Application of TPPU, product of TPPU, and use of TPPU and product of TPPU

Abstract

The invention relates to the technical field of improvement of sensitive skin, in particular to application of TPPU in preparation of a product for improving skin sensitivity, the product and a method for improving skin sensitivity by applying TPPU or the product thereof. The invention specifically provides application of TPPU in preparation of products for improving skin sensitivity and / or promoting skin soothing, or a method for improving skin sensitivity and / or resisting skin aging by applying TPPU. The TPPU can improve skin sensitivity and / or promote skin soothing, and especially has a good effect on skin sensitive people.

Description

Technical Field

[0001] The present application relates to the technical field of improving skin conditions, and in particular to the use of TPPU in the preparation of products for improving skin sensitivity and / or promoting skin soothing, products, and the use of TPPU or its products to improve skin sensitivity and / or promote skin soothing. Background Art

[0002] TPPU is a compound in the class of soluble epoxide hydrolase inhibitors that can inhibit the activity of soluble epoxide hydrolase. Its chemical name is 1-(1-propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea, CAS No. 1222780-33-7, molecular weight: 359, molecular formula: C 16 H 20 F3N3O3, chemical structure is shown in the following formula I:

[0003]

[0004] What is currently known is the aforementioned chemical components, whose functions and effects are concentrated on the treatment of inflammation or specific pathological conditions of internal organs, nerves, blood vessels, etc., such as neuropathic pain, mental disorders, vascular structure / function disorders, etc., and reference may be made to CN101084216A, CN101505797A, etc.

[0005] In addition to the above-mentioned conventional disease treatment uses, there are literature reports that sEH inhibitors can be used to penetrate the skin and reach blood vessels to treat microvascular structural / functional disorders caused by diabetic diseases, such as ulcers. Summary of the invention

[0006] Although the above-mentioned existing literature reports the treatment of specific inflammation or specific pathological conditions by sEH inhibitors, and also discloses a method of applying the ingredient through the skin, it is known from the literature that 50% DMSO is used as a solvent and penetrant for the sEH inhibitor to promote the sEH inhibitor to penetrate into the skin and subcutaneous tissue, thereby achieving the treatment of microvascular structural / functional pathological conditions, but DMSO itself is not a skin-friendly ingredient. High concentrations of DMSO itself may make the skin more sensitive, especially when the subject itself has sensitive skin. The use of DMSO as a solvent and penetrant will further increase the subject's skin sensitivity, leading to the occurrence of adverse effects. Therefore, in response to the experimental conclusions of the existing literature, the applicant applied it (TPPU) to the subject's skin and concluded that TPPU itself can improve skin sensitivity, especially for those with sensitive skin.

[0007] Therefore, the present application provides an application of TPPU in the preparation of a product for improving skin sensitivity and / or promoting skin soothing, or a method of using TPPU to improve skin sensitivity and / or promote skin soothing. The method or application can effectively improve skin sensitivity, for example, it can effectively prevent, alleviate or treat skin sensitivity or improve the sensitivity of sensitive skin. The prevention of skin sensitivity can effectively play a role in, for example, UV protection and sun protection, or prevent, alleviate or treat skin allergy symptoms such as skin redness, skin tissue pain, and microvascular dilation caused by sunburn, external dressings, etc. The relief or treatment of skin sensitivity can effectively relieve and improve the aforementioned skin allergy symptoms to reduce the patient's suffering.

[0008] The present application has found in the study that, compared with the aforementioned literature description, when TPPU acts on skin cells or tissues, it can effectively prevent and relieve skin allergy symptoms, improve allergic skin or promote skin soothing. TPPU is an sEH inhibitor. In existing studies, sEH is a soluble epoxide hydrolase, which can convert fatty acid epoxides produced by P450 enzymes into corresponding diols. sEH inhibitors can inhibit the aforementioned conversion process, thereby increasing the level of fatty acid epoxides and reducing the level of diols, such as the increase of ingredients such as 12,13-epoxyoctadecenoic acid. It is currently known that sEH inhibitors can effectively play an anti-inflammatory role in nerves, organs, blood vessels, etc. However, for the TPPU component as one of the sEH inhibitors, after it acts on the skin, it can effectively prevent or relieve skin allergy symptoms, such as skin redness, skin tissue pain, microvascular dilation, etc. The experimental confirmation on this point can refer to the subsequent embodiment section.

