. 2) It has excellent anti-glycation properties. Glycation produces brown substances that make the skin appear dark; niacinamide's anti-glycation properties help whiten the skin and brighten its complexion.

[0059] This disclosure combines arbutin and nicotinamide through non-covalent bonds to form a supramolecular compound. The resulting supramolecular compound has the advantage of high stability and also possesses the efficacy of arbutin, significantly improving the problem of poor stability of arbutin.

[0060] This disclosure provides a supramolecular arbutin nicotinamide, which includes arbutin and nicotinamide, and the arbutin and nicotinamide are linked by a non-covalent bond.

[0061] The structural formula of supramolecular arbutin nicotinamide is:

[0062] In some embodiments, the molar ratio of arbutin to nicotinamide in supramolecular arbutin nicotinamide is 1:1.

[0063] This disclosure also provides a method for preparing supramolecular arbutin nicotinamide as described above, comprising: mixing arbutin, nicotinamide and a first solvent, and carrying out a supramolecular modification reaction under heating conditions to obtain supramolecular arbutin nicotinamide;

[0064] The temperature of the supramolecular modification reaction is less than 100℃.

[0065] According to embodiments of this disclosure, the molar ratio of arbutin to nicotinamide is 1:1.

[0066] According to embodiments of this disclosure, the temperature of the supramolecular modification reaction is 50–80°C, preferably 70–80°C. This range provides sufficient thermal energy to drive the supramolecular modification reaction toward the synthesis of supramolecular arbutin nicotinamide, while effectively preventing 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; while when the reaction temperature is too high, it leads to the decomposition of the reactants and an increase in reaction byproducts.

[0067] For example, the temperature of the supramolecular modification reaction can be any value between 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, or 50℃ to 80℃.

[0068] And / or, the supramolecular modification reaction time is 4–24 h, preferably 4–8 h; within this time range, sufficient time is allowed for the reactants to interact fully, ensuring the reaction proceeds completely and helping to improve the product yield. If the reaction time is too short, there will be problems such as incomplete reaction and low product yield; if the reaction time is too long, it will increase the content of by-products, reduce the purity of the product, and increase energy consumption.

[0069] For example, the time for supramolecular modification reaction can be 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h or any value between 4 and 24h.

[0070] And / or, the first solvent includes a first organic solvent or a mixture of a first organic solvent and water, wherein the first organic solvent includes any one of methanol, ethanol, isopropanol, and acetone;

[0071] And / or, the mixing of arbutin, nicotinamide and the first solvent is carried out under stirring conditions of 100 to 200 rpm;

[0072] And / or, the supramolecular modification reaction is carried out under the protection of an inert gas, including any one of nitrogen, argon, helium, and neon.

[0073] According to embodiments of this disclosure, after the supramolecular modification reaction is completed, the method further includes: cooling and stirring to crystallize, thereby obtaining supramolecular arbutin nicotinamide.

[0074] According to embodiments of this disclosure, the cooling temperature is 0 to 5°C; for example, the cooling temperature can be any value between 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, or 0 to 5°C.

[0075] And / or, the stirring speed for crystallization is 10–300 rpm, preferably 50–100 rpm. When the stirring speed for crystallization is within the above range, it can ensure that the cooling and crystallization rates of the reaction system are moderate, the system has good fluidity, and it can also avoid explosive precipitation and reduce impurity entrainment, which is conducive to obtaining high-quality products. If the stirring speed for crystallization is too low, it will reduce the cooling rate of the reaction system, resulting in slower crystallization, and will also lead to poor system fluidity, making it easy to precipitate blocky crystals of different sizes during crystallization. If the stirring speed for crystallization is too high, it is easy to cause explosive precipitation, crystals that are too small, and impurities that are easily entrained.

[0076] For example, the stirring speed for crystallization can be any value between 10 rpm, 50 rpm, 60 rpm, 70 rpm, 80 rpm, 90 rpm, 100 rpm, 150 rpm, 200 rpm, 250 rpm, 300 rpm, or 10 to 300 rpm.

[0077] And / or, the stirring crystallization time is 12 to 48 hours. For example, the stirring crystallization time can be 12 hours, 15 hours, 18 hours, 20 hours, 23 hours, 25 hours, 28 hours, 30 hours, 33 hours, 35 hours, 38 hours, 40 hours, 43 hours, 45 hours, 48 ​​hours or any value between 12 and 48 hours.

[0078] According to embodiments of this disclosure, mixing arbutin, nicotinamide, and a first solvent includes: mixing an arbutin extract with nicotinamide, wherein the arbutin extract comprises arbutin and a first solvent;

[0079] Arbutin extract is obtained by mixing arbutin-containing raw material with a second solvent, extracting under heating conditions, and then performing solid-liquid separation after extraction to obtain arbutin extract.

[0080] Furthermore, high-performance liquid chromatography (HPLC) combined with external standard method can be used to accurately detect the content of arbutin, the active ingredient in arbutin extract.

[0081] 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;

[0082] 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 any value between 5:95, 15:85, 25:75, or (5-25):(95-75).

[0083] According to embodiments of this disclosure, 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.

[0084] Furthermore, before mixing the arbutin-containing raw material with the second solvent, the method further includes pulverizing the arbutin-containing raw material, thereby improving the extraction efficiency.

