A glabridin-betaine eutectic and its preparation method and use

Abstract

The present invention discloses a glabridin-betaine eutectic and its preparation method and uses, belonging to the technical field of eutectics. The eutectic comprises betaine and glabridin molecules. The molecular formula of the glabridin-betaine eutectic is C 45 H 51 NO 10 . The molar ratio of betaine to glabridin is 1:2. The betaine and glabridin molecules are interconnected by hydrogen bonding. The eutectic is fully characterized, demonstrating that the eutectic has high chemical purity and chemical stability. Moreover, compared with the betaine monomer, the eutectic exhibits excellent solid-state stability under higher humidity conditions. And the eutectic is generally neutral, mild and non-irritating, and is naturally suitable for cosmetics or health products.

Description

Technical Field

[0001] The present invention relates to the technical field of eutectics, and specifically relates to a glabridin-betaine eutectic and its preparation method and uses. Background Art

[0002] Betaine is a quaternary ammonium type water-soluble alkaloid derived from sugar beets and is an intermediate product of animal metabolism. It is widely present in nature and plays a very important role in the metabolism of nutrients. In the molecular structure of betaine, there are both anionic charges and cationic charges in the same molecule, while the human skin is all negatively charged under normal physiological conditions. Therefore, molecules containing positive charges have a natural affinity for the skin and have the effect of enhancing skin moisturization, elasticity and hydration, and are particularly suitable for skin care products; betaine is prone to deliquescence under high humidity conditions, posing potential risks in storage and transportation.

[0003] Glabridin, known as the "star drug" in the cosmetics industry, is highly favored for its excellent antioxidant, anti-aging, anti-inflammatory and whitening effects. However, glabridin has poor solubility and stability problems, which limit its application in cosmetics.

[0004] The eutectic technology is a method of forming a crystalline material with regular arrangement in the same crystal lattice by intermolecular interactions such as hydrogen bonds, π-π interactions, and van der Waals forces between two or more different molecules. Compared with monomers, eutectics can change the physical and chemical properties of substances such as solubility, melting point, hygroscopicity, compressibility, and density, providing an effective way to improve the performance of cosmetic ingredients. At present, the eutectic technology has been widely used in industries such as cosmetics and health products. However, there is currently no combination of betaine-glabridin eutectic supramolecular compounds on the market. Therefore, a glabridin-betaine eutectic and its preparation method and uses are proposed. Summary of the Invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art. For this reason, one object of the present invention is to propose a glabridin-betaine eutectic and its preparation method and uses.

[0006] To achieve the above object, the present invention provides the following technical solutions:

[0007] A glabridin-betaine eutectic, the eutectic includes betaine and glabridin molecules, and the betaine-glabridin molecular formula is C 45 H 51 NO 10 , and the molar ratio of betaine to glabridin is 1:2;

[0008] The X-ray powder diffraction pattern of the betaine-glabridin eutectic has characteristic peaks at least at 2θ angles of 4.0°±0.2°, 8.0°±0.2°, 12.0°±0.2°, 15.5°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 18.7°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 24.1°±0.2°, and 24.7°±0.2°.

[0009] As a further optimized solution of the present invention, the eutectic is a monoclinic system, space group P21, and the unit cell parameters are: α = 90°, β = 92.30(3)°, γ = 90°,

[0010] As a further optimized solution of the present invention, the differential scanning calorimetry analysis spectrum of the eutectic has a characteristic endothermic peak near 236.3±2°C.

[0011] As a further optimized solution of the present invention, the infrared analysis spectrum of the eutectic is at 3467.37 cm -1 ±2 cm -1 、2975.92 cm -1 ±2 cm -1 、1634.76 cm -1 ±2 cm -1 、1524.75 cm -1 ±2 cm -1 、1329.82 cm -1 ±2 cm -1 、1374.91 cm -1 ±2 cm -1 、1213.10 cm -1 ±2 cm -1 、1087.61 cm -1 ±2 cm -1 、1173.41 cm -1 ±2 cm -1 、1114.72 cm -1 ±2 cm -1 、1155.40 cm -1 [[ID=5�]]±2 cm -1 、1288.22 cm -1 ±2 cm -1 、803.49 cm -1 ±2 cm -1 、772.03 cm -1 ±2 cm -1 、717.46 cm -1 ±2 cm -1, 981.63 cm -1 ±2 cm -1 , 837.53 cm -1 ±2 cm -1 , 632.81 cm -1 ±2 cm -1 , 531.24 cm -1 ±2 cm -1 , 486.91 cm -1 ±2 cm -1 has characteristic peaks at;

