CN111714403B

CN111714403B - Novel application of tetrahydropyrimidines and cooling preparation containing tetrahydropyrimidines

Info

Publication number: CN111714403B
Application number: CN202010489571.1A
Authority: CN
Inventors: 董艳美; 王冠凤; 石艳丽; 钱晓路; 陈晨; 郭学平
Original assignee: Bloomage Biotech Co Ltd; Shandong Bloomage Hyinc Biopharm Co Ltd
Current assignee: Bloomage Biotech Co Ltd
Priority date: 2020-06-02
Filing date: 2020-06-02
Publication date: 2023-02-03
Anticipated expiration: 2040-06-02
Also published as: CN111714403A

Abstract

The invention discloses a new application of tetrahydropyrimidines and a cooling preparation containing the tetrahydropyrimidines. The ectoine substances and the ethanol are compounded to prepare the cool and cool preparation, the cool and cool preparation contains the ethanol with high concentration, the body surface temperature can be effectively reduced, the thermal injury of the skin is avoided, and cool and pleasant use experience is formed. The cooling preparation is efficient, portable, economical and easily available, and is suitable for skin cooling care in daily life.

Description

Novel application of tetrahydropyrimidines and cooling preparation containing tetrahydropyrimidines

Technical Field

The invention relates to a new application of tetrahydropyrimidines, in particular to a new application of tetrahydropyrimidines in a cooling preparation containing high-concentration ethanol for reducing or avoiding damage of the high-concentration ethanol to skin, and also relates to a cooling preparation containing tetrahydropyrimidines, belonging to the technical field of daily necessities.

Background

In daily life, the skin is often required to be cooled and nursed, for example, in hot weather, the skin is not only uncomfortable but also easily burnt and dehydrated, so that the body is required to be cooled and nursed to maintain the normal temperature of the body surface and obtain the comfortable sensation in the sense, and a product which is economical, safe, portable, convenient to use and capable of quickly reducing the skin temperature of the human body is required.

Ethanol is one of the most common spraying solvents and is most applied due to excellent volatilization cooling capacity and economical efficiency, and an ethanol solution of 10-70% (v/v) is usually used as a main raw material. In actual use, however, ethanol molecules have great protein penetrating and denaturing capacities, have great skin irritation, damage cell membranes, destroy skin surface proteins, have certain destructive effect on normal cells and skin barriers, and evaporate ethanol to take away a large amount of moisture of the skin, so that the ethanol-containing cooling spray can cause skin damage such as skin dryness, desquamation, chapping, dermatitis and the like after being used for a long time.

These damages of ethanol to the skin severely restrict the use of ethanol in cooling agents, especially cooling sprays. Therefore, many cooling products achieve the sensory cooling effect by adding substances such as peppermint oil, menthol and menthyl ester, for example, patent CN 108347979A, but cooling spray added with peppermint oil can make people feel cool, and menthol only stimulates nerve endings of the human body to generate temporary cold feeling, and the purpose of skin cooling care is not achieved. In another part of applications, only low-concentration ethanol is used for reducing skin irritation, such as adding 0.1-10% of ethanol in patent CN 108186398A and 2-9 parts of ethanol in patent CN 110179720A, but the low-concentration ethanol causes the skin to have a reduced cool feeling, and has a slow cooling speed and a small cooling amplitude. In a very small part of applications, such as CN105473128B, high-concentration ethanol (30% -70%) is added to increase the cooling effect and quick-drying property of the cooling agent, but the damage to the skin caused by the ethanol is not considered.