[0085] And / or, the mass ratio of the second solvent to the arbutin-containing raw material is (5 to 10):1; for example, the mass ratio of the second solvent to the arbutin-containing raw material can be any value between 5:1, 6:1, 7:1, 8:1, 9:1, 10:1 or (5 to 10):1.

[0086] And / or, the mixing of the arbutin-containing raw material with the second solvent is carried out under stirring conditions of 150 to 300 rpm. For example, the stirring speed of the arbutin-containing raw material with the second solvent can be any value between 150 rpm, 180 rpm, 200 rpm, 230 rpm, 250 rpm, 280 rpm, 300 rpm, or 150 to 300 rpm.

[0087] According to embodiments of this disclosure, the extraction temperature is 40–50°C; for example, the extraction temperature can be 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C or any value between 40°C and 50°C.

[0088] 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.

[0089] And / or, solid-liquid separation methods include centrifugation at a speed of 8000–10000 r / min. For example, the centrifugation 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 substances can be removed through solid-liquid separation.

[0090] This disclosure also provides a daily chemical product comprising the supramolecular arbutin nicotinamide described above or supramolecular arbutin nicotinamide prepared by the preparation method of the supramolecular arbutin nicotinamide described above.

[0091] Preferably, daily chemical products include skin care products and cosmetics.

[0092] The embodiments of this disclosure will be described in detail below with reference to specific examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of this disclosure. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0093] I. Preparation of supramolecular arbutin nicotinamide

[0094] Example 1

[0095] Example 1 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0096] (1) Pulverize 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by 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.

[0097] (2) Place the suspension into a centrifuge, set the centrifuge speed to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0098] The content of arbutin in the filtrate was accurately determined using high performance liquid chromatography in conjunction with the external standard method.

[0099] The reagents and equipment used were as follows: chromatographic column: Agilent ZORBAX SB-C18 column (4.6×250mm, 5μm); column temperature: 30℃; detector: ultraviolet detector; wavelength: 280nm; injection volume: 10.0μL; mobile phase A: methanol, mobile phase B: ultrapure water; flow rate: 1.0mL / min.

[0100] Preparation of solutions: a. Preparation of arbutin standard solution: Weigh approximately 100 mg of arbutin standard accurately, place it in a 100 mL volumetric flask, add water to dissolve and dilute to the mark, shake well, and a reference solution with an arbutin content of 1000 ppm is obtained. b. Preparation of test solution: The filtrate collected in step (2) is the test solution.

[0101] Test steps: a. Construction of standard curves: 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 and place them in 5 mL volumetric flasks respectively. Dilute each flask with ultrapure water to the mark and shake well. These solutions will serve as linear standard curves 1 to 6. Construct standard curves with arbutin concentration as the abscissa and peak area as the ordinate. b. Take the filtrate collected in step (2) as the test solution. Analyze the solution according to the above chromatographic conditions and calculate the arbutin concentration of the filtrate collected in step (2) using the external standard method based on the peak area.

[0102] The test results showed that the concentration of arbutin in the filtrate was 1.46 wt%.

[0103] (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 from step (2), turn on the stirrer, set the stirring speed to 150 rpm, turn on the heater, set the reaction temperature to 75 ℃, and carry out the supramolecular modification reaction for 6 h. After the reaction is completed, set the crystallization temperature to 0 ℃, the stirring speed to 50 rpm, and carry out crystallization for 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0104] The mass of supramolecular arbutin nicotinamide was weighed to be 59.49 g, and the yield was calculated to be 75.43%.

[0105] Example 2

[0106] Example 2 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0107] (1) Pulverize 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by 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.

[0108] (2) Place the suspension into a centrifuge, set the centrifuge speed to 8000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0109] The concentration of arbutin in the filtrate was detected using the external standard method of Example 1, and the result was: the concentration of arbutin in the filtrate was 1.27 wt%.

[0110] (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 from step (2), start stirring, set the stirring speed to 200 rpm, start heating, set the heating reaction temperature to 75℃, and carry out the supramolecular modification reaction for 6 h. After the reaction is completed, set the crystallization temperature to 0℃, the stirring speed to 50 rpm, and carry out crystallization for 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0111] The mass of supramolecular arbutin nicotinamide was weighed to be 55.44 g, and the yield was calculated to be 70.29%.

[0112] Example 3

[0113] Example 3 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0114] (1) Pulverize 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by 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.

[0115] (2) Place the suspension into a centrifuge, set the centrifuge speed to 10000 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 using the external standard method of Example 1, and the result was: the concentration of arbutin in the filtrate was 1.34 wt%.

[0117] (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 from step (2), start stirring at 100 rpm, start heating at 75°C, and carry out supramolecular modification reaction for 6 h. After the reaction is completed, set the temperature to 0°C and the stirring speed to 50 rpm to carry out crystallization for 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0118] The mass of supramolecular arbutin nicotinamide was weighed to be 55.75 g, and the yield was calculated to be 70.69%.

[0119] Example 4

[0120] Example 4 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0121] (1) Pulverize 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by 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.

[0122] (2) Place the suspension into a centrifuge, set the centrifuge speed to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0123] The concentration of arbutin in the filtrate was detected using the external standard method of Example 1, and the result was: the concentration of arbutin in the filtrate was 1.44 wt%.