[0012] In particular, the infrared analysis spectrum of the eutectic also shows characteristic peaks at 1400.69 cm -1 ±2 cm -1 , 1477.75 cm -1 ±2 cm -1 , 1329.82 cm -1 ±2 cm -1 , 1052.65 cm -1 ±2 cm -1 , 1433.05 cm -1 ±2 cm -1 , 1359.85 cm -1 ±2 cm -1 , 1583.81 cm -1 ±2 cm -1 , 1009.33 cm -1 ±2 cm -1 , 933.32 cm -1 ±2 cm -1 , 849.62 cm -1 ±2 cm -1 , 898.44 cm -1 ±2 cm -1 , 1052.65 cm -1 ±2 cm -1 has characteristic peaks at.

[0013] A preparation method of glabridin-betaine eutectic, applied to the glabridin-betaine eutectic described above, the method is selected from one of the following two methods:

[0014] Method 1, Solid-state synthesis method:

[0015] Weigh about 50 mg of glabridin into a sample bottle and add the corresponding solvent to make it in a suspension state. Then add 0.5 - 1 eq. of betaine and stir overnight at room temperature. If no solid precipitates, the solid is precipitated by evaporation crystallization or antisolvent crystallization, and the solid is collected by centrifugation for XRPD testing;

[0016] Method 2: Wet grinding method:

[0017] Weigh a certain amount of glabridin and betaine and mix them. Then add 200 μL of the corresponding solvent and grind the solid in a mortar. After that, collect the powder for PXRD testing.

[0018] As a further optimized scheme of the present invention, in Method 2, the stoichiometric ratio of glabridin to betaine is 2:1.

[0019] As a further optimized scheme of the present invention, in Method 1, the solvent is one or more of methanol, ethanol, ethyl acetate, and acetone / water mixed solvent;

[0020] In Method 2, the solvent is one or more of methanol, ethanol, acetonitrile, ethyl acetate, and acetone / water mixed solvent.

[0021] Use of glabridin-betaine eutectic in the preparation of cosmetics.

[0022] Compared with the prior art, the beneficial effects of the present invention are:

[0023] The present invention proposes a brand-new eutectic supramolecular compound - glabridin-betaine eutectic. This eutectic is formed by the hydrogen bond interaction between betaine and glabridin molecules. This eutectic exhibits neutral characteristics, is mild and non-irritating, and is suitable as an active ingredient in cosmetics or health products.

[0024] Compared with glabridin monomer, the glabridin-betaine eutectic in the present invention has higher chemical purity and good chemical stability. Compared with betaine monomer, the glabridin-betaine eutectic in the present invention shows excellent solid-state stability. Betaine monomer will deliquesce within 5 days under high humidity environment (25°C & 90% RH) and accelerated conditions (40°C & 75% RH), affecting the storage and transportation of products. However, the eutectic of the present invention remains stable within 30 days under the same conditions, significantly improving the storage resistance and transportation resistance of products. Description of the drawings

[0025] Figure 1 One of the characterization result diagrams of the glabridin-betaine eutectic of the present invention;

[0026] Figure 2 Another characterization result diagram of the glabridin-betaine eutectic of the present invention;

[0027] Figure 3 Another characterization result diagram of the glabridin-betaine eutectic of the present invention;

[0028] Figure 4 Another characterization result diagram of the glabridin-betaine eutectic of the present invention;

[0029] Figure 5 This is the single crystal structure diagram of glabridin-betaine of the present invention;

[0030] Figure 6 This is the comparison diagram of the co-crystal of glabridin-betaine of the present invention between the large-scale experiment and the small-scale experiment;

[0031] Figure 7 This is one of the result diagrams of the stability test of the co-crystal of glabridin-betaine of the present invention;