[0009] Skin sensitivity as described in this application includes but is not limited to redness, swelling, pain, itching, capillary dilation, etc. of the epidermis, dermis, and subcutaneous tissue. Skin sensitivity as described in this application does not refer to skin problems caused by disease lesions, such as microvascular structure / function disorders, ulcers, etc. Skin sensitivity as described in this application mainly refers to skin allergic symptoms caused by external factors, and the skin, skin cells, tissues, organs, etc. do not have substantial structural or functional lesions.

[0010] The products described in this application can be used for medical purposes, or for cosmetics or skin care products; the products described in this application can be external dressings or minimally invasive skin injections; external dressings can be directly applied to the skin surface, and minimally invasive skin injections can be injected subcutaneously with TPPU components by microneedles to achieve better therapeutic effects. The products described in this application are not limited to their specific preparation forms, and can be gels, solutions, suspensions, creams or patches, etc., and can be in any preparation form suitable for external dressings or minimally invasive skin injections.

[0011] The skin sensitivity described in this application may be caused by any of skin care products, cosmetics, topical drugs, and light. The skin allergy described in this application is related to personal constitution, mainly to sensitive skin. Its sensitivity is not a pathological change, but an allergic symptom caused by changes in skin homeostasis. The allergens described vary depending on the individual constitution, and the possible causes of personal allergies are also varied and are not limited to the aforementioned ones.

[0012] The nature of sensitive skin is different from skin allergies. It is generally believed that sensitive skin is a metastable state, with reduced tolerance and increased sensitivity to a variety of internal and external factors. The formation mechanism of sensitive skin is relatively complex, and the possible formation mechanisms include, for example, damaged skin barrier, increased vascular reactivity, immune and inflammatory reactions, etc.

[0013] Damage to the skin barrier mainly refers to the "brick wall" structure, which is composed of stratum corneum cells and lipids and natural moisturizing factors between cells, and the skin surface structure with sebum membrane attached to its surface is damaged, resulting in an imbalance of the microecology on the skin surface, resulting in the loss of water and nutrients, invasion of foreign bacteria, etc. Eventually, the skin epidermis becomes thinner, the resistance to the outside world is weakened, and it is more affected by external irritation. Such a vicious cycle is repeated, which can easily lead to sensitive skin and even cause skin inflammation.

[0014] In people with sensitive skin, TRPV-1 is overexpressed, and the more frequently it is expressed, the more severe the skin sensitivity. Dynamic optical coherence tomography measurements have found that people with sensitive skin have increased vascular reactivity. Compared with normal skin, sensitive skin has a higher vascular density and superficial microvessels are closer to the epidermis. More superficial blood vessels are more susceptible to external stimuli that cause vascular overreaction and the release of inflammatory mediators, and the vasodilation of sensitive skin is stronger than that of people with normal skin conditions.

[0015] In addition to causing increased vascular reactivity, TRPV-1 can also induce mast cell degranulation and cause neurogenic inflammation by promoting the secretion of endothelin. Under external stress, it can cause skin erythema and edema, making the skin sensitive.

[0016] The factors that trigger sensitive skin are usually diverse and can be divided into exogenous factors (living environment, daily behavior, physical or chemical stimulation) and endogenous factors (race, genetic inheritance, endocrine, etc.).

[0017] It is currently believed that the occurrence of sensitive skin is a complex process of skin barrier-neurovascular-immune inflammation. The clinical sensory characteristics of allergic skin usually include tingling, redness, itching, desquamation, etc.

[0018] In the products described in this application, the effective application amount of TPPU is not too limited, and can be preferably 0.001 g / cm 2~0.5g / cm 2 . It may also be preferably 0.01 g / cm 2 ~0.2g / cm 2 , or 0.05g / cm 2 ~0.1g / cm 2 .

[0019] In the present application, TPPU itself can prevent, alleviate or treat skin sensitivity, but it is also preferred that TPPU is mixed with a polar protic solvent for application / application to dissolve TPPU and better prepare it into a product. The polar protic solvent may preferably be one or more of ethylene glycol, propylene glycol, isopropanol, butanediol, hexanediol, and water. In particular, propylene glycol or isopropanol may be preferred.

[0020] After the TPPU is mixed with the polar protic solvent, the mass proportion of TPPU may be preferably 1% to 50%, further preferably 5% to 30%, and more preferably 5% to 10%. Polar protic solvents are different from other solvents, most of which contain trace amounts of H + Solvent, as distinguished from polar aprotic solvents such as DMSO.

[0021] In the present application, TPPU may be preferably used in combination with any one or more of a polar protic solvent, a permeation enhancer, and a patch; TPPU mixed with a polar protic solvent may promote its slight dissolution, and after adding a permeation enhancer, it may more effectively penetrate into the subcutaneous tissue through the skin to achieve a better therapeutic effect. The permeation enhancer may preferably be one or more of squalane, cetyl alcohol ester, and sodium hyaluronate. Squalane may be particularly preferred.

