Whitening composition containing N-acetylneuraminic acid and application thereof

Abstract

The invention provides a whitening composition containing N-acetylneuraminic acid and application thereof.The whitening composition comprises N-acetylneuraminic acid (sialic acid), nicotinamide, protein peptide and acerola cherry extract, and the mass of the protein peptide and the mass of the acerola cherry extract both do not exceed two times of the mass of sialic acid. The sialic acid, the nicotinamide, the protein peptide and the acerola cherry extract are reasonably combined, so that an excellent whitening effect can be achieved, particularly, the melanin relieving effect is obvious, the sialic acid can effectively prevent attenuation of effective components, and the browning and attenuation phenomena of the sialic acid can be stabilized by adding the nicotinamide.

Description

Technical Field

[0001] The invention relates to the field of food biotechnology, in particular to a whitening composition containing N-acetylneuraminic acid and application thereof. Background Art

[0002] At present, the research on whitening mechanism mainly aims at interfering (inhibiting) the influence of non-genetic factors on melanin production, such as inhibiting the proliferation and differentiation of melanocytes, inhibiting melanin synthase (tyrosinase, etc.), blocking the transportation of melanin particles, accelerating the metabolism of epidermal cells, blocking the signal transduction pathway in the process of melanin production, etc. In addition, there is also the negative impact of exogenous factors such as ultraviolet rays and oxygen free radicals on the physiological process of melanin formation by scavenging free radicals.

[0003] As the whitening mechanism is explored more and more deeply, consumers' demand for whitening ingredients is becoming more and more diversified. For example, the emerging raw material N-acetylneuraminic acid (also known as bird's nest acid, sialic acid), its active hydroxyl group can provide active hydrogen to combine with superoxide anion radicals (O2-) and hydroxyl radicals (-OH), and play a role in resisting free radical oxidation. In addition, hydroxyl groups can also complex with metal ions to reduce the generation of free radicals. Studies have shown that N-acetylneuraminic acid can effectively inhibit the activity of tyrosine hydroxylase and dopahydroxylase, and prevent the formation of melanin. Among many oral beauty ingredients, protein peptides have always been far ahead in terms of both awareness and usage, such as collagen and elastin. Collagen can promote cell division, repair damaged skin, and make the skin firm, tender and elastic. In addition, collagen can effectively inhibit the activity of tyrosinase in the human body, reduce the formation of melanin, and play a role in whitening. Elastin can maintain the elasticity of the skin by supporting collagen. Acerola cherry extract is recognized as the "king of natural vitamin C" and has a strong antioxidant effect. It can resist the damage of ultraviolet light to the skin and prevent skin aging. At the same time, it can promote collagen production and thus achieve beauty effects. However, due to the different physiological and physical and chemical properties of each whitening ingredient, the ingredients will attenuate and the solution dosage form will change color after being compounded, which will damage the efficacy of each ingredient. At the same time, the color change of terminal solution dosage form products such as oral liquids and beverages is also difficult for consumers to accept. Summary of the invention

[0004] In view of the deficiencies in the prior art, the present invention provides a whitening composition containing N-acetylneuraminic acid and application thereof.

[0005] In a first aspect, the present invention provides a whitening composition comprising N-acetylneuraminic acid, niacinamide, protein peptide and acerola cherry extract, wherein the mass of the protein peptide and the acerola cherry extract is no more than 2 times the mass of N-acetylneuraminic acid.

