A transdermal emulsion for treating dry eye

Abstract

The present invention relates to a transdermal emulsion for treating dry eye, which comprises low-concentration menthol as the only active ingredient, an oil phase matrix, an emulsifier and an aqueous phase; the mass concentration of menthol in the emulsion composition is 1.5%-7%, and the mass of the oil phase matrix in the emulsion composition does not exceed 30%. The mass concentration of menthol in the emulsion of the present invention is 1.5%-7%, and the content of the oil phase matrix does not exceed 30%. It can effectively promote the tear secretion of dry eye patients to treat dry eye while avoiding skin irritation and greasy feeling, improve the patient's use experience, maintain the efficacy of long-term use, and is more friendly to users with oily skin, avoiding the strong greasy feeling and acne or local dermatitis caused by applying oily liquid preparations to the skin around the eyes or the nose (the area around the nose is a grease-rich area).

Description

Technical Field

[0001] The invention relates to the technical field of drugs for preventing and treating dry eyes, and in particular to a transdermal emulsion for treating dry eyes. Background Art

[0002] The pathogenesis of dry eye is very complex and has not been fully understood. Therefore, there is no good treatment for dry eye so far. The causes of dry eye are diverse. Environmental factors, eye inflammation, systemic diseases, electronic equipment and air conditioning facilities can all cause dry eye. Dry eye can cause a lot of eye discomfort, such as dry eyes and itching. In some patients, severe dry eye may even lead to a certain degree of damage to the corneal epithelium, a large amount of eye secretions, conjunctival congestion, and even serious eye lesions, which will seriously affect vision in the long run. Tears contain a variety of lysozymes, mucopolysaccharides, immune proteins and other ingredients, which can prevent eye infections, moisturize and lubricate the ocular surface, and play an important protective and nutritional role for the eyes. The main symptom of dry eye is a significant decrease in tear secretion, which causes eye discomfort. Therefore, the treatment of dry eyes should start with protecting tears and promoting tear secretion.

[0003] At present, there are many eye drops on the market for the treatment of dry eye, such as sodium hyaluronate eye drops, cyclosporine A eye drops, etc. However, due to the complex etiology of dry eye, its mechanism is not yet fully understood. Although the eye drops for the treatment of dry eye that are available on the market can make patients feel comfortable for a short period of time after administration and reduce symptoms such as eye pain, the effect of relieving dry eye symptoms often lasts for a short time, and patients need to use eye drops repeatedly. Long-term and repeated use of eye drops will cause complications such as corneal toxicity and drug-induced dry eye, which will further aggravate the dry eye symptoms of patients, thus forming a vicious circle (Malik Kahoo, Cullen T. Vogelson, Usha Sivaprasad, David A. Ammar. Comparison of the toxic effects of different artificial tears on human corneal and conjunctival epithelial cells cultured in vitro [J]. Chinese Journal of Ophthalmology, 2012, 48(2): 170-172.). In addition, long-term use of artificial tears and other eye drops will affect the function of the eye itself, making the eye dependent on eye drops and reducing tear secretion. The tear secretion function of the lacrimal gland will gradually degenerate, thus forming another vicious cycle (Lv Bin. Be careful of "dry eyes" when using eye drops [J]. Family Science·New Health, 2010(5):27.).

[0004] The drug OC-01 (varenicline, CAS: 249296-44-4) nasal spray involved in invention patent application CN202010304809 can also treat dry eyes. The drug has been launched abroad and is currently undergoing clinical trials in China. The drug is administered through the nasal cavity to stimulate the trigeminal nerve and stimulate tear secretion. However, the drug has a strong nasal irritation. According to statistics, it will cause 82% of patients to sneeze, and 5-16% of patients will experience adverse reactions such as nasal irritation, cough, sore throat, etc. (the data comes from the drug instructions for the drug listed in the United States. The drug's trade name is Tyrvaya).