Disclosure of Invention

Tetrahydropyrimidines are compatible solutes that are synthesized and accumulated intracellularly by halophilic microorganisms in order to maintain the osmotic pressure balance inside and outside the cell, prevent dehydration of the cell, are compatible with intracellular metabolism and do not affect the biomacromolecule function or physiological processes of the cell. Tetrahydropyrimidine is not only an important osmotic pressure compensation solute, but also has a good protection effect on cells and biological macromolecules (biomembranes, proteins, enzymes and nucleic acids) under the stimulation of adverse environments such as high temperature, high salt, freezing, drying, radiation and the like, and is a powerful protective agent. The complex formed by the amino acid derivative and water molecules around the amino acid derivative can form a stable protective layer inside and outside epidermal cells so as to surround cells, enzymes, proteins and other biomolecules. Tetrahydropyrimidines restore and stabilize the barrier function of the stratum corneum and have protective and anti-inflammatory effects. Therefore, the tetrahydropyrimidine has important application value and wide application prospect in the fields of cosmetics, cell protective agents, biological agent stabilizers, pharmaceutical preparations and the like, and has the effects of protecting cell membranes of skin cells, preserving moisture (long-acting moisture preservation), resisting inflammation (protecting immune cells and reducing the release of inflammatory factors), promoting skin repair, reducing the damage of UV radiation to the skin and the like when being applied to the skin.

According to the application, the tetrahydropyrimidines can effectively avoid or reduce skin damage caused by independently using high-concentration ethanol, so that the application of the tetrahydropyrimidines in a cooling preparation containing high-concentration ethanol is provided for reducing or avoiding the damage of the high-concentration ethanol to the skin, and the ethanol can be better applied to the cooling product, not only can play a good cooling effect by using the high-concentration ethanol, but also can avoid or reduce the damages of skin dryness, desquamation, chapping, dermatitis and the like caused by using the high-concentration ethanol.

Further, in the above cooling and cooling preparation containing ethanol at a high concentration, ethanol at a high concentration means that the concentration of ethanol in the cooling and cooling preparation is 20% or more, preferably 30% or more, more preferably 30 to 90%, and still more preferably 60 to 90% by volume. With the increase of the ethanol concentration, the cooling effect is increased, but the damage degree of the skin caused by frequent use is also increased.

Furthermore, in the cooling preparation containing high-concentration ethanol, the mass volume fraction of the tetrahydropyrimidine substances in the cooling preparation is 0.1-10%, and the mass volume fraction refers to the mass (g) of the tetrahydropyrimidine divided by the volume (ml) of the whole cooling preparation. When the addition amount of the tetrahydropyrimidines is more than or equal to 0.1%, the effect of avoiding or reducing the loss of the ethanol to the skin can be better, the effect is more obvious along with the increase of the addition amount of the tetrahydropyrimidines within the range of 0.1-5%, when the addition amount is more than 5%, the effect of avoiding or reducing the skin damage is similar to that of the addition amount of 5%, and the skin has sticky feeling after frequent use. Therefore, the mass volume fraction of the tetrahydropyrimidines in the cooling preparation is 1-5%.

Further, the tetrahydropyrimidines include one of tetrahydropyrimidines and their pharmaceutically acceptable salts or/and esters, hydroxypyrimidines and their pharmaceutically acceptable salts or/and esters, or a combination of two or more. The action of the tetrahydropyrimidines in the present invention is similar.

According to the outstanding effects of the tetrahydropyrimidines, the invention also provides a cooling preparation, and the active ingredients of the cooling preparation at least comprise the tetrahydropyrimidines, ethanol and water. In the cooling preparation, the volume fraction of ethanol is greater than or equal to 20%, preferably greater than or equal to 30%, more preferably 30-90%, and more preferably 60-90%. The mass volume fraction of the tetrahydropyrimidines in the cooling preparation is 0.1-10%, preferably 1-5%.

The tetrahydropyrimidine substance and the high-concentration ethanol are compounded to form the cool and cool preparation, and the cool and cool preparation is mainly used for cooling the body surface, maintaining the normal temperature of the body surface, avoiding the thermal injury of the skin and obtaining cool and comfortable sensation in sense. The preparation contains high-concentration ethanol (the volume concentration is more than or equal to 20 percent), can quickly and effectively reduce the body surface temperature to form cool and pleasant use experience, can reduce or even avoid damages such as cell membrane damage, water content reduction and the like caused by the use of the high-concentration ethanol on the skin by the tetrahydropyrimidine substances in the preparation, is economical and convenient, and can be frequently used.