[0032] Figure 8 This is another result diagram of the stability test of the co-crystal of glabridin-betaine of the present invention;

[0033] Figure 9 This is yet another result diagram of the stability test of the co-crystal of glabridin-betaine of the present invention;

[0034] Figure 10 This is still another result diagram of the stability test of the co-crystal of glabridin-betaine of the present invention;

[0035] Figure 11 This is the fifth result diagram of the stability test of the co-crystal of glabridin-betaine of the present invention. Detailed implementation mode

[0036] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0037] A glabridin-betaine co-crystal, the co-crystal includes betaine and glabridin molecules, and the betaine-glabridin molecular formula is C 45 H 51 NO 10 , and the molar ratio of betaine to glabridin is 1:2.

[0038] Sample test conditions:

[0039] (1)XRPD

[0040] Detection instrument: Rigaku SmartLab SE

[0041] Detection conditions: X-ray tube voltage 40O, X-ray tube current 40mA, scanning range 3-40°(2θ), step size 0.02°, scanning speed 5° / min.

[0042] Detection basis: Appendix Ⅸ F X-ray powder diffraction method (2) TGA in the Second Edition of the People's Republic of China (2010)

[0043] Detection instrument: Netzsch STA 449F3

[0044] Detection conditions: Nitrogen, 50 mL / min

[0045] Scanning program: 30 - 400 °C, heating rate: 10 °C / min

[0046] Mass of the detection sample: 5 mg (aluminum oxide sample pan)

[0047] Detection basis: General Rules for Thermal Analysis Methods JY / T 014 - 1996

[0048] (3) DSC

[0049] Detection instrument: Netzsch STA 449F3

[0050] Detection conditions: Nitrogen, 50 mL / min

[0051] Scanning program: 30 - 400 °C, heating rate: 10 °C / min

[0052] Mass of the detection sample: 3 mg (aluminum oxide sample pan)

[0053] Detection basis: General Rules for Thermal Analysis Methods JY / T 014 - 1996

[0054] (4) Micro ED

[0055] Detection instrument: JEOL 2100PLUS

[0056] Detection conditions: Ambient temperature 100 K, acceleration voltage 200 kV, wavelength

[0057] (5) Infrared spectrum

[0058] Detection instrument: PE Fourier transform infrared microscope system (Spotlight 200i)

[0059] Detection conditions: Potassium bromide tablet pressing method

[0060] Detection basis: General Rules for Infrared Spectrum Analysis Methods GB / T 6040 - 2002

[0061] [[ID=�8]]Technical solution provided by the present invention:

[0062] Example 1

[0063] Weigh 50 mg of glabridin into a sample vial, add 1 mL of methanol, and make it into a suspension. After adding 1 eq. of betaine, it becomes clear. Then, stir it overnight with an open mouth at room temperature, volatilize the solid and conduct XRPD testing to obtain the glabridin-betaine cocrystal.

[0064] The DSC / TGA spectra, IR spectra, PXRD spectra, NMR spectra, and single crystal structure diagrams of the cocrystal are as Figures 1 - 5 shown. The crystal structure data are shown in Tables 1 - 7.

[0065]

[0066] Table 1 Crystallographic parameters and structure refinement parameters

[0067]

[0068]

[0069]

[0070] Table 2 Atomic coordinates and isotropic parameters

[0071]

[0072]

[0073] Table 3 Bond lengths

[0074]

[0075]

[0076] Table 4 Bond angles

[0077]

[0078] Table 5 Hydrogen bonds

[0079]

[0080]

[0081]

[0082] Table 6 Torsion angles

[0083]

[0084]

[0085]

[0086] Table 7 Hydrogen atom coordinates

[0087] Example 2

[0088] Weigh 50 mg of glabridin into a sample bottle and add 1 mL of ethanol to make it in a suspended state. After adding 1 eq. of betaine, it still becomes thick. Then stir overnight at room temperature. The solid is collected by centrifugation and subjected to XRPD testing to obtain glabridin-betaine cocrystal.