[0022] The mass ratio of the total mass of the TPPU and the polar protic solvent to the penetration enhancer may preferably be 1:(0.1-50), may further preferably be 1:(0.2-20), and may more preferably be 1:(0.5-10).

[0023] The mass ratio of the total mass of the TPPU and the polar protic solvent to the penetration enhancer and the patch may preferably be 1:(0.1-50):(0.1-50), may further preferably be 1:(0.2-20):(0.2-20), and may more preferably be 1:(0.5-10):(0.5-10).

[0024] To this end, the specific solutions provided by this application are as follows:

[0025] The application of TPPU or the use of TPPU is to prepare products for improving skin sensitivity and / or promoting skin soothing by using TPPU, and the use is to apply TPPU to improve skin sensitivity and / or promote skin soothing.

[0026] Optionally, the skin sensitivity includes any one or more of capillary dilation, skin stinging, redness, itching, desquamation, and dryness.

[0027] Optionally, the skin includes an epidermis, a dermis and / or subcutaneous microvessels and tissues.

[0028] Optionally, the product is an external application or a minimally invasive skin injection, or the method of use is external application or minimally invasive skin injection.

[0029] Optionally, the external application product includes any one of cosmetics, skin care products, and external application medicines.

[0030] Optionally, the improvement includes any one of prevention, alleviation or treatment.

[0031] Optionally, the application amount of TPPU is 0.01 mg / cm 2 ~0.5mg / cm 2 , preferably 0.05 mg / cm 2 ~0.3mg / cm 2 , more preferably 0.1 mg / cm 2 ~0.2mg / cm 2 .

[0032] Optionally, the product is any one of a gel, a solution, a suspension, a cream or a patch.

[0033] Optionally, the skin sensitivity originates from any one of skin care products, cosmetics, external application medicines, and light.

[0034] Optionally, TPPU is used / applied in combination with a polar protic solvent.

[0035] Optionally, TPPU is used / applied in combination with polar protic solvents and penetration enhancers.

[0036] Optionally, TPPU is applied / administered in combination with a polar protic solvent, a penetration enhancer, or an adhesive.

[0037] Optionally, the polar protic solvent is selected from one or more of water, ethylene glycol, propylene glycol, isopropanol, butylene glycol, and hexylene glycol.

[0038] Optionally, the mass proportion of the TPPU is 1% to 50%, preferably 5% to 30%, and more preferably 5% to 10%.

[0039] Optionally, the penetration enhancer is selected from one or more of squalane, cetyl alcohol esters, and sodium hyaluronate.

[0040] Optionally, the mass ratio of the total mass of the TPPU and the polar protic solvent to the penetration enhancer is 1:(0.1-50), preferably 1:(0.2-20), and more preferably 1:(0.5-10).

[0041] Optionally, the patch is selected from one or more of glycerin and vaseline.

[0042] Optionally, the mass ratio of the total mass of the TPPU and the polar protic solvent to the penetration enhancer and the patch is 1:(0.1-50):(0.1-50), preferably 1:(0.2-20):(0.2-20), and more preferably 1:(0.5-10):(0.5-10).

[0043] The present application also provides a product for improving skin sensitivity and / or promoting skin soothing, wherein the product comprises TPPU.

[0044] Optionally, the improving skin sensitivity and / or promoting skin soothing includes improving any one or more of capillary dilation, skin stinging, redness, itching, desquamation, and dryness.

[0045] Optionally, the skin includes an epidermis, a dermis and / or subcutaneous microvessels and tissues.

[0046] Optionally, the product is an external dressing or a minimally invasive skin injection.

[0047] Optionally, the external application product includes any one of cosmetics, skin care products, and external application medicines.

[0048] Optionally, the improvement includes any one of prevention, alleviation or treatment.

[0049] Optionally, the application amount of TPPU is 0.01 mg / cm 2 ~0.5mg / cm 2 , preferably 0.05 mg / cm 2 ~0.3mg / cm 2 , more preferably 0.1 mg / cm 2 ~0.2mg / cm 2 .

[0050] Optionally, the product is any one of a gel, a solution, a suspension, a cream or a patch.

[0051] Optionally, the skin sensitivity originates from any one of skin care products, cosmetics, external application medicines, and light.

[0052] Optionally, the preparation further comprises a polar protic solvent.

[0053] Optionally, the preparation further comprises a polar protic solvent and a penetration enhancer.