Further, in the cooling and refreshing preparation, the definition of the tetrahydropyrimidines is the same as that described above.

Furthermore, the cooling preparation can also comprise other cooling agents besides the tetrahydropyrimidines, ethanol and water, and the other cooling agents can be peppermint oil, menthol and derivatives thereof, menthyl esters and derivatives thereof, borneol and derivatives thereof and the like. The other cooling agents can amplify the sensory cooling experience of the preparation, enhance the cooling effect and increase the pleasant feeling of use. The mass volume fraction of the other cooling agents in the cooling preparation is 0-2.0%, and preferably 0.1-0.5%.

Furthermore, the cooling preparation can comprise one or more than one of the components such as a surfactant, a thickening agent, an acid-base regulator, a food pigment, a food flavor and the like besides the tetrahydropyrimidines, the ethanol and the water.

Further, the surfactant may be any amphoteric surfactant or combination thereof, which is reported in the prior art to be usable in skin products such as cosmetics, skin care products, etc., such as amino acid type amphoteric surfactants, betaine type amphoteric surfactants, alkyl polysaccharide anhydrides, etc. The surfactant can adjust the surface tension of the cooling and cooling preparation. The addition amount of the surfactant is conventional, and the mass volume fraction of the surfactant in the cooling preparation is usually 0.01-2.0%, and preferably 0.1-0.5%.

Further, the thickener may be any thickener that can be used in skin products such as cosmetics, skin care products, etc. reported in the prior art, such as carbomer series, agar, guar gum, alginate, xanthan gum, dextran, cellulose derivatives, hyaluronic acid, etc. The thickening agent can adjust the viscosity of the cooling and refreshing preparation and thicken and shape the cooling and refreshing preparation. Generally, the mass volume fraction of the thickening agent in the cooling and temperature-reducing preparation is 0-2%, preferably 0.01-1%.

Further, the ph modifier may be any ph modifier known in the art that can be applied to the skin, such as citric acid, lactic acid, tartaric acid, malic acid, sodium citrate, potassium citrate, and the like. The pH regulator can maintain or change the pH value of the cooling preparation, maintain the stability of each component of the preparation and make the preparation more skin-friendly and applicable. The mass volume fraction of the acid-base regulator in the cooling and temperature-reducing preparation is 0-2%, preferably 0.01-1%.

Further, the food color may be any color known in the art that can be applied to the skin, such as gardenia yellow, safflower yellow, red rice red, monascorubin, shellac color, carminic acid, and the like, and combinations thereof. The pigment can adjust the color of the cooling preparation and enhance the sensory satisfaction of the product. The mass volume fraction of the edible pigment in the cooling and temperature-reducing preparation is 0-1%, preferably 0.01-0.5%.

Further, the flavorant may be any flavor, scent, fragrance, or combination thereof known in the art that can be applied to the skin, such as peppermint oil, orange oil, and the like, which has a pleasant odor to meet the user's wishes to create a satisfactory sensory experience. The mass volume fraction of the edible essence in the cooling preparation is 0-2%, preferably 0.05-1%.

Furthermore, the type of the cooling and refreshing preparation can be aerosol, spray or aqueous solution. The aerosol is prepared by filling the above cooling preparation, and then spraying when in use. The spray is prepared by filling the cooling preparation into a spray bottle and forming spray through the spray bottle. The aqueous solution can be applied directly to the corresponding area of skin. From the comprehensive consideration of convenience in use, cooling effect, sensory effect, etc., the composition is preferably made into aerosol or spray.