[0005] There are also literature reports that oral bromhexine, pilocarpine hydrochloride, neostigmine and other drugs can promote the secretion of tears in some patients, but the actual efficacy is still uncertain. In addition, patients with dry eye need to take medication for a long time, and the defect of oral medication is that the toxic side effects cannot be ignored. For example, the oral drug pilocarpine, its drug instructions clearly state: it may cause nausea, vomiting, abdominal pain, diarrhea, salivation, pupil constriction, heartbeat first fast and then slow, microtracheal spasm and excessive mucus secretion, etc., which can lead to breathing difficulties. Taking this product can cause visual discomfort and reduce the safety of night driving. If the patient sweats continuously while taking this product and cannot replenish enough drinks, he must go to the hospital for examination and treatment to prevent collapse. This is also the main reason why oral drugs are rarely used in the clinical treatment of dry eye.

[0006] Menthol, also known as menthol, hexahydrothymol, hexahydrothymol, and 5-methyl-2-isopropyl cyclohexanol, is the main component of mint and peppermint essential oils. In nature, menthol mainly exists in the essential oils of mint plants in the form of L. Modern medicine has proved that mint has an excitatory effect, can dilate the skin capillaries, evacuate wind and heat, and can be used to treat colds and wind and heat; it has a beneficial effect on the throat, can be used to treat wind-heat sore throat and cough; it also has a permeating effect, which can help measles to permeate. Mint also has certain analgesic and itchy, bactericidal and insecticidal effects. Rubbing fresh mint leaves and sticking them on the temples can treat vasodilatory headaches. In addition, mint can also treat rhinitis, resist sepsis, treat skin diseases, etc., and is widely used as a flavor in toothpaste, chewing gum, wine, beverages, and cosmetics.

[0007] US patent application US202117511238A (invention name: Treatment for Dry Eyes) discloses a balm mixture containing Menthoxypropanediol, Menthonediol, Menthol and Caffeine, which is applied to the skin around the eyes for the treatment of dry eyes. However, the active ingredient mixture disclosed in the invention patent has a complex composition, with a concentration of Menthoxypropanediol of 30-40%, a concentration of Menthonediol of 30-40%, a concentration of Menthol of 30-40%, and a concentration of Caffeine of 0.01-0.25%. The overall content of menthol and related mint ingredients in the drug prescription of the invention is as high as 20-60%. When applied to the skin adjacent to the lower eyelid, it is very easy to cause strong skin irritation due to excessive concentration, including redness, swelling, burning sensation, itching and other discomforts of the skin at the application site. Since the skin around the eyes is thinner than the skin in other parts, and the stratum corneum is also relatively thin, the skin around the eyes is sensitive and fragile, and menthol and its analogs are highly irritating to the skin, and the higher the concentration, the greater the irritation. In addition, the composition is a solid waxy substance. When applied to the skin, the active ingredients such as menthol are blocked by the waxy substance and cannot be quickly absorbed through the skin. On the contrary, due to the high concentration of menthol and its analogs staying near the eyelids for a long time and the strong volatility of menthol, the volatile substances irritate the eyes, causing extreme discomfort to the patient's eyes, and the user experience is poor; most importantly, despite the use of menthol and its analogs at a concentration of up to 20-60%, its effect of promoting tear secretion is not ideal. Therefore, the efficacy of the composition disclosed in the patent application is very low, and the strong irritation and other side effects will also lead to low patient compliance.

[0008] Previously, the applicant has submitted a patent application to the National Patent Office for a transdermal composition for treating dry eye prepared with low-concentration menthol as the only active ingredient (application number 202311621663.0). The pharmaceutical composition is mainly an oily liquid preparation dispersed in vegetable oil, which can be sprayed or applied. The oil content in the composition is as high as 90-97%. Experiments have shown that the composition can effectively promote the secretion of tears in patients with dry eye, treat dry eye without causing skin irritation, but in the further trial process, patients reported that the composition had a poor experience. The specific reason is that dry eye is a chronic disease and requires long-term medication. The liquid preparation with high oil content has a strong greasy feeling. After repeated medication, the patient's skin experience is not good, especially for oily skin. After repeated application, not only the greasy feeling of the face and the oil secreted by the human body around the nose are aggravated, and the mixture is easy to cause acne and local skin inflammation, but also the medication site has been covered with oil before, and the oil molecules clog the pores. The efficacy will decrease if it is used continuously and repeatedly. In order to improve the user experience and long-term efficacy, improvement plans need to be proposed.