[0124] (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 from step (2), start stirring at 150 rpm, start heating at 70°C, and carry out supramolecular modification reaction for 6 h. After the reaction is completed, set the temperature to 0°C and the stirring speed to 50 rpm to carry out crystallization for 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0125] The mass of supramolecular arbutin nicotinamide was weighed to be 59.41 g, and the yield was calculated to be 75.33%.

[0126] Example 5

[0127] Example 5 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0128] (1) Pulverize 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 150 rpm, heat to 45°C, and extract for 4 h to obtain a suspension.

[0129] (2) Place the suspension into a centrifuge, set the centrifuge speed to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0130] The concentration of arbutin in the filtrate was detected using the external standard method of Example 1, and the result was: the concentration of arbutin in the filtrate was 1.73 wt%.

[0131] (3) Weigh 3.147 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.73 wt%, then add 24.42 g of nicotinamide to the filtrate from step (2), start stirring at 150 rpm, start heating at 80 °C, and carry out supramolecular modification reaction for 6 h. After the reaction is completed, crystallize at 0 °C and 50 rpm for 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0132] The mass of supramolecular arbutin nicotinamide was weighed to be 55.36 g, and the yield was calculated to be 70.19%.

[0133] Example 6

[0134] Example 6 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0135] (1) Weigh 1 kg of dried bearberry leaves and crush them. Then add 10 kg of a mixed solvent made of ethanol and water in a volume ratio of 15:85. Start stirring at 150 rpm and heat to 45°C. Extract for 4 hours to obtain a suspension.

[0136] (2) Place the suspension into a centrifuge, set the centrifuge speed to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0137] The concentration of arbutin in the filtrate was determined using the external standard method of Example 1, and the result was 1.48 wt%.

[0138] (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 from step (2), start stirring at 150 rpm, start heating at 75 °C, and carry out supramolecular modification reaction for 4 h. After the reaction is completed, crystallize at 0 °C and 50 rpm for 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0139] The mass of supramolecular arbutin nicotinamide was weighed to be 59.77 g, and the yield was calculated to be 75.78%.

[0140] Example 7

[0141] Example 7 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0142] (1) Pulverize 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by 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.

[0143] (2) Place the suspension into a centrifuge, set the centrifuge speed to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0144] The concentration of arbutin in the filtrate was detected using the external standard method of Example 1, and the result was: the concentration of arbutin in the filtrate was 1.45 wt%.

[0145] (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 from step (2), start stirring, set the stirring speed to 150 rpm, start heating, set the reaction temperature to 75℃, and carry out the supramolecular modification reaction for 8 h. After the reaction is completed, crystallize at a crystallization temperature of 0℃ and a stirring speed of 50 rpm for 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0146] The mass of supramolecular arbutin nicotinamide was weighed to be 58.34 g, and the yield was calculated to be 73.97%.

[0147] Example 8

[0148] Example 8 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0149] (1) Pulverize 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by 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.

[0150] (2) Place the suspension into a centrifuge, set the centrifuge speed to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0151] The concentration of arbutin in the filtrate was detected using the external standard method of Example 1, and the result was: the concentration of arbutin was 1.47 wt%.

[0152] (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 from step (2), turn on the stirrer, set the stirring speed to 150 rpm, turn on the heater, set the reaction temperature to 75 ℃, and carry out the supramolecular modification reaction for 6 h. After the reaction is completed, crystallize at a crystallization temperature of 5 ℃ and a stirring speed of 50 rpm for 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0153] The mass of supramolecular arbutin nicotinamide was weighed to be 59.46 g, and the yield was calculated to be 75.39%.

[0154] Example 9

[0155] Example 9 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0156] (1) 1 kg of dried bearberry leaves were crushed and then 10 kg of a mixed solvent of ethanol and water in a volume ratio of 15:85 was added. Stirring was started at 150 rpm and heated to 45°C for 4 h to obtain a suspension.

[0157] (2) Place the suspension into a centrifuge, set the centrifuge speed to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0158] The concentration of arbutin in the filtrate was detected using the external standard method of Example 1, and the result was: the concentration of arbutin in the filtrate was 1.45 wt%.

[0159] (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 from step (2), turn on the stirrer, set the stirring speed to 150 rpm, turn on the heater, set the reaction temperature to 75 ℃, and carry out the supramolecular modification reaction for 6 h. After the reaction is completed, crystallize at a crystallization temperature of 0 ℃ and a stirring speed of 50 rpm for 12 h. The resulting solid is supramolecular arbutin nicotinamide.

[0160] The mass of supramolecular arbutin nicotinamide was weighed to be 52.94 g, and the yield was calculated to be 67.12%.

[0161] Example 10

[0162] Example 10 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0163] (1) Pulverize 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by 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.

[0164] (2) Place the suspension into a centrifuge, set the centrifuge speed to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0165] The concentration of arbutin in the filtrate was detected using the external standard method of Example 1, and the result was: the concentration of arbutin in the filtrate was 1.46 wt%.