Furthermore, the cooling preparation is simple to prepare, and is prepared by uniformly mixing the tetrahydropyrimidines, the ethanol, the water and other components (if any), and then packaging. The tetrahydropyrimidines, ethanol and water can be mixed in any order. For example, the tetrahydropyrimidines may be added to an aqueous ethanol solution, or an aqueous tetrahydropyrimidines solution may be added to absolute ethanol or an aqueous ethanol solution.

In a specific embodiment of the invention, the tetrahydropyrimidines are dissolved in a proper amount of water (the volume of the tetrahydropyrimidines is less than that of the formula water) to form a tetrahydropyrimidines water solution, the tetrahydropyrimidines water solution is fully dissolved and then mixed with the formula amount of anhydrous ethanol, and then water is added to the mixture to reach a constant volume, so as to obtain the cooling preparation.

In a specific embodiment of the invention, firstly, an ethanol aqueous solution with the concentration slightly higher than the target concentration is prepared, the required tetrahydropyrimidine substances are added, and after the tetrahydropyrimidine substances are fully dissolved, a small amount of water is added to complement the constant volume, so that the cooling preparation is obtained.

In a specific embodiment of the invention, the tetrahydropyrimidines are dissolved in a proper amount of water (the volume of which is less than that of the formula water) to form a tetrahydropyrimidines water solution, an ethanol water solution with the concentration higher than a target concentration is prepared, then the tetrahydropyrimidines water solution and the ethanol solution are uniformly mixed, and the cooling preparation is obtained by constant volume.

The invention discovers the new application of the tetrahydropyrimidines, and compounds the tetrahydropyrimidines and ethanol to prepare the cooling preparation according to the research result. The preparation contains high-concentration ethanol, can effectively reduce the body surface temperature, avoids thermal injury of skin, forms cool and pleasant use experience, and simultaneously greatly reduces or even avoids the problems of skin barrier damage, dehydration and dryness, desquamation, chapping, erythra, skin inflammation and the like caused by the use of ethanol as a cool and cool component while ensuring the cool and cool effect of the preparation by compounding the tetrahydropyrimidine and the ethanol. The cooling preparation is efficient, portable, economical and easily available, and is suitable for skin cooling care in daily life.

Detailed Description

The following illustrates several exemplary embodiments of the invention for further explanation. Various details of the present application implementation are included in the examples to facilitate understanding, and they should be considered exemplary only. Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope and spirit of the present application. Also, descriptions of well-known functions and constructions are omitted in the following description for clarity and conciseness.

In the following examples, the units of the mass-volume fractions are all in g/ml unless otherwise specified.

In the examples described below, tetrahydropyrimidine was from Hua Xi, biotech, inc, hydroxytetrahydropyrimidine was from Sigma-Aldrich, absolute ethanol was from the national drug group, menthyl acetate was from fu lu, su, biotechnology, inc, and peppermint oil was from north huolong, multi-biotechnology, inc.

Example 1

Accurately measuring absolute ethyl alcohol, adding a proper amount of deionized water to dilute the absolute ethyl alcohol to obtain an ethanol solution, adding tetrahydropyrimidine into the ethanol solution, fully dissolving, adding deionized water to supplement the required volume to ensure that the volume fraction of the ethanol is 30 percent and the mass volume fraction of the tetrahydropyrimidine is 0.1 percent, uniformly mixing, and filling to obtain the cooling aerosol.

Examples 2 to 23

A cooling aerosol was prepared according to the method of example 1, except that: the contents and components of the cooling aerosol are different, and are specifically shown in table 1.

Comparative examples 1 to 3

A cooling aerosol was prepared according to the method of example 1, except that: the contents and components of the cooling and cooling aerosol are different, and are specifically shown in table 1.

Comparative examples 4 to 7

A cooling aerosol was prepared according to the method of example 1, except that: the contents of ethanol and tetrahydropyrimidine were varied and are specifically shown in table 1.