[0054] Optionally, the preparation further comprises a polar protic solvent, a penetration enhancer and an adhesive.

[0055] Optionally, the polar protic solvent is selected from one or more of water, ethylene glycol, propylene glycol, isopropanol, butylene glycol, and hexylene glycol.

[0056] Optionally, the mass proportion of the TPPU is 1% to 50%, preferably 5% to 30%, and more preferably 5% to 10%.

[0057] Optionally, the penetration enhancer is selected from one or more of squalane, cetyl alcohol esters, and sodium hyaluronate.

[0058] Optionally, the mass ratio of the total mass of the TPPU and the polar protic solvent to the penetration enhancer is 1:(0.1-50), preferably 1:(0.2-20), and more preferably 1:(0.5-10).

[0059] Optionally, the patch is selected from one or more of glycerin and vaseline.

[0060] Optionally, the mass ratio of the total mass of the TPPU and the polar protic solvent to the penetration enhancer and the patch is 1:(0.1-50):(0.1-50), preferably 1:(0.2-20):(0.2-20), and more preferably 1:(0.5-10):(0.5-10).

[0061] The present application also provides a use of any of the aforementioned products, including applying the product to improve skin sensitivity and / or promote skin soothing.

[0062] Optionally, the method of use is external application or minimally invasive skin injection. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 This is a diagram of the mechanism of action of TPPU on the skin;

[0064] Figure 2 to Figure 12 This is a comparison of photos of the patient's skin before and after using this product in the clinical trial. DETAILED DESCRIPTION

[0065] To make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be described in detail below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other implementation methods obtained by ordinary technicians in this field without creative work belong to the scope of protection of the present invention.

[0066] The above technical solution is described in detail below in conjunction with specific embodiments.

[0067] The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, etc. used in the following examples are all commercially available unless otherwise specified.

[0068] In order to prove that TPPU has the effect of improving skin allergies, the following several implementation methods are now described.

[0069] Mechanism of action

[0070] TPPU was invented and synthesized by Professor Bruce Hammock, a partner of the applicant's company and a member of the American Academy of Sciences. Professor Bruce Hammock and his team of researchers have been committed to studying its in vivo efficacy, mechanism of action, metabolic kinetics, and other in-depth and detailed systematic studies using a variety of model animals such as mice, rats, and crab-eating macaques for more than 10 years. It has been clearly shown that TPPU is a soluble epoxide hydrolase inhibitor that can inhibit the activity of soluble epoxide hydrolases (ref3). Its mechanism of action is as follows: Epoxyeicosatrienoic acid (EET) and related epoxy fatty acids (EpFA) are endogenous anti-inflammatory compounds in organisms, but they can be converted into dihydroxyeicosatrienoic acid (DHETs) with weaker biological effects by soluble epoxide hydrolases. Therefore, by inhibiting the activity of soluble epoxide hydrolases, the level of EETs can be significantly increased, thereby reducing the levels of various related inflammatory factors (IL-12, INF-γ, Tbet, IL17, IL23) in the body, thereby inhibiting the level of inflammation in the body.

[0071] In the research literature published by Professor Bruce Hammock, it is clearly shown that the levels of inflammatory cytokines such as IL-12, INF-γ, Tbet, IL17, IL23 in the inflammatory model mice (inflammatory group) have been greatly increased compared with the negative control group (normal saline group). After being treated with the new structure compound small molecule (inflammatory model mice new structure compound treatment group), the levels of the above inflammatory cytokines have been significantly reduced, reflecting the ability to effectively inhibit the expression of inflammatory cytokines ( Figure 1). (IL23, IL-17, IL-12 and INF-γ are all strong inflammatory factors in the body. Overexpression in the body can cause many different inflammatory responses.) Therefore, TPPU can inhibit the over-activation and over-release of multiple inflammatory factors in skin cells by broadly inhibiting the in vivo expression levels of inflammatory cytokines in the Th1 and Th17 spectrums, and reduce the level of inflammatory factors, thereby relieving vasodilation, redness and swelling, etc. The research results prove that it has great application prospects and market value as a new cosmetic raw material in the field of skin soothing in cosmetics (improving skin irritation, itching, redness and swelling, etc.).

[0072] Figure 1 The following is a schematic diagram of its mechanism of action. IL-23, IL-17, IL-12 and INF-γ are all strong inflammatory factors in the body. The aggregation of these inflammatory factors can cause vasodilation and redness, which is one of the main indicators of skin inflammation. If they are overexpressed in the body, they will cause many different inflammatory responses and autoimmune diseases. The experimental results in the figure below show that the levels of inflammatory cytokines such as IL-12, INF-γ, Tbet, IL-17, IL-23 in the inflammatory model mice (inflammatory group) have been greatly improved compared with the negative control group (normal saline group). After TPPU treatment, the levels of the above inflammatory cytokines have been significantly reduced, reflecting the efficient ability to inhibit the expression of inflammatory cytokines.