[0006] As mentioned above, N-acetylneuraminic acid, also known as bird's nest acid and sialic acid, has active hydroxyl groups that can provide active hydrogen to combine with superoxide anion radicals (O2-) and hydroxyl radicals (-OH), playing a role in resisting free radical oxidation. In addition, hydroxyl groups can also be complexed with metal ions to reduce the generation of free radicals. Studies have shown that N-acetylneuraminic acid can effectively inhibit the activity of tyrosine hydroxylase and dopahydroxylase, and prevent the formation of melanin. Protein peptides such as collagen and elastin are also commonly used components for beauty. The acerola cherry extract of the present invention is mainly in the form of acerola cherry powder at the application end, which is usually prepared by drying acerola cherry extract concentrate. Acerola cherry extract is recognized as the "king of natural vitamin C" and has a strong antioxidant effect. It resists the damage of ultraviolet light to the skin and prevents skin aging. At the same time, it can promote collagen production to achieve beauty effects. The Vc content in conventional acerola cherry extract is between 15% and 30%, and this range does not affect the effects of the present invention. In a specific implementation case of the present invention, the Vc content in acerola cherry powder is 25%.

[0007] Nicotinamide, also known as vitamin B3 or vitamin PP, belongs to the vitamin B family and is one of the 13 essential vitamins for the human body. Nicotinamide is a component of coenzyme I and coenzyme II. It plays a role in hydrogen transfer in human biological metabolism, promotes tissue respiration, biological oxidation process and metabolism, and is of great significance to maintaining the integrity of body tissues such as skin, digestive tract, heart system and nervous system. In medicine, it can also be used for skin diseases such as pellagra, stomatitis, liver disease and solar dermatitis. For the skin, niacinamide is a recognized skin care ingredient in the field of cosmetic dermatology. Its cosmetic effects on the skin are as follows: 1. It enhances the skin barrier function by increasing the content of ceramide in the stratum corneum and reduces transepidermal water loss; 2. It reduces the production of fatty acids and triglycerides in sebum, thereby shrinking pores; 3. The generation of glycosylated protein is one of the main causes of skin aging. Nicotinamide increases reduced coenzyme II to play an anti-glycosylation role, thereby reducing the yellowing of aging skin and improving skin quality.

[0008] The present invention has found that the combination of N-acetylneuraminic acid, niacinamide, protein peptide and acerola cherry extract can not only achieve a synergistically enhanced whitening effect, but also reduce the attenuation of the active ingredients. The solution product prepared with the four ingredients is not easy to change color and is easy for consumers to accept. It is worth mentioning that the addition of niacinamide has no effect on the acidity and alkalinity of the solution of the composition, the solution is still acidic, and the taste of the composition will not change.

[0009] Among them, if the amount of protein peptide and acerola cherry extract used is too much, exceeding twice the mass of N-acetylneuraminic acid, the active ingredients of the resulting composition will decay more (after being placed at 60°C for 10 days, the active ingredients will decay by more than 7%).

[0010] Furthermore, in the whitening composition, the mass ratio of N-acetylneuraminic acid, niacinamide, protein peptide and acerola cherry extract is 1: (0.003-5): (0.5-2): (0.5-2).

[0011] When the nicotinamide content is lower than a certain ratio, the stability of N-acetylneuraminic acid in the solution cannot be maintained, thereby affecting the stability of the overall composition.

[0012] Wherein, the protein peptides include collagen peptides and elastin peptides in any proportion.

[0013] After the composition of the present invention is added with water to prepare a composition solution, the formula of the composition solution is: 0.1-0.5% N-acetylneuraminic acid, 0.0003%-2.5% nicotinamide, 0.05%-1% protein peptide, 0.05%-1% acerola cherry extract and the balance water.

[0014] In a second aspect, the present invention provides use of the whitening composition in preparing food, health care products or skin care products with whitening efficacy.

[0015] Furthermore, the food or health product is a powdered reconstituted food, baked food, beverage, candy, milk and dairy products, fermented products, pasta products or oral preparations.

[0016] The skin care product can be an emulsion, a cream, a film, a solution or a gel.

[0017] Specifically, the present invention provides a whitening oral liquid, comprising the above-mentioned whitening composition.

[0018] According to the whitening oral liquid provided by the present invention, the mass percentage of N-acetylneuraminic acid in the whitening oral liquid is 0.1-0.5%, preferably 0.4-0.5%.

[0019] It is understandable that the whitening oral solution may also include other functional ingredients and acceptable excipients.