[0009] The inventors have found that preparing menthol into an emulsion can well solve the problems of the above-mentioned oily liquid preparations. Moreover, a lower concentration of menthol in the emulsion can achieve the desired effect of promoting tear secretion. Summary of the invention

[0010] 1. Technical issues to be resolved

[0011] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a transdermal emulsion for treating dry eye, wherein the mass concentration of menthol in the emulsion is 1.5%-7%, and the content of the oil phase matrix does not exceed 30%. The emulsion can effectively promote the tear secretion of dry eye patients themselves to treat dry eye while avoiding skin irritation and greasiness, thereby improving the patient's use experience and maintaining the therapeutic effect of long-term use, and is especially more friendly to users with oily skin.

[0012] (II) Technical solution

[0013] The present invention includes the following technical solutions:

[0014] In a first aspect, the present invention provides a transdermal emulsion for treating dry eye, comprising low-concentration menthol as the only active ingredient, an oil phase matrix, an emulsifier and an aqueous phase; the mass concentration of menthol in the emulsion is 1.5%-7%, and the mass concentration of the oil phase matrix in the emulsion does not exceed 30%; preferably, the mass concentration of menthol in the emulsion is 2%-6%, more preferably 3%-5%.

[0015] When the oil phase matrix accounts for no more than 30% of the mass of the emulsion, the greasy feeling when applied to the face can be greatly reduced, and while treating dry eyes, skin irritation and greasiness can be avoided, thereby improving the patient experience and being more friendly to users with oily skin. Due to the low oil content, it will not leave a thick layer of oil on the last application area after application, which helps to maintain the therapeutic effect of long-term use. It is suitable for patients to apply frequently for a long time to effectively promote the tear secretion of dry eye patients themselves.

[0016] According to a preferred embodiment of the present invention, the menthol is natural menthol or synthetic menthol.

[0017] According to a preferred embodiment of the present invention, the oil phase matrix is ​​selected from one or more of tea oil, olive oil, soybean oil, coconut oil, sunflower seed oil, corn oil, avocado oil, shea butter, grape seed oil, almond oil, castor oil, jojoba oil, lanolin, beeswax, medium chain triglycerides, isopropyl palmitate, safflower oil, stearyl alcohol, stearic acid, cetyl alcohol, cholesterol, silicone oil, dimethicone, liquid paraffin, and light liquid paraffin.

[0018] According to a preferred embodiment of the present invention, the emulsifier is at least one selected from lecithin, polyoxyethylene (35) castor oil, polyoxyethylene (40) castor oil, polyoxyethylene (40) hydrogenated castor oil, Tween 80, Span 80, poloxamer 188, poloxamer 407, sodium stearate, potassium stearate, sodium lauryl sulfate, sodium hexadecyl sulfate, cetyl alcohol, polyoxyethylene 40 stearate, polyoxyethylene lauryl ether, and sucrose fatty acid ester.

[0019] According to a preferred embodiment of the present invention, the emulsion is composed of 1.5%-7% menthol, 3%-25% oil phase matrix, 0.05%-3% emulsifier and the balance of water phase. Preferably, the mass concentration of menthol is 2%-6%, more preferably 3%-5%. Among them, the oil phase matrix is ​​preferably 5-20%, more preferably 5-15%. The lower the content of the oil phase matrix, the clearer and thinner the emulsion is, and the more refreshing and comfortable it will be after being applied to the facial skin (skin around the eyelids or skin on both sides of the nose and nasolabial groove).

[0020] Preferably, the emulsion preparation method is as follows: dissolving menthol in an oil phase matrix to obtain an oil phase; if the emulsifier is a water-soluble emulsifier, dissolving the water-soluble emulsifier in water; if the emulsifier is an oil-soluble emulsifier, dissolving the oil-soluble emulsifier in an oil phase matrix; after mixing the water phase and the oil phase, quickly stirring or homogenizing with a homogenizer or shearing with a shearing machine to obtain the emulsion.