[0166] (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 from step (2), turn on the stirrer, set the stirring speed to 150 rpm, turn on the heater, set the reaction temperature to 75 ℃, and carry out the supramolecular modification reaction for 6 h. After the reaction is completed, crystallize at a crystallization temperature of 0 ℃ and a stirring speed of 50 rpm for 48 h. The resulting solid is supramolecular arbutin nicotinamide.

[0167] The mass of supramolecular arbutin nicotinamide was weighed to be 60.99 g, and the yield was calculated to be 77.33%.

[0168] Example 11

[0169] Example 11 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0170] (1) Pulverize 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by 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.

[0171] (2) Place the suspension into a centrifuge, set the centrifuge speed to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0172] The concentration of arbutin in the filtrate was detected using the external standard method of Example 1, and the result was: the concentration of arbutin in the filtrate was 1.48 wt%.

[0173] (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 from step (2), turn on the stirrer, set the stirring speed to 150 rpm, turn on the heater, set the reaction temperature to 75 ℃, and carry out the supramolecular modification reaction for 6 h. After the reaction is completed, crystallize at a crystallization temperature of 0 ℃ and a stirring speed of 100 rpm for 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0174] The mass of supramolecular arbutin nicotinamide was weighed to be 54.47 g, and the yield was calculated to be 69.06%.

[0175] Example 12

[0176] Example 12 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0177] (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.

[0178] (2) Place the suspension into a centrifuge, set the centrifuge speed to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0179] The concentration of arbutin in the filtrate was detected using the external standard method of Example 1, and the result was: the concentration of arbutin in the filtrate was 0.43 wt%.

[0180] (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 from step (2), start stirring at 150 rpm, start heating at 75°C, and carry out supramolecular modification reaction for 6 h. After the reaction is complete, set the temperature to 0°C and the stirring speed to 50 rpm for crystallization for 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0181] The mass of supramolecular arbutin nicotinamide was weighed to be 9.45 g, and the yield was calculated to be 11.98%.

[0182] Compared with Example 1, Example 12 changed the extraction solvent for bearberry leaves, replacing the ethanol and water mixture (volume ratio 15:85) with anhydrous ethanol. Using anhydrous ethanol as the extraction solvent for bearberry leaves resulted in poor extraction efficiency, leading to a lower concentration of arbutin. This, in turn, resulted in a higher solvent volume in the subsequent supramolecular modification reaction, a lower concentration of the reaction precursor in the reaction system, poor reaction efficiency, and a lower yield. This indicates that the solvent used in this disclosure is preferably a mixture of ethanol and water.

[0183] Example 13

[0184] Example 13 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0185] (1) Pulverize 1 kg of dried pear leaves, then add 10 kg of a mixed solvent prepared by 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.

[0186] (2) Place the suspension into a centrifuge, set the centrifuge speed to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0187] The concentration of arbutin in the filtrate was detected using the external standard method of Example 1, and the result was: the concentration of arbutin in the filtrate was 1.35 wt%.

[0188] (3) Weigh 4.033 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.35 wt%, then add 24.42 g of nicotinamide to the filtrate from step (2), start stirring at 150 rpm, start heating at 50 °C, and carry out supramolecular modification reaction for 24 h. After the reaction is completed, crystallize at 0 °C and 50 rpm for 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0189] The mass of supramolecular arbutin nicotinamide was weighed to be 19.22 g, and the yield was calculated to be 24.37%.

[0190] Compared with Example 1, Example 13 reduced the temperature of the supramolecular modification reaction in step (3) and extended the time of the supramolecular modification reaction. The yield of the supramolecular product in Example 13 was lower than that in Example 1, indicating that the preferred temperature for the supramolecular modification reaction is 70-80°C and the preferred time for the supramolecular modification reaction is 4-8h.

[0191] Example 14

[0192] Example 14 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0193] (1) Pulverize 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by 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.

[0194] (2) Place the suspension into a centrifuge, set the centrifuge speed to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0195] The concentration of arbutin in the filtrate was detected using the external standard method of Example 1, and the result was: the concentration of arbutin in the filtrate was 1.44 wt%.

[0196] (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 from step (2), turn on the stirrer, set the stirring speed to 150 rpm, turn on the heater, set the reaction temperature to 75 ℃, and carry out the supramolecular modification reaction for 6 h. After the reaction is completed, crystallize at a crystallization temperature of 0 ℃ and a stirring speed of 10 rpm for 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0197] The mass of supramolecular arbutin nicotinamide was weighed to be 55.46 g, and the yield was calculated to be 70.32%.

[0198] Compared with Example 1, Example 14 reduced the stirring speed in step (3) for crystallization. The system in Example 14 had poor fluidity, and crystal aggregation occurred during crystallization, resulting in uneven crystals and larger particle sizes. Therefore, the preferred stirring speed for crystallization is 50-100 rpm.

[0199] Example 15

[0200] Example 15 provides a supramolecular arbutin nicotinamide, the preparation method of which includes:

[0201] (1) Pulverize 1 kg of dried bearberry leaves, then add 10 kg of a mixed solvent prepared by 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.

[0202] (2) Place the suspension into a centrifuge, set the centrifuge speed to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0203] The concentration of arbutin in the filtrate was detected using the external standard method of Example 1, and the result was: the concentration of arbutin in the filtrate was 1.44 wt%.