[0020] Exemplarily, the other functional ingredients include one or more of sodium hyaluronate, orange juice concentrate, frozen concentrated grapefruit juice, blood orange juice concentrate, decolorized and deacidified concentrated apple juice, γ-aminobutyric acid, tomato concentrate powder (white), and yeast extract.

[0021] The acceptable auxiliary materials include one or more of erythritol, citric acid, sodium bicarbonate, sucralose, and food flavors.

[0022] In some embodiments of the present invention, the composition of the whitening oral liquid is: N-acetylneuraminic acid 0.1-0.5%, niacinamide 0.0003%-2.5%, protein peptide 0.05%-1%, acerola cherry extract 0.05%-1%, sweetener 0.1-0.5%, flavor 0.01-0.1% and the balance water.

[0023] The whitening oral liquid provided by the present invention is placed in a glass bottle at 25° C. for 6 months, and the loss of N-acetylneuraminic acid does not exceed 2%, and the decay of VC content does not exceed 4%; when the glass bottle is placed at 37° C. for 6 months, the loss of N-acetylneuraminic acid does not exceed 5%, and the decay of VC content does not exceed 5%; and under the above conditions, the whitening oral liquid of the present invention does not change color.

[0024] Specifically, in practical applications, the dosage of the whitening oral solution is based on a daily intake of 100-200 mg of N-acetylneuraminic acid.

[0025] In a third aspect, the present invention provides a method for maintaining an N-acetylneuraminic acid aqueous solution from browning, comprising: preparing an aqueous solution of N-acetylneuraminic acid with nicotinamide, protein peptide and acerola cherry extract in a mass ratio of 1: (0.003-5): (0.5-2): (0.5-2).

[0026] In the above technical solution, under the premise of the presence of protein peptides and acerola cherry extract, the ratio of niacinamide can be very low, as low as 1:0.003 (N-acetylneuraminic acid: niacinamide), which can also prevent N-acetylneuraminic acid from browning.

[0027] The present invention provides a whitening composition containing N-acetylneuraminic acid and its application. By rationally combining N-acetylneuraminic acid, nicotinamide, protein peptide and acerola cherry extract, an excellent whitening effect can be achieved, especially an obvious effect of reducing melanin, and N-acetylneuraminic acid can effectively prevent the attenuation of effective ingredients, and the addition of nicotinamide can stabilize the browning and attenuation of N-acetylneuraminic acid itself. The whitening oral liquid obtained by the present invention can achieve the same level of efficacy as existing whitening products at a lower dosage, and has a broader market prospect. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is a diagram showing the whitening efficacy experimental results of the whitening oral liquid of the present invention.

[0029] Figure 2 is the melanin signal intensity of the zebrafish head after sample treatment. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0031] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0032] In the following examples, SA is the abbreviation of N-acetylneuraminic acid.

[0033] Example 1 In this embodiment, a whitening aqueous solution is prepared, the composition of which is 0.4% SA, 0.003% niacinamide, 0.6% acerola extract, 0.8% protein peptide (including 0.4% collagen peptide and 0.4% elastin peptide), and the rest is water.

[0034] Example 2

[0035] In this embodiment, a whitening aqueous solution is prepared, the composition of which is SA 0.45%, niacinamide 0.002%, acerola cherry extract 0.38%, protein peptide 0.38% (including collagen peptide 0.2%, elastin peptide 0.18%), and the rest is water.

[0036] Example 3

[0037] In this embodiment, a whitening aqueous solution is prepared, the composition of which is SA 0.4%, niacinamide 2%, acerola cherry extract 0.25%, protein peptide 0.2% (including collagen peptide 0.1%, elastin peptide 0.1%), and the rest is water.

[0038] Comparative Example 1 In this comparative example, an aqueous solution is prepared, the composition of which is 0.003% niacinamide, 0.6% acerola cherry extract, 0.8% protein peptide (including 0.4% collagen peptide and 0.4% elastin peptide), and the rest is water.