[0089] Example 3

[0090] Weigh 50 mg of glabridin into a sample bottle and add 1 mL of ethyl acetate to make it in a suspended state. After adding 1 eq. of betaine, it still becomes thick. Then stir overnight at room temperature. The solid is collected by centrifugation and subjected to XRPD testing to obtain glabridin-betaine cocrystal (a small amount of betaine).

[0091] Example 4

[0092] Weigh 50 mg of glabridin into a sample bottle and add 1 mL of acetone / water mixed solvent to make it in a suspended state. After adding 1 eq. of betaine, it becomes clear. Then stir overnight at room temperature with the container open. The solid is volatilized and subjected to XRPD testing to obtain glabridin-betaine cocrystal.

[0093] Example 5

[0094] Weigh 50 mg of glabridin into a sample bottle and add 1 mL of methanol to make it in a suspended state. After adding 0.5 eq. of betaine, it becomes clear. Then stir overnight at room temperature with the container open. The solid is volatilized and subjected to XRPD testing to obtain glabridin-betaine cocrystal.

[0095] Example 6

[0096] Weigh 50 mg of glabridin into a sample bottle and add 1 mL of ethanol to make it in a suspended state. After adding 0.5 eq. of betaine, it still becomes thick. Then stir overnight at room temperature. The solid is collected by centrifugation and subjected to XRPD testing to obtain glabridin-betaine cocrystal.

[0097] Example 7

[0098] Weigh 50 mg of glabridin into a sample bottle and add 1 mL of ethyl acetate to make it in a suspended state. After adding 0.5 eq. of betaine, it still becomes thick. Then stir overnight at room temperature. The solid is collected by centrifugation and subjected to XRPD testing to obtain glabridin-betaine cocrystal.

[0099] Example 8

[0100] Weigh 50 mg of glabridin into a sample vial, add 1 mL of acetone / water mixed solvent to make it in a suspended state. After adding 0.5 eq. of betaine, it becomes clear. Then stir it overnight with an open mouth at room temperature, volatilize the solid and conduct XRPD test to obtain glabridin-betaine cocrystal.

[0101] Example IX

[0102] Weigh 50 mg of glabridin, add 200 μL of methanol, grind it with 0.5 eq of betaine in a mortar, and then collect the powder for PXRD test to obtain glabridin-betaine cocrystal.

[0103] Example X

[0104] Weigh 50 mg of glabridin, add 200 μL of ethanol, grind it with 0.5 eq of betaine in a mortar, and then collect the powder for PXRD test to obtain glabridin-betaine cocrystal.

[0105] Example XI

[0106] Weigh 50 mg of glabridin, add 200 μL of acetonitrile, grind it with 0.5 eq of betaine in a mortar, and then collect the powder for PXRD test to obtain glabridin-betaine cocrystal.

[0107] Example XII

[0108] Weigh 50 mg of glabridin, add 200 μL of ethyl acetate to grind in a mortar, grind it with 0.5 eq of betaine in a mortar, and then collect the powder for PXRD test to obtain glabridin-betaine cocrystal.

[0109] Example XIII

[0110] Weigh 50 mg of glabridin and betaine, add 200 μL of acetone / water mixed solvent, grind it with 0.5 eq of betaine in a mortar, and then collect the powder for PXRD test to obtain glabridin-betaine cocrystal.

[0111] Example XIV

[0112] Scale up the preparation of glabridin-betaine cocrystal. Weigh 1 g of glabridin into a sample vial, add 10 mL of ethanol to make it in a suspended state. Then add 0.5 eq. of betaine and it remains suspended. Stir it overnight at room temperature. The solid is collected by suction filtration and subjected to XRPD test to obtain glabridin-betaine cocrystal.

[0113] In this example, the comparison between the cocrystal of glabridin-betaine on a large scale (batch ZY-24-1) and on a small scale (batch ZY-23-1) is as Figure 6 shown.