[0021] According to a preferred embodiment of the present invention, the aqueous phase is water, or an aqueous solution containing a water-soluble auxiliary agent, wherein the water-soluble auxiliary agent is, for example, at least one of a water-soluble flavor, a preservative (such as propylparaben), and a stabilizer (such as disodium EDTA).

[0022] In a second aspect, the present invention relates to the use of the above emulsion in the preparation of a drug for treating dry eye.

[0023] Preferably, the application includes: applying the emulsion to the skin around the eyes or the skin of the nose wings and nasolabial folds on both sides. The skin around the eyes includes the skin of the upper eyelid and the skin of the lower eyelid. More preferably, the emulsion is applied to the skin of the lower eyelid and the skin of the nose wings and nasolabial folds on both sides.

[0024] The inventors found in their research that only applying low-concentration menthol to the skin around the eyes (skin at the upper eyelid and skin at the lower eyelid), or to the skin at the nose wings and nasolabial grooves on both sides, can significantly promote the secretion of tears in patients with dry eye syndrome, effectively treat dry eye syndrome, and is non-irritating to the skin, with great potential for clinical application. Furthermore, the inventors found that the low-concentration menthol is prepared into an emulsion with pharmaceutically acceptable excipients, and compared with oily liquid preparations, the emulsion is more conducive to the transdermal absorption of menthol, thereby improving the therapeutic effect and onset speed of low-concentration menthol in treating dry eye syndrome. Subsequent studies of the present invention further found that the emulsion containing the low-concentration menthol is more conducive to the transdermal absorption of menthol, further improving the efficacy of low-concentration menthol in treating dry eye (the menthol concentration required for the same therapeutic effect is lower than that of the oily liquid preparation), solving the problem that the efficacy of the oily liquid preparation decreases after repeated use because the skin at the medication site is already covered with a large amount of oil layer, and the problem of greasy skin caused by repeated use is effectively solved, thereby improving the user experience, and being more friendly to patients with oily skin.

[0025] (III) Beneficial effects

[0026] The present invention provides a transdermal emulsion with low-concentration menthol as the only active ingredient. The composition can effectively promote the secretion of the patient's own tears and has a significant effect on relieving the dry eye symptoms of patients with dry eye. Since the menthol content is very low, it does not irritate the facial skin and will not cause the problem of being difficult to open the eyes due to smoke.

[0027] The mass concentration of menthol in the emulsion of the present invention is 1.5%-7%, and the content of the oil phase matrix does not exceed 30%. It can effectively promote the tear secretion of patients with dry eye to treat dry eye while avoiding skin irritation and greasy feeling, improving the patient's use experience, maintaining the efficacy of long-term use, and is more friendly to users with oily skin, avoiding the strong greasy feeling and acne or local dermatitis caused by applying the oily liquid preparation around the nose wing (the area around the nose wing is a sebum-rich area).

[0028] In addition, compared with oily liquid preparations with the same therapeutic effect, the required menthol concentration in the emulsion of the present invention is lower, which solves the problem that after the oily liquid preparation is used repeatedly, the medication site is already covered with an oil layer, and the efficacy decreases after continuous and repeated use, and the user experience is better. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 These are photos of skin irritation of experimental drug group 2 in the experiment of Example 2.

[0030] Figure 2 These are photos of skin irritation of 5 groups of experimental drugs in the experiment of Example 2.

[0031] Figure 3 These are photos of skin irritation of 8 groups of experimental drugs in the experiment of Example 2.

[0032] Figure 4 These are photos of skin irritation of three groups of oil-soluble control drugs in the experiment of Example 2.

[0033] Figure 5 These are photos of skin irritation of 7 groups of oil-soluble control drugs in the experiment of Example 2.

[0034] Figure 6 These are photos of skin irritation of 8 groups of oil-soluble control drugs in the experiment of Example 2.

[0035] Figure 7 This is a photo of the skin irritation of the solid control drug group 1 in the experiment of Example 2.