[0039] Comparative Example 2 In this comparative example, an aqueous solution is prepared, the composition of which is SA 0.4%, acerola cherry extract 0.6%, protein peptide 0.8% (including collagen peptide 0.4%, elastin peptide 0.4%), and the rest is water.

[0040] Comparative Example 3 In this comparative example, an aqueous solution is prepared, the composition of which is SA 0.4%, acerola cherry extract 1%, protein peptide 1% (including collagen peptide 0.5%, elastin peptide 0.5%), and the rest is water.

[0041] Comparative Example 4 In this comparative example, an aqueous solution is prepared, the composition of which is SA 0.4%, niacinamide 0.003%, and the rest is water.

[0042] Comparative Example 5 In this comparative example, an aqueous solution is prepared, the composition of which is SA 0.4%, niacinamide 0.003%, acerola cherry extract 1%, protein peptide 1% (including collagen peptide 0.5%, elastin peptide 0.5%), and the rest is water.

[0043] Comparative Example 6 In this comparative example, an aqueous solution is prepared, the composition of which is SA 0.4%, acerola cherry extract 0.6%, protein peptide 0.8% (including collagen peptide 0.4%, elastin peptide 0.4%), carrageenan 0.8%, and the rest is water.

[0044] Comparative Example 7 In this comparative example, an aqueous solution is prepared, the composition of which is SA 0.4%, acerola cherry extract 0.6%, protein peptide 0.8% (including collagen peptide 0.4%, elastin peptide 0.4%), sodium carboxymethyl cellulose 0.15%, and the rest is water.

[0045] Comparative Example 8 In this comparative example, an aqueous solution is prepared, the composition of which is SA 0.4%, acerola cherry extract 0.6%, protein peptide 0.8% (including collagen peptide 0.4%, elastin peptide 0.4%), locust bean gum 0.7%, and the rest is water.

[0046] Comparative Example 9 In this comparative example, an aqueous solution is prepared, the composition of which is SA 0.4%, acerola cherry extract 0.6%, protein peptide 0.8% (including collagen peptide 0.4%, elastin peptide 0.4%), sodium alginate 1%, and the rest is water.

[0047] Comparative Example 10 In this comparative example, an aqueous solution is prepared, the composition of which is SA 0.4%, niacinamide 0.001%, acerola cherry extract 0.38%, protein peptide 0.38% (including collagen peptide 0.2%, elastin peptide 0.18%), and the rest is water.

[0048] Comparative Example 11 In this comparative example, an aqueous solution is prepared, the composition of which is SA 0.4%, acerola cherry extract 0.6%, protein peptide 0.8% (including collagen peptide 0.4%, elastin peptide 0.4%), yeast extract 1%, and the rest is water.

[0049] Performance Testing 1. Stability test The aqueous solutions of the examples and comparative examples were subjected to an accelerated stability test at 60° C. for 10 days. The results are shown in Table 1.

[0050] Whether the solution color becomes darker is observed with the naked eye, with an unaccelerated sample as a control. Each time the accelerated sample is taken out at a certain time point and compared with the control to observe the color change. "-" means that the color does not darken, and "+" means that the color darkens.

[0051] The SA content was determined by high performance liquid chromatography (HPLC): the instrument was Shimadzu Lc-15c; the detection column was Bio-Rad AMINEX HPX 87H Organic Analysis Column (300×7.8 mm); the column temperature was 60°C; the mobile phase was 6 mmol sulfuric acid; the flow rate was 0.6 mL / min; and the detection wavelength was 210 nm (all experimental data were repeated 3 times, and the results were the average of 3 times).

[0052] The VC content was determined by high performance liquid chromatography (HPLC): the instrument was Shimadzu LC-10Ai, octadecylsilane bonded silica gel was used as filler, the chromatographic column was 4.6 mm × 250 mm (5 μm), the mobile phase was 0.15% oxalic acid solution, the detection wavelength was 245 nm, the column temperature was 25 °C, the flow rate was 0.8 ml / min, and the injection volume was 10 μl.