[0073] In the present application, it was found that in the skin environment, sEH is a key epoxide hydrolase in the human body, and its level is not good if it is too high or too low. Existing conventional sEH inhibitors can inhibit inflammatory factors, but they also inhibit sEH, and are more sensitive, causing sEH activity to be at a lower state, which is not conducive to the homeostasis of the skin environment. TPPU applied to the skin can promote sEH in skin tissue and microvessels to be at an appropriate level (low in non-pathological state). The main model used in the prior art is the double knockout mouse model, and the sensitivity (IC 50 =27pM) is 150 times that of TPPU (IC 50 =3.7nM), resulting in too low sEH levels in the measured results (low in pathological conditions, or even no expression at all). Therefore, the TPPU used in this application is more suitable for direct application to the skin, and can effectively improve skin sensitivity and / or promote skin soothing. Figure 1 It can be seen that TPPU can reduce inflammatory cytokines, but it does not adjust them to an excessively low state.

[0074] Example Description

[0075] For the TPPU component, it is made into products with the following composition ratios to facilitate subsequent experimental tests. For specific composition ratios, please refer to the table below. The composition ratios in the table are in parts by weight; for example, Example 1 is 0.01 parts by weight of TPPU and 0.99 parts by weight of ethylene glycol, without other components or containing trace impurities, etc.; when used, it can be adapted according to the sensitive area of ​​the skin to be applied, usually the dosage of conventional external dressings or minimally invasive skin injections, such as (0.01mg~0.5mg) / cm 2 .

[0076] The specific composition ratio is as follows:

[0077] Table 1

[0078]

[0079]

[0080]

[0081] According to the above-mentioned composition ratio in Table 1 and referring to the conventional preparation method of external dressings, the preparations of the embodiments in Table 1 were prepared for subsequent experiments. The preparation method of the above-mentioned embodiments can refer to the conventional preparation method of existing external dressings, and the TPPU can also be prepared according to the existing conventional preparation method.

[0082] 1. Animal Experiment (Phototoxicity Experiment-Sunscreen)

[0083] 1. Skin safety evaluation of TPPU:

[0084] Experimental animals: Select a number of adult, healthy, normal-grade albino guinea pigs with no skin damage. Female guinea pigs are not pregnant and have never given birth. Initial weight range: 298-339g. Provided by Jiashan County Golden Rabbit Industry Professional Cooperative (production).

[0085] Relevant toxicology tests were carried out in accordance with the "Technical Specifications for Safety of Cosmetics" (2015 edition). The specific operations are as follows:

[0086] (a) 24 hours before the test, the skin on both sides of the spine of the guinea pig's back was shaved with a razor close to the skin, and care was taken to avoid damaging the animal's skin. According to the method of "7 Skin Phototoxicity Test" in "Chapter 6 Toxicological Test Methods" of "Technical Specifications for Safety of Cosmetics" (2015 Edition), the guinea pig's hair removal area was divided into a, b, c, d, e, f, g, and h hair removal areas, each area was 2cm×2cm.

[0087] (b) Fix the animal, wet the hair removal areas a and b with distilled water, and then evenly apply 0.2 g of the test substance (Examples 1 to 60), wet the hair removal areas c and d with distilled water, and then evenly apply the control (the auxiliary agent used in Examples 1 to 60, i.e., the components other than TPPU, the control), and set up a separate hair removal area without any component (blank). After 30 minutes of application, irradiate with light. Cover the hair removal areas a, c, and blank with aluminum foil and fix with tape, and irradiate the hair removal areas b, d, and blank with UVA365nm, with an irradiation dose of 10J / cm 2 .

[0088] (c) After the irradiation, remove the residual test substance with warm water. Observe the skin reaction at 1h, 24h, 48h and 72h, and determine the skin reaction score of each animal according to the "Skin Irritation Reaction Score" in "7 Skin Phototoxicity Test" of "Chapter 6 Toxicology Test Methods" of "Technical Specifications for Safety of Cosmetics" (2015 Edition).

[0089] Result evaluation: No skin reaction was recorded as 0, skin reaction was recorded as 1, and the test substance was judged to be phototoxic. The above experiment was used to evaluate the preventive effect of TPPU on ultraviolet light allergy.