TABLE 1 comparison table of raw material compositions of examples and comparative examples

Note: in table 1, the percentage contents of tetrahydropyrimidines, menthyl acetate and peppermint oil in the cooling aerosol are mass volume contents, unit g/ml, and the percentage content of ethanol in the cooling aerosol is volume percentage content.

Test example 1 skin cooling effect of cooling aerosol formed by compounding tetrahydropyrimidines and ethanol

The cooling effect was evaluated by measuring the difference in skin temperature before and after application of the cooling aerosol in a high temperature (37 ℃ C.) environment.

1. Laboratory apparatus

A non-contact infrared thermometer JXB-182 (beierkang medical devices limited, guangzhou).

2. Experimental methods

(1) Environment: the temperature is 37 ℃ plus or minus 2 ℃ and the relative humidity is 40 percent plus or minus 10 percent.

(2) Measurement of skin temperature difference before and after application of cooling aerosol: 54 volunteers between 20-50 years of age were selected for the trial, 27 of which were male and female. On each volunteer forearm Qu Ceshi each of the cooling aerosols prepared in examples 1-23 and comparative examples 1-4 above was applied at a rate of 3.0mg/cm ² The area of application was 4cm × 4cm, and the application was performed every 5min for 3 times in total. Measuring the skin temperature before application and the skin temperature after the 3 rd application, wherein the skin temperature after the 3 rd application is measured 1min after the third application of the cooling aerosol, and if the cooling aerosol applied after 1min can not be completely evaporated, the skin temperature is measured after being wiped dry by a paper towel. Each volunteer tried 4 products.

3. Data processing

(1) Skin temperature difference (c) after 3 applications: the sample of each example or control was evaluated for 8 groups and the difference between the skin temperature after application and the temperature before application was averaged to obtain the skin temperature difference after 3 applications for the sample.

(2) Sensory evaluation of cooling:

the evaluation was made based on the self-sensation of cool feeling after use. The scoring standard is divided into 10 points, wherein 0 point has no cool feeling, 10 points have the best cool feeling effect, and the higher the score is, the better the effect is.

4. Results of the experiment

The skin cooling effect and sensory cooling evaluation of the cooling aerosol prepared by compounding the tetrahydropyrimidines and ethanol are shown in the following table 2.

TABLE 2

As can be seen from the data in Table 2, the cooling aerosols prepared in examples 1 to 23 can effectively reduce the skin temperature in a high temperature environment, and avoid skin damage caused by a hot environment. Wherein, the cooling effect and the cooling effect are enhanced along with the increase of the concentration of the ethanol in the cooling aerosol, and are basically not influenced by the addition of the tetrahydropyrimidine and the hydroxyl tetrahydropyrimidine. Comparative example 1 shows that the cooling aerosol containing low-concentration absolute ethyl alcohol reduces the skin temperature by 0.27 ℃, has extremely small cooling amplitude and has no obvious effect. The cooling aerosol prepared by the comparative examples 2-3 can form sensory cooling experience, but does not show obvious cooling effect, namely, the menthyl acetate and the peppermint oil are added, so that the cooling effect is not actual, in a high-temperature environment, only skin receptors can be stimulated to form a cooling false image, skin damage caused by high temperature and high heat cannot be avoided, even judgment of a human body on the temperature is interfered, and serious skin thermal damage is caused by long-time stay in the high-temperature and high-heat environment. Comparative example 4 shows that the addition of only tetrahydropyrimidine has no cooling effect and does not form a sensory cooling experience.

As can be seen from Table 2, the cool and cool aerosol of the present invention can not only reduce skin temperature effectively, but also form cool and pleasant sensory experience, protect skin and avoid thermal damage to skin caused by high temperature and high heat environment.

Test example 2 Effect of a cooling aerosol prepared by compounding tetrahydropyrimidines and ethanol on skin conditions

The influence on the skin condition was evaluated by the moisture content of the skin, the appearance (presence or absence of inflammatory manifestations such as dryness, desquamation, chapping and erythema) and the skin feel experience after frequent use of cooling and cooling aerosols.