[0114] Experimental Example XV

[0115] Physical stability test of glabridin-betaine eutectic: Take about 30 mg of the eutectic sample prepared in Example XIV and betaine monomer respectively and place them in an environment of 60 °C (closed), 25 °C & 90% RH (open), light (5000 Lux ± 500 Lux; closed) and accelerated conditions of 40 °C & 75% RH (open) for 5 days, 10 days, 20 days, and 30 days, and perform XRPD detection respectively. The test results are shown in Table 8 Figure 7 as follows:

[0116]

[0117]

[0118] Table 8

[0119] As can be seen from Table 8, the glabridin-betaine eutectic did not show obvious changes in crystal form in an environment of 60 °C (closed), 25 °C & 90% RH (open), light (5000 Lux ± 500 Lux; closed) and accelerated conditions of 40 °C & 75% RH (open) for 5 days, 10 days, 20 days, and 30 days, and maintained physical stability. The betaine monomer samples were deliquescent in an environment of 25 °C & 90% RH (open) and accelerated conditions of 40 °C & 75% RH (open) for 5 days. It shows that compared with the betaine monomer, the glabridin-betaine eutectic in the present invention exhibits excellent solid-state stability.

[0120] Experimental Example XVI

[0121] Chemical stability test of glabridin-betaine eutectic: Take about 30 mg of the eutectic sample prepared in Example XIV and place it in an environment of 60 °C (closed), 25 °C & 90% RH (open), light (5000 Lux ± 500 Lux; closed) and accelerated conditions of 40 °C & 75% RH (open) for 5 days, 10 days, 20 days, and 30 days, and perform HPLC detection respectively. The test results are as Figures 8 - 11 follows.

[0122] The purity of the eutectic was determined by high performance liquid chromatography. Chromatographic conditions: The chromatographic column was C18, 4.6x250 mm (5 μm), the mobile phase was potassium dihydrogen phosphate - acetonitrile - methanol (0 - 2 min, 90:5:5; 6 min, 35:10:55; 10 min, 35:20:45; 12 min, 35:55:10; 20 min, 35:55:10; 25 min, 95:5:5), the detection wavelength was 230 nm, and the flow rate was 1.0 mL·min －1, the column temperature was 35 °C and the injection volume was 5 μL. The test results are shown in Table 9 as follows:

[0123]

[0124]

[0125] Table 9

[0126] As can be seen from Table 9, compared with the glabridin monomer, the glabridin-betaine eutectic in the present invention has higher chemical purity. And the eutectic samples were placed in environments of 60 °C (closed), 25 °C & 90% RH (open), light (5000 Lux ± 500 Lux; closed), and accelerated conditions of 40 °C & 75% RH (open) for 30 days, and the purity of the samples did not change significantly, indicating that the eutectic has good chemical stability.

[0127] Example XVII

[0128] The percutaneous penetration experiment test was carried out on the glabridin monomer and the eutectic sample of Example XV, and the steps are as follows:

[0129] Step 1: Add water to the receiving cell and preheat it (the solubility of the sample needs to meet the sink condition during the experiment, and the temperature is 37 ± 1 °C);

[0130] Step 2: Fix the appropriately sized pig skin in the middle of the supply cell and the receiving cell;

[0131] Step 3: Supplement the liquid in the receiving cell, remove the bubbles, and place it in the diffusion cell for stirring;

[0132] Step 4: Add the sample to be tested to the supply cell;

[0133] Step 5: Take samples and take / replenish the liquid at regular intervals (1 - 6 h), and then perform HPLC testing on the filtrate.

[0134] The test results are shown in Table 10 as follows:

[0135]

[0136]

[0137] Table 10

[0138] Example XVIII

[0139] Biological medium solubility test: Weigh a certain mass of glabridin monomer and the eutectic sample of Example 15 into a sample bottle, and then add 1 - 2 mL of water respectively to form suspensions. All the suspensions are oscillated at a speed of 200 rpm at 37°C, and samples are taken at the time points of 0.5 h, 2 h, 6 h, and 24 h. Then, HPLC tests are carried out on the filtrates. The test results are shown in Table 11:

[0140]

[0141] Table 11

[0142] As can be seen from Table 11, compared with the glabridin monomer, the solubility of the eutectic in the aqueous solvent has increased, although the increase is not significant. This helps the eutectic raw materials to be more evenly dispersed in the aqueous solvent during application, thereby improving their bioavailability on human skin and enhancing the exertion of their efficacy.