[0090] The experimental results are shown in Table 2, from which it can be seen that the phototoxicity test result of the test substance TPPU on guinea pig skin is: no skin phototoxicity is observed.

[0091] Table 2-TPPU skin reaction scores on guinea pigs

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102] 2. Safety and Toxicity Experiments

[0103] For the TPPU ingredient, relevant toxicology tests were carried out in accordance with the "Technical Specifications for Safety of Cosmetics" (2015 edition). The toxicological characteristics of the raw materials are as follows:

[0104] 1. Materials and methods

[0105] 1. Test article:

[0106] 1.1 Physical state: Off-white to white solid.

[0107] 1.2 Preparation method: Since the sample is insoluble in water, vegetable oil is used as the solvent. 5g of sample is added to 20mL of vegetable oil and the mixture is thoroughly mixed to prepare the test solution for tube feeding.

[0108] 2. Experimental animals and breeding environment:

[0109] 2.1 Experimental animals: SD rats, SPF grade, 10 rats, half male and half female, male weight (180-194) g, female weight (180-192) g. Provided by Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd., production license number: SCXK (Zhe) 2024-0001.

[0110] 2.2 Reasons for animal selection: The Technical Specifications for Safety of Cosmetics (2015 edition) stipulates that rats are one of the preferred animals for acute oral toxicity tests.

[0111] 2.3 Feeding environment: The experimental animals were kept in plastic feeding boxes (L466×W314×H200 mm) in a barrier environment, and the cages were changed twice a week. Environmental conditions: temperature: (20-22)℃, relative humidity: (52-60)%, 12-hour alternating lighting, experimental animal use license number: SYXK(Shanghai)2023-0046.

[0112] 2.4 Feed and drinking water: Animal feed was provided by Shanghai Zhouyu Biotechnology Co., Ltd., registration number: Shanghai Feed Certificate (2021) 04027. Animal drinking water complies with the requirements of the national GB5749 "Sanitary Standards for Drinking Water", and animals were free to eat and drink during the entire test period.

[0113] 3. Equipment: Electronic scale Model: ACS-3A 90401582

[0114] Electronic balance model: BS310S 91006909

[0115] 4 Test methods:

[0116] 4.1 Preliminary test: Select 2 male and 2 female SPF SD rats, and orally gavage the animals with 5000 mg / kg of the drug, with a gavage volume of 1 mL / 100 g body weight, twice within 24 hours, with an interval of 6 hours. Observe and record the signs of poisoning and death of the test animals. The formal test dose is determined based on the death of rats within 48 hours.

[0117] 4.2 Formal test: According to the results of the preliminary test, no obvious signs of poisoning or death were observed in the rats after oral administration within 48 hours. Therefore, according to the results of the preliminary test, the test substance was tested at a dose of 5000 mg / kg body weight, that is, 6 rats (half male and half female) were orally administered with this dose, and the oral administration volume was 1 mL / 100 g body weight, and the oral administration was divided into 2 times within 24 hours, with an interval of 6 hours.

[0118] 5Clinical observation and examination

[0119] 5.1 Observe once at 0.5 hours, 1 hour, 2 hours, and 4 hours after exposure, and observe regularly every day for the next 14 days, and record the individual conditions of each animal in detail, including clinical status, toxic signs, and deaths. Weigh the animals once before dosing and once a week after exposure. Weigh the animals again at the end of the experiment.

[0120] 5.2 At the end of the experiment, all animals were anesthetized and autopsied to observe gross pathological changes with the naked eye and record all lesions seen with the naked eye. If necessary, pathological histological analysis was performed; if no obvious abnormalities were found in the gross autopsy, pathological histological examination was not necessary.

[0121] 6. Data processing:

[0122] Determine the LD50 value based on the number of animal deaths.

[0123] (ii) Results:

[0124] 1After exposure, all animals showed no other obvious symptoms of poisoning and no death, see the table below for details.

[0125]

[0126] 2 Gross anatomy:

[0127] At the end of the experiment, all experimental animals were subjected to gross anatomical examination, and no organs with gross pathological changes were found, so no pathological histological examination was performed.

[0128] (III) Conclusion:

[0129] Under the conditions of this experiment, the test substance 1-(1-propyl-4-piperidinyl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU) has an acute oral median lethal dose (LD50) of greater than 5000 mg / kg body weight for male and female rats, which is practically non-toxic.

[0130] 3. Skin Clinical Trials

[0131] Recruit a number of skin-sensitive patients, for example, skin-sensitive patients who suffer from dry skin, scaling, redness, swelling, stinging, etc. caused by allergies due to the application of external dressings; use human efficacy experiments (arm skin wheal pixel area, forearm skin hemoglobin content, lactic acid stinging, itching score) to evaluate the soothing effect of the following formula examples.