[0036] Figure 8 These are photos of the skin irritation of Group 2 of solid-state control drugs in the experiment of Example 2.

[0037] Fig. 9 The following are comparison photos of the effects of different preparations on skin oiliness in the experiment of Example 5.

[0038] Fig.10 These are the cornea images of each group stained with sodium fluorescein in the experiment of Example 9.

[0039] Fig.11 This is the average score result of sodium fluorescein staining in each group in the experiment of Example 9.

[0040] Fig.12 The results are for measuring the tear secretion of each group in the experiment of Example 9.

[0041] Fig.13 The results are for measuring the tear secretion of each group in the experiment of Example 10.

[0042] Fig.14This is the staining image of corneal fluorescein sodium in each group in the experiment of Example 11.

[0043] Fig.15 This is the average score result of sodium fluorescein staining in each group in the experiment of Example 11.

[0044] Fig.16 These are the measurement results of tear secretion in each group in the experiment of Example 11. DETAILED DESCRIPTION

[0045] In order to better explain the present invention and facilitate understanding, the present invention is described in detail below through specific implementation modes in conjunction with the accompanying drawings.

[0046] Example 1: Preparation of an emulsion with menthol as the only active ingredient

[0047] Specifically, this embodiment provides a specific example of a menthol-based pharmaceutical composition for skin use, and the following specific example drugs and their preparation are as follows:

[0048] Experimental drug 1: 0.1 g of menthol was dissolved in 0.9 g of olive oil, 0.2 g of Tween 80 was dissolved in 8.8 ml of water, and then 8.8 ml of water containing Tween 80 was slowly added to the olive oil under rapid stirring to obtain a 1% emulsion (oil content 9%).

[0049] Experimental drug 2: 0.15 g of menthol was dissolved in 0.85 g of olive oil, 0.2 g of Tween 80 was dissolved in 8.8 ml of water, and then 8.8 ml of water containing Tween 80 was slowly added to the olive oil under rapid stirring to obtain a 1.5% emulsion (8.5% oil content).

[0050] Experimental drug 3: 0.2 g of menthol was dissolved in 0.8 g of olive oil, 0.2 g of Tween 80 was dissolved in 8.8 ml of water, and then 8.8 ml of water containing Tween 80 was slowly added to the olive oil under rapid stirring to obtain a 2% emulsion (containing 8% oil).

[0051] Experimental drug 4: 0.3 g of menthol was dissolved in 1.5 g of olive oil, 0.2 g of Tween 80 was dissolved in 8 ml of water, and then 8 ml of water containing Tween 80 was slowly added to the olive oil under rapid stirring to obtain a 3% emulsion (15% oil content).

[0052] Experimental drug 5: 0.4 g of menthol was dissolved in 2 g of olive oil, 0.2 g of Tween 80 was dissolved in 7.4 ml of water, and then 7.4 ml of water containing Tween 80 was slowly added to the olive oil under rapid stirring to obtain a 4% emulsion (containing 20% ​​oil).

[0053] Experimental drug 6: 0.5 g of menthol was dissolved in 2.5 g of olive oil, 0.2 g of Tween 80 was dissolved in 6.8 ml of water, and then 6.8 ml of water containing Tween 80 was slowly added to the olive oil under rapid stirring to obtain a 5% emulsion (containing 25% oil).

[0054] Experimental drug 7: 0.6 g of menthol was dissolved in 2.5 g of olive oil, 0.2 g of Tween 80 was dissolved in 6.7 ml of water, and then 6.7 ml of water containing Tween 80 was slowly added to the olive oil under rapid stirring to obtain a 6% emulsion (containing 25% oil).

[0055] Experimental drug 8: 0.7 g of menthol was dissolved in 2.5 g of tea oil, 0.06 g of poloxamer 188 was dissolved in 6.74 ml of water, and then 6.74 ml of water dissolved with Tween 80 was slowly added to the tea oil under rapid stirring to obtain a 7% emulsion (containing 25% oil).