[0204] (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 from step (2), turn on the stirrer, set the stirring speed to 150 rpm, turn on the heater, set the reaction temperature to 75 ℃, and carry out the supramolecular modification reaction for 6 h. After the reaction is completed, crystallize at a crystallization temperature of 0 ℃ and a stirring speed of 300 rpm for 24 h. The resulting solid is supramolecular arbutin nicotinamide.

[0205] The mass of supramolecular arbutin nicotinamide was weighed to be 65.41 g, and the yield was calculated to be 82.93%.

[0206] Compared with Example 1, Example 15 increased the crystallization stirring speed in step (3). In Example 15, the crystallization stirring speed was faster, the system temperature dropped too quickly, and crystal bursting occurred, resulting in a higher yield and lower purity. In addition, other impurities were carried in during the precipitation process, indicating that the crystallization stirring speed is preferably 50 to 100 rpm.

[0207] Comparative Example 1

[0208] (1) Pulverize 1 kg of dried pear leaves, then add 10 kg of a mixed solvent prepared by 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.

[0209] (2) Place the suspension into a centrifuge, set the centrifuge speed to 9000 r / min, centrifuge to separate the solid and liquid, remove the insoluble matter, and collect the filtrate.

[0210] The concentration of arbutin in the filtrate was detected using the external standard method of Example 1, and the result was: the concentration of arbutin in the filtrate was 1.35 wt%.

[0211] (3) Weigh 4.033 kg of the filtrate obtained in step (2) with an arbutin concentration of 1.35 wt%, then add 24.42 g of nicotinamide to the filtrate from step (2), start stirring at 150 rpm, start heating, and heat the reaction at 100 °C to carry out supramolecular modification reaction for 6 h. After the reaction is completed, crystallization is carried out at 0 °C and a stirring speed of 50 rpm for 24 h. No product precipitation was observed after crystallization.

[0212] Comparative Example 1 did not yield supramolecular arbutin nicotinamide product.

[0213] Compared with Example 1, Comparative Example 1 increased the temperature of the supramolecular modification reaction in step (3). The temperature of the supramolecular modification reaction in Comparative Example 1 was 100°C, which is a relatively high temperature. Under this condition, the precursor will decompose and generate byproducts. This indicates that the temperature for the supramolecular modification reaction needs to be less than 100°C.

[0214] II. Structural Characterization of Supramolecular Arbutin Nicotinamide

[0215] (1) Powder X-ray single crystal diffraction test

[0216] Instruments and parameters: X-ray diffractometer model: XRD-MiniFlex600; test target: copper target; scanning range: 5-85°; scanning rate: 5° / min.

[0217] Experimental Results: Powder X-ray single-crystal diffraction (XRD) tests were performed on the supramolecular arbutin nicotinamide prepared in Example 1, as shown in Figure 1. The XRD patterns of the supramolecular arbutin nicotinamide were as follows: at 2θ angles of approximately 10.91°±0.2°, 12.26°±0.2°, 14.24°±0.2°, 15.16°±0.2°, 16.54°±0.2°, and 19.30°±0.2°. Characteristic peaks are present at 0.82°±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 31.63°±0.2°.

[0218] The X-ray powder diffraction data of supramolecular arbutin nicotinamide in Example 1 were compared with those of arbutin and nicotinamide monomers, as shown in Figure 2. As can be seen from Figure 2, the peaks in the powder X-ray single crystal diffraction pattern 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 formed a new eutectic under the conditions disclosed herein.

[0219] (2) Nuclear magnetic resonance (NMR) test

[0220] The supramolecular arbutin nicotinamide was analyzed by proton NMR and carbon NMR spectra.

[0221] Instruments and parameters: Bruker nuclear magnetic resonance spectrometer; solvent type: heavy water; experimental conditions: 1024 scans (carbon spectrum) and 16 scans (proton spectrum); the test environment was controlled by liquid nitrogen; data analysis: analysis was performed using the professional nuclear magnetic resonance (NMR) data analysis software—MestReNova.

[0222] Experimental results: The supramolecular arbutin nicotinamide obtained in Example 1 was subjected to 1H NMR spectroscopy (NMR spectroscopy). 1 H-NMR) testing, the hydrogen nuclear magnetic resonance spectrum data are as follows: 1 H NMR(600MHz,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).

[0223] As shown in Figure 3, the 1H NMR spectrum clearly shows four hydrogen atoms on the benzene ring of arbutin, five hydrogen atoms on the oxocyclic ring, two hydrogen atoms on the methylene group attached to the oxocyclic ring, and four hydrogen atoms on the nitrogen-containing ring of nicotinamide; the remaining peaks are those of deuterated reagents, and no obvious impurity peaks were observed. (The last sentence appears to be incomplete and possibly refers to a separate finding.) 1 H-NMR test results show that arbutin and nicotinamide exist in a molar ratio of 1:1 in the supramolecular arbutin nicotinamide obtained in Example 1.

[0224] The supramolecular arbutin nicotinamide obtained in Example 1 was subjected to carbon NMR spectroscopy. 13 Characterized by C1-NMR, D2O was used as the test solvent, and the carbon NMR data were as follows: 13 C NMR (150MHz, D2O) δ170.74,151.77,151.11,147.58,136.41,129.25,124.15,116.18,98.26,72.96,72.37,71.11,69.34,60.24ppm.