[0132] The results are shown in the following table. The "reduction in pixel area of ​​arm skin wheals" refers to: compared with "not using a soothing skin care composition", the percentage of pixel area of ​​arm skin wheals reduced after the subjects used the product for 1 hour. Similarly, "forearm skin hemoglobin content" refers to: compared with "not using a soothing skin care composition", the percentage of pixel area of ​​inner forearm skin wheals reduced after the subjects used the product for 5 minutes. The reduction in lactic acid stinging and itching scores refers to: compared with "not using a soothing skin care composition", the percentage of lactic acid stinging and itching scores reduced after the subjects used the product for 5 minutes. Attached Figures 2 to 12 The following are comparative photos of the patient's skin before and after applying the following embodiments of Table 3 and Table 7, wherein the drawings are arranged in order: Figure 2 The comparison photos of the skin before and after use of the user formula example in Table 3 are (TPPU+propylene glycol): squalane=1:2; Figure 3 The comparison photos of the skin before and after use of the user formula example in Table 3 are (TPPU+propylene glycol): squalane=1:5; Figure 4 The comparison photos of the skin before and after use of the user formula example in Table 3 are (TPPU+propylene glycol): squalane=1:10; Figure 5 The comparison photos of the skin before and after use of the user formula example of TPPU + propylene glycol in Table 3; Figure 6 The following are comparison photos of the skin before and after using the water as the user's formula example in Table 3; Figure 7 The comparison photos of the skin before and after use of the user formula example in Table 7 are TPPU + propylene glycol: isopropyl alcohol = 1:5; Figure 8 The comparison photos before and after use of the skin of the user formula example in Table 7 are TPPU + propylene glycol: cetyl alcohol ester = 1:5; Fig. 9 The comparison photos of the skin before and after use of the user formula example in Table 7 are TPPU + propylene glycol: butylene glycol = 1:5; Fig.10The comparison photos of the skin before and after use of the user formula example in Table 7 are TPPU+propylene glycol:squalane=1:5; Fig.11 The comparison photos of the skin before and after use of the user formula example in Table 7 are TPPU+propylene glycol: squalane: vaseline = 1:5:5; Fig.12 The following are comparison photos of the skin before and after use of the user formula example in Table 7, which is TPPU+propylene glycol:synthetic squalane=1:5.

[0133] Table 3

[0134]

[0135] Table 4

[0136]

[0137] Table 5

[0138]

[0139]

[0140] Table 6

[0141]

[0142] Table 7

[0143]

[0144] Table 8

[0145]

[0146]

[0147] Table 9

[0148]

[0149] Table 10

[0150]

[0151]

[0152] It can be seen from the above table that for skin allergic symptoms caused by sensitive skin, after external application or subcutaneous minimally invasive injection of the TPPU product of this application, the allergic symptoms (dry skin, desquamation, redness, swelling, itching, etc.) are alleviated and can even be cured.

[0153] The embodiments of the present application can be prepared into various preparation forms according to the actual drug administration method, such as ointments, suspensions, patches, etc.

[0154] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. Application of TPPU or use of TPPU, wherein the application is to prepare products for improving skin sensitivity and / or promoting skin soothing by using TPPU, and the use is to apply TPPU to improve skin sensitivity and / or promote skin soothing.

2. The application / use according to claim 1, characterized in that: The improving skin sensitivity and / or promoting skin soothing includes improving any one or more of capillary dilation, skin stinging, redness, itching, desquamation and dryness.

3. The application / use according to claim 1, characterized in that: The skin includes the epidermis, dermis and / or subcutaneous microvessels and tissues.

4. The application / use according to claim 1, characterized in that: The product is an external application product or a minimally invasive skin injection product, or the method of use is external application or minimally invasive skin injection.

5. The application / use according to claim 1, characterized in that: The external application product includes any one of cosmetics, skin care products, and external application medicines.

6. The application / use according to claim 1, characterized in that: The improvement includes any one of prevention, alleviation or treatment.

7. The application / use according to claim 1, characterized in that: The application amount of TPPU is 0.01 mg / cm 2 ~0.5mg / cm 2 , preferably 0.05 mg / cm 2 ~0.3mg / cm 2 , more preferably 0.1 mg / cm 2 ~0.2mg / cm 2 .

8. The application / use according to claim 1, characterized in that: The product is any one of a gel, a solution, a suspension, a cream or a patch.