[0056] Experimental drug 9: 0.3 g of menthol was dissolved in 1.5 g of soybean oil, 0.2 g of Tween 80 was dissolved in 8 ml of water, and then 8 ml of water containing Tween 80 was slowly added to the soybean oil under rapid stirring to obtain a 3% emulsion (15% oil content).

[0057] Experimental drug 10: 0.3 g of menthol was dissolved in 1.5 g of castor oil, 0.2 g of Tween 80 was dissolved in 8 ml of water, and then 8 ml of water containing Tween 80 was slowly added to the castor oil under rapid stirring to obtain a 3% emulsion (containing 15% oil).

[0058] Experimental drug 11: Melt 1.5 g of beeswax at 70°C, then dissolve 0.3 g of menthol in the beeswax, dissolve 0.2 g of Tween 80 in 8 ml of water and heat to 70°C, then slowly add the 8 ml of water to the beeswax with rapid stirring to obtain a 3% emulsion (containing 15% beeswax).

[0059] Experimental drug 12: 0.3 g of menthol was dissolved in 1.5 g of medium chain triglycerides, 0.2 g of Tween 80 was dissolved in 8 ml of water, and then the 8 ml of water was slowly added to the medium chain triglycerides under rapid stirring to obtain a 3% emulsion (containing 15% oil).

[0060] Experimental drug 13: 0.3 g of menthol was dissolved in 1.5 g of isopropyl palmitate, 0.2 g of Tween 80 was dissolved in 8 ml of water, and then the 8 ml of water was slowly added to the isopropyl palmitate under rapid stirring to obtain a 3% emulsion (containing 15% oil).

[0061] Experimental drug 14: 0.6 g of menthol was dissolved in 1.5 g of castor oil, 0.1 g of polyoxyethylene (40) castor oil was dissolved in 7.8 ml of water, and then the 7.8 ml of water was slowly added to the castor oil under rapid stirring to obtain a 6% emulsion (oil content 15%).

[0062] Experimental drug 15: 0.3 g of menthol was dissolved in 1.5 g of castor oil, 0.1 g of polyoxyethylene (40) castor oil was dissolved in 8.1 ml of water, and then the 8.1 ml of water was slowly added to the castor oil under rapid stirring to obtain a 3% emulsion (oil content 15%).

[0063] Experimental drug 16: 0.6 g of menthol was dissolved in 1.5 g of tea oil, 0.1 g of polyoxyethylene (35) castor oil was dissolved in 7.8 ml of water, and then the 7.8 ml of water was slowly added to the tea oil under rapid stirring to obtain a 6% emulsion (15% oil content).

[0064] Experimental drug 17: 0.6 g of menthol was dissolved in 1.5 g of tea oil, 0.1 g of poloxamer 188 was dissolved in 7.8 ml of water, and then the 7.8 ml of water was slowly added to the tea oil under rapid stirring to obtain a 6% emulsion (15% oil content).

[0065] Experimental drug 18: 0.3 g of menthol was dissolved in 1.5 g of tea oil, 0.1 g of polyoxyethylene (35) castor oil was dissolved in 8.1 ml of water, and then the 8.1 ml of water was slowly added to the tea oil under rapid stirring to obtain a 3% emulsion (15% oil content).

[0066] Experimental drug 19: 0.3 g of menthol was dissolved in 1.5 g of tea oil, 0.06 g of poloxamer 188 was dissolved in 8.14 ml of water, and then the 8.14 ml of water was slowly added to the tea oil under rapid stirring to obtain a 3% emulsion (containing 15% oil).

[0067] Experimental drug 20: 0.4 g of menthol was dissolved in 2.5 g of tea oil, 0.06 g of poloxamer 188 was dissolved in 7.04 ml of water, and then the 7.04 ml of water was slowly added to the tea oil under rapid stirring to obtain a 4% emulsion (containing 25% oil).

[0068] Experimental drug 21: 0.7 g of menthol was dissolved in 2.5 g of tea oil, 0.06 g of poloxamer 188 was dissolved in 6.74 ml of water, and then the 6.74 ml of water was slowly added to the tea oil under rapid stirring to obtain a 7% emulsion (containing 25% oil).