[0225] As shown in Figure 4, the carbon atoms of arbutin and nicotinamide can be clearly found in the carbon NMR spectrum, with no obvious impurity peaks observed. (The last sentence appears to be incomplete and possibly refers to a separate finding: "Through carbon NMR spectroscopy...") 13 C-NMR test results show that the arbutin and nicotinamide in the supramolecular arbutin nicotinamide obtained in Example 1 exist in a molar ratio of 1:1.

[0226] (3) Calculation of interaction forces

[0227] Supramolecular structures are generally composed of two or more molecules held together by intermolecular forces such as hydrogen bonds, van der Waals forces, and π-π stacking. These complex, organized structures maintain a certain integrity, giving them a defined microscopic structure and macroscopic properties. π-π stacking is a special spatial arrangement in aromatic compounds, referring to a weak interaction that often occurs between aromatic rings. It typically exists between two molecules that are relatively electron-rich and electron-deficient, and is a non-covalent interaction as important as hydrogen bonds.

[0228] Arbutin contains a benzene ring structure, while nicotinamide contains a nitrogen heterocycle. Structurally, arbutin and nicotinamide may form a stable supramolecular structure through π-π stacking.

[0229] The interaction forces between arbutin and nicotinamide were calculated and analyzed. Figure 5 (ESP plot) shows electrostatic attraction between regions with positive electrostatic potential (red) and regions with negative electrostatic potential (blue). The blue areas in the IRI isosurface plot and scatter plot represent attractive forces, such as hydrogen bonds and halogen bonds of moderate strength; the red areas represent repulsive forces; and the green areas represent van der Waals forces. Figure 7 (IRI isosurface plot and scatter plot of supramolecular arbutin-nicotinamide) shows that the isosurface between arbutin and nicotinamide is predominantly green, indicating that the interaction is mainly van der Waals. Further analysis in Figure 6 (weak IRI interaction) reveals two distinct hydrogen bonds at the points of electrostatic attraction, while large areas of van der Waals interaction exist between the two rings of the two small molecules. Combining Figures 5, 6, and 7, it can be seen that arbutin and nicotinamide have certain hydrogen bonds and van der Waals forces, promoting the formation of supramolecular arbutin-nicotinamide through self-assembly.

[0230] III. Particle size testing of supramolecular arbutin nicotinamide

[0231] Particle size control is of great significance to the bioavailability and efficacy of active ingredients. During the preparation process, controlling the particle size is beneficial for the dissolution of active ingredients and for the absorption of poorly soluble active ingredients by the human body, thereby improving the application effect and bioavailability of active ingredients.

[0232] The supramolecular arbutin nicotinamide prepared in Examples 1-15 and Comparative Example 1 was subjected to dry particle size analysis, and the results are shown in Table 1.

[0233] Test methods: A laser particle size analyzer is used for testing. This method measures the angle and intensity of laser light scattered on the surface of the particles being tested, and then performs particle size analysis based on Mie scattering and Freudian diffraction theories. The dry method uses air as the dispersion medium, utilizing the principle of turbulent dispersion to fully disperse the sample particles before introducing them into the optical path system for testing.

[0234] Table 1 Summary of Particle Size Test Results for Supramolecular Arbutin Nicotinamide

[0235] As shown in Table 1, the particle sizes of Examples 1-15 range from 6 to 40 μm. Specifically, the particle sizes of supramolecular arbutin nicotinamide in Examples 1-13 range from 10 to 20 μm. A particle size of 10-20 μm is considered suitable, effectively improving the bioavailability of supramolecular arbutin and increasing the specific surface area of ​​the particles. In Example 14, the particle size of supramolecular arbutin nicotinamide was too large, and in Example 15, the particle size was too small, both of which are detrimental to the bioavailability of supramolecular arbutin.

[0236] Compared with Examples 12 and 13, Examples 1-11 have a higher yield of supramolecular product, indicating that the reaction conditions in Examples 1-11 are the preferred reaction conditions. The supramolecular arbutin nicotinamide has a higher yield, and the crystal form and crystal size distribution of the product are more uniform, which is beneficial to enhancing skin permeability and improving bioavailability.

[0237] IV. Stability Test of Supramolecular Arbutin Nicotinamide

[0238] (1) Arbutin stability test

[0239] Samples for stability testing: 1. Supramolecular arbutin nicotinamide aqueous solutions of different concentrations, namely 1.0%, 5.0%, and 10%; 2. Supramolecular arbutin nicotinamide aqueous solutions of different pH values, all with a concentration of 5.0% and pH values ​​of 1.0, 7.0, and 13; 3. Arbutin monomer and nicotinamide monomer were prepared into corresponding physically mixed aqueous solution samples according to the above conditions in a molar ratio of 1:1.

[0240] 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 hydroquinone content in the samples.

[0241] The supramolecular arbutin nicotinamide prepared in Example 1 was used to prepare corresponding aqueous solutions according to the above method, and stability tests were conducted. The hydroquinone content was tested at regular intervals, and 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 and at 50°C for 28 days. The hydroquinone content was tested at 0, 7, 14, and 28 days. The test results are shown in Tables 2 and 3.