9. The application / use according to claim 1, characterized in that: The skin sensitivity is caused by any one of skin care products, cosmetics, external application medicines, and light.

10. The application / use according to claim 1, characterized in that: TPPU is used / applied in combination with a polar protic solvent.

11. The application / use according to claim 1, characterized in that: TPPU is used in combination with polar protic solvents and penetration enhancers.

12. The application / use according to claim 1, characterized in that: TPPU is applied / administered in combination with polar protic solvents, penetration enhancers, and adhesives.

13. The use according to any one of claims 10, 11 or 12, characterized in that: The polar protic solvent is selected from one or more of water, ethylene glycol, propylene glycol, isopropanol, butylene glycol, and hexylene glycol.

14. The application / use according to claim 10, characterized in that: The mass proportion of the TPPU is 1% to 50%, preferably 5% to 30%, and more preferably 5% to 10%.

15. The application / use according to any one of claims 11 or 12, characterized in that: The penetration enhancer is selected from one or more of squalane, cetyl alcohol esters, and sodium hyaluronate.

16. The application / use according to claim 11, characterized in that: The mass ratio of the total mass of the TPPU and the polar protic solvent to the penetration enhancer is 1:(0.1-50), preferably 1: (0.2~20), more preferably 1:(0.5~10).

17. The application / use according to claim 12, characterized in that: The patch is selected from one or more of glycerin and vaseline.

18. The application / use according to claim 12, characterized in that: The mass ratio of the total mass of the TPPU and the polar protic solvent to the penetration enhancer and the patch is 1:(0.1-50): (0.1~50), preferably 1:(0.2~20):(0.2~20), more preferably 1:(0.5~10):(0.5~10).

19. A product for improving skin sensitivity and / or promoting skin soothing, characterized in that: The article comprises TPPU.

20. The article according to claim 19, characterized in that The improving skin sensitivity and / or promoting skin soothing includes improving any one or more of capillary dilation, skin stinging, redness, itching, desquamation and dryness.

21. The article according to claim 19, characterized in that The skin includes the epidermis, dermis and / or subcutaneous microvessels and tissues.

22. The article according to claim 19, characterized in that The product is an external dressing or a minimally invasive skin injection.

23. The article according to claim 22, characterized in that The external application product includes any one of cosmetics, skin care products, and external application medicines.

24. The article of claim 19, wherein: The improvement includes any one of prevention, alleviation or treatment.

25. The article of claim 19, wherein: The application amount of TPPU is 0.01 mg / cm 2 ~0.5mg / cm 2 , preferably 0.05 mg / cm 2 ~0.3mg / cm 2 , more preferably 0.1 mg / cm 2 ~0.2mg / cm 2 .

26. The article of claim 19, wherein: The product is any one of a gel, a solution, a suspension, a cream or a patch.

27. The article of claim 19, wherein: The skin sensitivity is caused by any one of skin care products, cosmetics, external application medicines, and light.

28. The article according to claim 19, characterized in that The preparation also includes a polar protic solvent.

29. The article according to claim 19, characterized in that The preparation also includes a polar protic solvent and a penetration enhancer.

30. The article of claim 19, wherein: The preparation further comprises a polar protic solvent, a penetration enhancer and an adhesive.

31. The product according to any one of claims 28, 29 or 30, characterized in that The polar protic solvent is selected from one or more of water, ethylene glycol, propylene glycol, isopropanol, butylene glycol, and hexylene glycol.

32. The article of claim 28, wherein: The mass proportion of the TPPU is 1% to 50%, preferably 5% to 30%, and more preferably 5% to 10%.

33. The product according to any one of claims 29 and 30, characterized in that The penetration enhancer is selected from one or more of squalane, cetyl alcohol esters, and sodium hyaluronate.

34. The article of manufacture according to claim 29, wherein: The mass ratio of the total mass of the TPPU and the polar protic solvent to the penetration enhancer is 1:(0.1-50), preferably 1:(0.2-20), and more preferably 1:(0.5-10).

35. The article of manufacture according to claim 30, wherein: The patch is selected from one or more of glycerin and vaseline.

36. The article of claim 30, wherein: The mass ratio of the total mass of the TPPU and the polar protic solvent to the penetration enhancer and the patch is 1:(0.1-50):(0.1-50), preferably 1:(0.2-20):(0.2-20), and more preferably 1:(0.5-10):(0.5-10).

37. Use of the preparation according to claim 19, comprising applying the preparation for improving skin sensitivity and / or promoting skin soothing.

38. Use of the product according to claim 37, characterized in that The method of use is external application or minimally invasive skin injection.

Images