[0143] Parts not involved in the present invention are the same as or can be implemented by the prior art. Although the embodiments of the present invention have been shown and described, for those of ordinary skill in the art, it can be understood that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A glabridin-betaine eutectic, characterized in that, The eutectic includes betaine and glabridin molecules, and the molecular formula of glabridin-betaine eutectic is C 45 H 51 NO 10 , and the molar ratio of betaine to glabridin is 1:2; The X-ray powder diffraction pattern of glabridin-betaine eutectic has characteristic peaks at least at 2θ angles of 4.0°±0.2°, 8.0°±0.2°, 12.0°±0.2°, 15.5°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 18.7°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 24.1°±0.2°, 24.7°±0.2°.

2. The glabridin-betaine eutectic according to claim 1, wherein: The eutectic is monoclinic, space group P21, unit cell parameters: α = 90°, β = 92.30(3)°, γ = 90°, 3. The glabridin-betaine eutectic according to claim 1, characterized in that: The differential scanning calorimetry spectrum of the eutectic has a characteristic endothermic peak near 236.3±2 °C.

4. The glabridin-betaine eutectic according to claim 1, characterized in that: The infrared analysis spectrum of the eutectic is at 3467.37 cm -1 ± 2 cm -1 、2975.92 cm -1 ± 2 cm -1 、1634.76 cm -1 ± 2 cm -1 、1524.75 cm -1 ± 2 cm -1 、1329.82 cm -1 ± 2 cm -1 、1374.91 cm -1 ± 2 cm -1 、1213.10 cm -1 ± 2 cm -1 、1087.61 cm -1 ± 2 cm -1 、1173.41 cm -1 ± 2 cm -1 、1114.72 cm -1 ± 2 cm -1 、1155.40 cm -1 ± 2 cm -1 、1288.22 cm -1 ± 2 cm -1 、803.49 cm -1 ± 2 cm -1 、772.03 cm -1 ± 2 cm -1 、717.46 cm -1 ± 2 cm -1 、981.63 cm -1 ± 2 cm -1 、837.53 cm -1 ± 2 cm -1 、632.81 cm -1 ± 2 cm -1 、531.24 cm -1 ± 2 cm -1 、486.91 cm -1 ± 2 cm -1 、1400.69 cm -1 ± 2 cm -1 、1477.75 cm -1 ± 2 cm -1 、1329.82 cm -1 ± 2 cm -1 、1052.65 cm -1 ± 2 cm -1 、1433.05 cm -1 ± 2 cm -1 、 1359.85 cm -1 ± 2 cm -1 、 1583.81 cm -1 ± 2 cm -1 、 1009.33 cm -1 ± 2 cm -1 、 933.32 cm -1 ± 2 cm -1 、 849.62 cm -1 ± 2 cm -1 、 898.44 cm -1 ± 2 cm -1 、 1052.65 cm -1 ± 2 cm -1 has characteristic peaks at 5. The preparation method of the glabridin-betaine eutectic according to any one of claims 1 to 4, characterized in that, The method is selected from one of the following two methods: Method 1, solid-state synthesis method: Weigh 50 mg of glabridin into a sample bottle and add the corresponding solvent to make it in a suspension state. Then add 0.5-1 eq. of betaine and stir overnight at room temperature. If no solid precipitates, the solid is precipitated by evaporation crystallization or antisolvent crystallization, and the solid is collected by centrifugation or suction filtration for XRPD testing. Method 2, wet grinding method: Weigh a certain amount of glabridin and betaine and mix them. Then add 200 μL of the corresponding solvent and grind the solid in a mortar. Then collect the powder for PXRD testing.

6. The preparation method of glabridin-betaine eutectic according to claim 5, wherein: In Method 2, the stoichiometric ratio of glabridin to betaine is 2:

1.

7. The preparation method of glabridin-betaine eutectic according to claim 5, characterized in that: In Method 1, the solvent is one or more of methanol, ethanol, ethyl acetate, acetone / water mixed solvent; In Method 2, the solvent is one or more of methanol, ethanol, acetonitrile, ethyl acetate, acetone / water mixed solvent.

8. Use of a glabridin-betaine eutectic according to any one of claims 1 to 4 in the preparation of cosmetics.

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