1. Instrumentation and equipment

The skin moisture tester Corneometer CM 825 (Courage Khazaka, germany).

2. Experimental methods

The cooling aerosol formulations of examples 1 to 23 and comparative examples 5 to 7 were used as test samples. 52 volunteers, aged 20-50 years, were recruited, male and female. 4cm multiplied by 4cm test areas are marked on the left and right front arms Qu Cebiao of the testee, samples are respectively smeared, and 4 products are tried on each volunteer. The coating amount is 3.0mg/cm ² And naturally drying after smearing, smearing 8 times every day for 5 days continuously, measuring the moisture content of the skin in a sample smearing area by using a skin moisture meter on the 6 th day, observing the skin state by naked eyes, and evaluating the skin feeling experience of the smeared sample.

3. Data processing

3.1 the moisture content of the skin before application and after the application on the 6 th day was measured, and 8 groups of values were measured for each sample of the examples or the comparative examples, and the average value was obtained, and the moisture content loss rate of the skin was calculated according to the following equation.

3.2 skin condition is judged according to the following criteria:

skin condition rating	Skin condition
		++++	Four inflammation indications of dryness, desquamation, rhagadia and erythra
+++	Three of four inflammation indications of dryness, desquamation, rhagadia and erythra
		++	Two of four inflammation indicators of dryness, desquamation, rhagadia and rubella
+	Only signs of dryness appeared
		-	Compared with the skin which is not coated with the cooling aerosol, no obvious difference is seen

3.3 the skin feel experience is judged according to the following criteria:

skin feel experience level	Skin feel experience
		++	Thick, sticky and greasy
+	Slightly sticky feeling
		-	Has no sticky feeling

4. Results of the experiment

The skin moisture content loss rate, skin state and skin feel experience of the cooling aerosol prepared by compounding tetrahydropyrimidines and ethanol after high-frequency use are shown in the following table 3.

TABLE 3

As can be seen from the data in Table 3, the cooling aerosol prepared by compounding the tetrahydropyrimidines and the ethanol can obviously reduce the loss rate of the moisture content of the skin and reduce the skin inflammation indication caused by frequent use of the ethanol cooling aerosol compared with the cooling aerosol prepared by only containing the ethanol in the comparative example 5. As can be seen from the comparison of examples 1-23 and comparative example 5, in the cooling aerosol with 30% -90% of ethanol content, the addition of 0.1% of tetrahydropyrimidine can reduce the loss rate of the moisture content of the skin and improve the inflammatory state of the skin, and the skin basically has no rash; when the addition amount of the tetrahydropyrimidines is increased to 1-10%, the water content loss rate of the skin is further reduced, and the skin is not obviously changed when being observed by naked eyes compared with the skin without the cooling aerosol. When the amount of the tetrahydropyrimidines is 5 to 10%, heavy sticky skin feel occurs when the skin is used at high frequencies, and therefore, the amount of the tetrahydropyrimidines is preferably 1 to 5%.

Therefore, the cooling aerosol formed by compounding 0.1-10% (w/v) tetrahydropyrimidine substances and ethanol can effectively reduce the damage of cell membrane damage, water content reduction and the like caused by the use of the ethanol cooling aerosol without losing the cooling effect of the ethanol cooling aerosol, and can reduce or even avoid the inflammation of dryness, scurf, rhagadia and erythra caused by the high-frequency use of the ethanol cooling aerosol. Preferably, the cooling aerosol prepared by compounding 1-5% (w/v) tetrahydropyrimidine and ethanol has the advantages of minimal damage to skin and refreshing and comfortable skin feel.