[0243] Table 2. Results of changes in hydroquinone content in samples of different concentrations after 28 days in an oven at 50℃.

[0244] Table 3. Results of changes in hydroquinone content in samples of different concentrations after 28 days of exposure to sunlight.

[0245] As shown in Tables 2 and 3, under the same concentration conditions, the hydroquinone content of the supramolecular arbutin nicotinamide aqueous solution after 28 days was significantly lower than that of the physically mixed arbutin nicotinamide aqueous solution. Furthermore, the physically mixed arbutin nicotinamide aqueous solution sample began to show hydroquinone as early as day 7, while the supramolecular arbutin nicotinamide aqueous solution, under sunlight conditions, began to show a small amount of hydroquinone on day 28. This indicates that the supramolecular arbutin nicotinamide prepared in this disclosure has improved stability compared to the physically mixed arbutin nicotinamide.

[0246] Supramolecular arbutin nicotinamide aqueous solutions and physically mixed arbutin nicotinamide aqueous solutions, both with a concentration of 5.0% and pH values ​​of 1.0, 7.0, and 13, were placed under sunlight and 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.

[0247] Table 4. Results of changes in hydroquinone content in samples with different pH values ​​after 28 days in a 50℃ oven.

[0248] Table 5. Results of changes in hydroquinone content in samples with different pH values ​​after 28 days of exposure to sunlight.

[0249] As shown in Tables 4 and 5, at pH 7.0, the hydroquinone content produced by the decomposition of supramolecular arbutin nicotinamide aqueous solution and the physically mixed arbutin nicotinamide aqueous solution was much lower than at pH 1.0 and 13.0. Under excessively acidic or alkaline conditions, hydroquinone was detected in both 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 disclosure is improved compared to the physically mixed arbutin nicotinamide solution.

[0250] V. Testing the whitening efficacy of supramolecular arbutin niacinamide

[0251] The inhibition of melanin production is mainly achieved through two approaches: firstly, inhibiting the activity of tyrosinase, and secondly, suppressing the signaling pathways involved in melanin production. Some skin-whitening agents, such as kojic acid and its derivatives, inhibit melanin production by suppressing tyrosinase activity. Others act on the melanin production signaling pathway, such as inhibitors of the α-melanocyte-stimulating hormone (-MSH) receptor MCIR protein. Furthermore, products with antioxidant properties can reduce dopaquinone to L-DOPA, which can be used to some extent in the development of skin-whitening products.

[0252] The experimental material used was supramolecular arbutin nicotinamide obtained in Example 1. The aim was to evaluate the effects of supramolecular arbutin nicotinamide on melanin content and tyrosinase activity in human melanocytes. This test induced melanocytes with α-MSH and used a colorimetric method to detect the effects of the sample on melanin production and tyrosinase inhibition, thereby evaluating the efficacy of supramolecular arbutin nicotinamide.

[0253] (1) Human melanocytes - melanin content test

[0254] The supramolecular arbutin nicotinamide obtained in Experiment Example 1 was used as the experimental material.

[0255] Experimental Procedure: a. Seed cells into 6-well plates and culture in DMEM medium containing 10% FBS (fetal bovine serum) for 20 h; b. Remove the original medium and add medium containing different concentrations of the test substance and α-MSH, culture continuously for 5 days, changing the medium once in between; c. After exposure, remove the culture medium, wash once with PBS, and collect cells from each well using a cell scraper; d. Add 1 mol / L NaOH solution (containing 10% DMSO) to dissolve the cells and obtain cell slurry; e. Heat the cell slurry at 80℃ for 30 min to lyse melanosomes; f. Measure the absorbance of the cell slurry at a wavelength of 490 nm. Data were analyzed using SPSS and expressed as mean ± standard deviation. A p < 0.05 was considered statistically significant. The test results are then summarized in Table 6.

[0256] The detection results of melanin content in human melanocytes treated with supramolecular arbutin nicotinamide are shown in Table 6.

[0257] Table 6 Detection results of melanin content in human melanocytes treated with supramolecular arbutin nicotinamide

[0258] Compared with the NC group, 0.01 < P < 0.05 is marked as *, P < 0.01 is marked as **, P < 0.001 is marked as ***. Compared with the negative control group (NC), p < 0.05 is marked as #.

[0259] It can be seen from Table 6 and Figure 8 that in the experiment on melanin content in 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 melanin content is reduced by 37.97%, 26.99% and 21.94% respectively compared with the model control group (M). This result indicates that supramolecular arbutin nicotinamide has the effect of inhibiting melanin production.

[0260] (2) Tyrosinase activity inhibition experiment on human melanocytes

[0261] The supramolecular arbutin nicotinamide obtained in Experimental Example 1 was used as the experimental material.

[0262] Experimental procedure: a. Seed the cells into a 96-well plate and culture for 20 h in DMEM medium containing 10% FBS (fetal bovine serum); b. Remove the original medium, add medium containing different concentrations of the test substance and α-MSH, and culture continuously for 3 days; c. After exposure, remove the culture solution, wash twice with PBS, add 90 μL of cell lysis buffer, and treat by repeated freeze-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 reaction at 37°C for 30 min. The data were analyzed by SPSS and expressed as mean ± standard deviation. The difference is considered statistically significant if p < 0.05, and the test results are statistically summarized in Table 7.