[0053] The calculation formulas for SA attenuation and Vc attenuation are: Attenuation = (accelerated sample content - initial content) × 100% / initial content.

[0054] Table 1

[0055] 2. Test on the stability and whitening effect of finished products Sweeteners and flavors were added to the aqueous solution of Example 2 to prepare an oral liquid, that is, the oral liquid formula was: SA 0.45%, niacinamide 0.002%, acerola cherry extract 0.38%, protein peptide 0.38% (including collagen peptide 0.2%, elastin peptide 0.18%), sweetener 0.5%, flavor 0.01%, and the rest was water.

[0056] The stability test results of the finished product are as follows: when placed in a glass bottle at 25°C for 6 months, the SA loss is 1.52%, and the VC content decays by 3.51%; when placed in a glass bottle at 37°C for 6 months, the SA loss is 4.86%, and the VC content decays by 4.11%. The color is light red, and there is no change.

[0057] The whitening effect experiment is as follows: 1. Test materials 1.1. Sample preparation information The oral liquid of the present invention is prepared by taking the stock solution and diluting it as required.

[0058] Positive control: Arbutin, white powder, batch number D2121116, Shanghai Aladdin Biochemical Technology Co., Ltd., stored in a dry and refrigerated place away from light. Prepared into a 30.0 mg / mL stock solution with standard dilution water, ready for use.

[0059] 1.2. Experimental animals Zebrafish were raised in fish farming water at 28°C (water quality: 200 mg of instant sea salt was added to every 1L of reverse osmosis water, conductivity was 450~550μS / cm; pH was 6.5~8.5; hardness was 50~100 mg / LCaCO3), bred and provided by our company's fish farming center, the experimental animal use license number is: SYXK(Zhejiang)2022-0004, and the breeding management complies with the requirements of the international AAALAC certification (certification number: 001458), IACUC ethics review number: IACUC-2023-7447-01.

[0060] Wild-type AB strain zebrafish were bred in natural pairs. Zebrafish aged 6 hours post fertilization (6hpf) were used for the determination of the maximum detection concentration (MTC) of the whitening efficacy of the samples and their efficacy evaluation.

[0061] 1.3. Instruments, consumables and reagents Dissecting microscope (SZX7, OLYMPUS, Japan); CCD camera (VertA1, Shanghai Tusen Vision Technology Co., Ltd., China); precision electronic balance (CP214, OHAUS, USA); 6-well plate (Zhejiang Bellanbo Biotechnology Co., Ltd., China). Methylcellulose (Batch No. C2004046, Shanghai Aladdin Biochemical Technology Co., Ltd., China).

[0062] 2. Detection Methods 2.1. MTC determination 6hpf wild-type AB strain zebrafish were randomly selected in a 6-well plate, and 30 zebrafish were treated in each well (experimental group). Water-soluble samples (concentrations shown in Table 2) were given, and a normal control group was set up at the same time, with a volume of 3 mL per well. After treatment at 28°C for 2 days, the MTC of the oral solution of the present invention on normal zebrafish was determined.

[0063] 2.2. Evaluation of whitening efficacy 6hpf wild-type AB strain zebrafish were randomly selected in a 6-well plate, and 30 zebrafish were treated in each well (experimental group). Water-soluble samples (concentrations are shown in Table 3), positive control arbutin concentration is 3000μg / mL, and a normal control group is set up at the same time, with a volume of 3mL per well. After 2 days of treatment at 28℃, 10 zebrafish were randomly selected from each experimental group and photographed under a dissecting microscope. ImageJ advanced image processing software was used to analyze and collect data, and the melanin signal intensity of the zebrafish head was analyzed. The statistical analysis results of this indicator were used to evaluate the whitening effect of the sample. The statistical analysis results are expressed as mean±SE. SPSS26.0 software was used for statistical analysis, and p<0.05 indicated that the difference was statistically significant.

[0064] 3. Test results 3.1. MTC measurement results Under the experimental conditions, the MTC of the oral solution of the present invention for normal zebrafish is 62.5 μL / mL. See Table 2 for details.