The refreshing and cooling aerosol prepared by compounding 0.1-0.5% (w/v) tetrahydropyrimidine substances and 30-90% (v/v) ethanol is used at high frequency, so that inflammation signs such as dry skin, dandruff, chap, erythra and the like are obviously improved; after the cooling aerosol formed by compounding 1-10% (w/v) tetrahydropyrimidine substances and 30-90% (v/v) ethanol is used at high frequency, the skin does not have inflammation such as dryness, scurf, chapping, erythra and the like, which indicates that the cooling aerosol formed by 0.1-10% (w/v) tetrahydropyrimidine substances and 30-90% (v/v) has no skin toxicity, no skin irritation or low skin irritation, is safe and mild cooling aerosol without anaphylaxis and with the functions of repairing and protecting the skin, and is suitable for skin cooling care.

Although embodiments of the present invention have been described above with reference to examples, the present invention is not limited to the above-described embodiments and fields of application, which are illustrative, instructive, and not restrictive. Those skilled in the art, having the benefit of this disclosure, may effect numerous modifications thereto and changes may be made without departing from the scope of the invention as defined by the appended claims.

Claims

1. The application of tetrahydropyrimidines in a cooling preparation containing high-concentration ethanol is characterized in that: the tetrahydropyrimidines are used for reducing or avoiding the damage of high-concentration ethanol to the skin; the volume concentration of ethanol in the cooling preparation is more than or equal to 20 percent; the mass volume fraction of the tetrahydropyrimidine substance in the cooling preparation is 1-10%; the tetrahydropyrimidine substance comprises one or more of tetrahydropyrimidine, a medical acceptable salt of tetrahydropyrimidine, a medical acceptable ester of tetrahydropyrimidine, hydroxyl tetrahydropyrimidine, a medical acceptable salt of hydroxyl tetrahydropyrimidine and a medical acceptable ester of hydroxyl tetrahydropyrimidine.

2. Use according to claim 1, characterized in that: the volume concentration of the ethanol in the cooling preparation is more than or equal to 30 percent.

3. Use according to claim 2, characterized in that: the volume concentration of the ethanol in the cooling preparation is 30-90%.

4. Use according to claim 3, characterized in that: the volume concentration of the ethanol in the cooling preparation is 60-90%.

5. Use according to claim 1, characterized in that: the mass volume fraction of the tetrahydropyrimidine substance in the cooling preparation is 1-5%.

6. A cooling preparation is characterized in that: the effective components comprise tetrahydropyrimidines, ethanol and water; the mass volume fraction of the tetrahydropyrimidine substances in the cooling preparation is 0.1-10%, and the volume fraction of the ethanol in the cooling preparation is more than or equal to 20%; the tetrahydropyrimidine substances comprise one or more of tetrahydropyrimidine, medical acceptable salts of tetrahydropyrimidine, medical acceptable esters of tetrahydropyrimidine, hydroxyl tetrahydropyrimidine, medical acceptable salts of hydroxyl tetrahydropyrimidine and medical acceptable esters of hydroxyl tetrahydropyrimidine.

7. A cooling formulation according to claim 6, which is characterized in that: the mass volume fraction of the tetrahydropyrimidines in the cooling preparation is 1-5%.

8. A cooling formulation according to claim 6, which is characterized in that: the volume fraction of ethanol in the cooling preparation is greater than or equal to 30%.

9. A cooling formulation according to claim 8, which is characterized in that: the volume fraction of ethanol in the cooling preparation is 30-90%.

10. A cooling formulation according to claim 9, which is characterized in that: the volume fraction of ethanol in the cooling preparation is 60-90%.

11. A cooling formulation according to any one of claims 6 to 10, which is characterized by: also comprises at least one of other algefacient, surfactant, thickener, pH regulator, edible pigment and edible essence.

12. A cooling preparation according to claim 11, which is characterized in that: the other cooling agent comprises at least one of peppermint oil, menthol and its derivatives, menthyl esters and its derivatives, and borneol and its derivatives.

13. A cooling formulation according to any one of claims 6 to 10, which is characterized by: the type is aerosol or spray.