[0263] The detection results of the inhibition test on tyrosinase activity in human melanocytes treated with supramolecular arbutin nicotinamide are shown in Table 7.

[0264] Table 7 Detection results of tyrosinase activity in human melanocytes treated with supramolecular arbutin nicotinamide

[0265] Compared with the NC group, 0.01 < P < 0.05 is marked as *, P < 0.01 is marked as **, P < 0.001 is marked as ***. When compared with the negative control (NC), P < 0.05 is marked as #.

[0266] It can be seen from Table 7 and Figure 9 that in the experiment of inhibiting tyrosinase activity in 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 activity is reduced by 19.26%, 13.81% and 12.62% respectively compared with the model control group (M), indicating that supramolecular arbutin nicotinamide has the effect of inhibiting tyrosinase activity.

[0267] Finally, it should be noted that the foregoing examples are only used to illustrate the technical solutions of the present disclosure, and are not intended to be limiting; although the present disclosure has been described in detail with reference to the foregoing examples, those of ordinary skill in the art should understand that: they can still modify the technical solutions described in the foregoing examples, or equivalently replace some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the examples of the present disclosure.

[0268] In addition, those skilled in the art can understand that although some embodiments herein include certain features but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the present disclosure and form different embodiments. For example, in the following claims, any of the claimed embodiments can be used in any combination. Information disclosed in the background technology section is only intended to deepen the understanding of the general background technology of the present disclosure, and should not be regarded as an acknowledgement or any form of suggestion that this information constitutes the prior art generally known to those skilled in the art. Industrial Applicability

[0269] The present disclosure provides a supramolecular arbutin nicotinamide, a preparation method thereof and a daily chemical product, which can exert a better whitening effect and can be applied in daily chemical products with whitening effect.

Claims

1. A supramolecular arbutin nicotinamide, characterized in that, The supramolecular arbutin nicotinamide comprises arbutin and nicotinamide, wherein the arbutin and nicotinamide are linked by non-covalent bonds; The structural formula of the supramolecular arbutin nicotinamide is as follows:

2. The supramolecular arbutin nicotinamide according to claim 1, characterized in that, The X-ray powder diffraction pattern of the supramolecular arbutin nicotinamide shows characteristic peaks at 2θ angles of 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 31.63°±0.2°.

3. A method for preparing supramolecular arbutin nicotinamide as described in claim 1 or 2, characterized in that, include: Arbutin, nicotinamide, and a first solvent were mixed and subjected to a supramolecular modification reaction under heating conditions. After cooling and stirring, crystallization was carried out to obtain supramolecular arbutin nicotinamide. The temperature of the supramolecular modification reaction is less than 100℃.

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

1.

5. The method for preparing supramolecular arbutin nicotinamide according to claim 3, characterized in that, The temperature of the supramolecular modification reaction is 50–80 °C.

6. The method for preparing supramolecular arbutin nicotinamide according to claim 3, characterized in that, The supramolecular modification reaction takes 4–24 h.

7. The method for preparing supramolecular arbutin nicotinamide according to claim 3, characterized in that, 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.

8. The method for preparing supramolecular arbutin nicotinamide according to claim 3, characterized in that, The cooling temperature is 0–5°C.

9. The method for preparing supramolecular arbutin nicotinamide according to claim 3, characterized in that, The stirring speed for the crystallization process is 10–300 rpm.

10. The method for preparing supramolecular arbutin nicotinamide according to claim 3, characterized in that, The stirring and crystallization time is 12–48 h.

11. The method for preparing supramolecular arbutin nicotinamide according to claim 3, characterized in that, The arbutin, nicotinamide, and the first solvent were mixed under stirring conditions of 100–200 rpm.

12. The method for preparing supramolecular arbutin nicotinamide according to claim 3, characterized in that, The supramolecular modification reaction is carried out under the protection of an inert gas, which includes any one of nitrogen, argon, helium, and neon.

13. The method for preparing supramolecular arbutin nicotinamide according to claim 3, characterized in that, The mixing of arbutin, nicotinamide, and the first solvent includes: mixing an arbutin extract with nicotinamide, wherein the arbutin extract comprises arbutin and the first solvent; The arbutin extract is obtained by mixing arbutin-containing raw materials with a second solvent, extracting under heating conditions, and then 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, wherein 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).

14. The method for preparing supramolecular arbutin nicotinamide according to claim 13, characterized in that, The arbutin-containing raw materials include any one of bearberry, bearberry leaves, and pear leaves; And / or, the mass ratio of the second solvent to the arbutin-containing raw material is (5-10):1; And / or, the arbutin-containing raw material is mixed with the second solvent under stirring conditions of 150-300 rpm.

15. The method for preparing supramolecular arbutin nicotinamide according to claim 13 or 14, 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, wherein the centrifugal separation speed is 8000-10000 r / min.

16. A daily chemical product, characterized in that, The daily chemical products include supramolecular arbutin nicotinamide as described in claim 1 or 2, or supramolecular arbutin nicotinamide prepared by any one of the preparation methods of supramolecular arbutin nicotinamide as described in any one of claims 3-15. The daily chemical products include skin care products and cosmetics.

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