[0065] Table 2 Results of the sample whitening efficacy concentration test (n=30)

[0066] 3.2. Evaluation of whitening efficacy Under the experimental conditions, the oral liquid of the present invention has a whitening effect. See Table 3 and Figure 1 , Figure 2 . Figure 1 This is a diagram showing the whitening efficacy experimental results of the whitening oral liquid of the present invention; Figure 2 is the melanin signal intensity of the zebrafish head after sample treatment.

[0067] Table 3 Sample whitening efficacy evaluation test results (n=10)

[0068] Compared with the normal control group, *** indicates p < 0.001.

[0069] It can be seen from the above results that arbutin and the oral solution of the present invention with a concentration of 31.2 uL / mL and 62.5 uL / mL can significantly reduce and lighten the melanin in the head of zebrafish.

[0070] Moreover, in this experiment, the oral liquid group added 62.5 uL / mL, which was converted to 281μg SA, 1.25μg nicotinamide, 237.5μg protein peptide, and 237.5μg acerola extract per milliliter. The total was 281μg+1.25μ+237.5μg+237.5μg=757.25μg<3000μg arbutin, indicating that the effective ingredient dosage of the composition of the present invention is much smaller than that of arbutin, and achieves better effects than arbutin.

[0071] It should be noted that the endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed in this article.

[0072] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "specific implementation methods", or "some specific implementation methods" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the embodiment of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0073] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A whitening composition, characterized in that: It includes N-acetylneuraminic acid, niacinamide, protein peptide and acerola cherry extract, among which the mass of protein peptide and acerola cherry extract is no more than 2 times the mass of N-acetylneuraminic acid.

2. The whitening composition according to claim 1, characterized in that In the whitening composition, the mass ratio of N-acetylneuraminic acid, nicotinamide, protein peptide and acerola cherry extract is 1: (0.003-5): (0.5-2): (0.5-2).

3. The whitening composition according to claim 1 or 2, characterized in that The protein peptides include collagen peptides and elastin peptides in any proportion.

4. Use of the whitening composition according to any one of claims 1 to 3 in the preparation of food, health care products or skin care products with whitening effects.

5. The use according to claim 4, characterized in that: The food or health product is a powdered reconstituted food, baked food, beverage, candy, milk and dairy products, fermented products, pasta products or oral preparations; The skin care product is an emulsion, a cream, a film, a solution or a gel.

6. A whitening oral liquid, characterized in that: The invention comprises the whitening composition according to any one of claims 1 to 3.

7. The whitening oral liquid according to claim 6, characterized in that: The mass percentage of N-acetylneuraminic acid in the whitening oral liquid is 0.1-0.5%, preferably 0.4-0.5%.

8. The whitening oral liquid according to claim 6, characterized in that: The whitening oral solution also includes other functional ingredients and acceptable excipients; The other functional ingredients include one or more of sodium hyaluronate, orange juice concentrate, frozen concentrated red grapefruit juice, blood orange juice concentrate, decolorized and deacidified concentrated apple juice, γ-aminobutyric acid, tomato concentrate powder (white), and yeast extract; The acceptable auxiliary materials include one or more of erythritol, citric acid, sodium bicarbonate, sucralose, and food flavors.

9. The whitening oral liquid according to any one of claims 6 to 8, characterized in that: The whitening oral liquid is composed of: 0.1-0.5% N-acetylneuraminic acid, 0.0003%-2.5% nicotinamide, 0.05%-1% protein peptide, 0.05%-1% acerola cherry extract, 0.1-0.5% sweetener, 0.01-0.1% flavor and the balance of water.

10. A method for maintaining an aqueous solution of N-acetylneuraminic acid from browning, characterized in that: include: N-acetylneuraminic acid, nicotinamide, protein peptide and acerola cherry extract are prepared into an aqueous solution in a mass ratio of 1: (0.003-5): (0.5-2): (0.5-2).

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