[0069] Experimental drug 22: 0.3 g of menthol was dissolved in 1.5 g of tea oil, 0.2 g of Tween 80 was dissolved in 8 ml of water, and then the 8 ml of water was slowly added to the tea oil under rapid stirring to obtain a 3% emulsion (15% oil content).

[0070] Experimental drug 23: 0.3 g of menthol was dissolved in 2.5 g of tea oil, 0.06 g of poloxamer 188 was dissolved in 7.14 ml of water, and then the 7.14 ml of water was slowly added to the tea oil under rapid stirring to obtain a 3% emulsion (containing 25% oil).

[0071] Experimental drug 24: 1.5 g of lanolin was melted under heating conditions at 45°C, and then 0.3 g of menthol was dissolved in the lanolin, 0.2 g of Tween 80 was dissolved in 8 ml of water and heated to 45°C, and then the 8 ml of water was slowly added to the lanolin under rapid stirring to obtain a 3% emulsion (containing 15% oil).

[0072] Comparison Example

[0073] (1) Prepare the following oil-soluble control composition:

[0074] Oil-soluble control drug 1: 0.1 g of menthol is dissolved in 9.9 g of olive oil to obtain a 1% oily liquid preparation.

[0075] Oil-soluble control drug 2: 0.2 g of menthol was dissolved in 9.8 g of olive oil to obtain a 2% oily liquid preparation.

[0076] Oil-soluble control drug 3: 0.3 g of menthol was dissolved in 9.7 g of olive oil to obtain a 3% oily liquid preparation.

[0077] Oil-soluble control drug 4: 0.4 g of menthol was dissolved in 9.6 g of olive oil to obtain a 4% oily liquid preparation.

[0078] Oil-soluble control drug 5: 0.6 g of menthol was dissolved in 9.4 g of olive oil to obtain a 6% oily liquid preparation.

[0079] Oil-soluble control drug 6: 0.8 g of menthol was dissolved in 9.2 g of olive oil to obtain an 8% oily liquid preparation.

[0080] Oil-soluble control drug 7: 1.0 g of menthol was dissolved in 9.0 g of olive oil to obtain a 10% oily liquid preparation.

[0081] Oil-soluble control drug 8: 1.2 g of menthol was dissolved in 8.8 g of olive oil to obtain a 12% oily liquid preparation.

[0082] (2) Prepare the following solid-state control composition:

[0083] Solid-state control drug 1: According to the optimal prescription and preparation process disclosed in US Patent Application No. US202117511238A (Invention Name: Treatment for Dry Eyes), the solid-state control drug 1 is prepared as follows: 2 g of active ingredient, composed of the following proportions: Menthoxypropanediol concentration 36.35%, Menthonediol concentration 36.36%, Menthol (menthol) concentration 27.27% and Caffeine concentration 0.018%; the base mixture (balm mixture) is 8 g of beeswax. The total concentration of menthol and related mint ingredients is about 20%.

[0084] Solid-state control drug 2: According to the optimal prescription and preparation process disclosed in US Patent Application No. US202117511238A (Invention Name: Treatment for Dry Eyes), the solid-state control drug 2 is prepared as follows: 6g of active ingredient, composed of the following proportions: Menthoxypropanediol concentration 36.35%, Menthonediol concentration 36.36%, Menthol (menthol) concentration 27.27% and Caffeine (caffeine) concentration 0.018%; the base mixture (balm mixture) is 4g of beeswax. The total concentration of menthol and related mint ingredients is about 60%.

[0085] Solid-state control drug 3: According to the optimal prescription and preparation process disclosed in US Patent Application No. US202117511238A (Invention Name: Treatment for Dry Eyes), the solid-state control drug 3 was prepared as follows: 0.6 g of active ingredient, composed of the following proportions: Menthoxypropanediol concentration 36.35%, Menthonediol concentration 36.36%, Menthol (menthol) concentration 27.27% and Caffeine (caffeine) concentration 0.018%; the base mixture (balm mixture) is 9.4 g of beeswax. The total concentration of menthol and related mint ingredients is 6%.

[0086] Example 2: The efficacy of the above compositions in promoting tear secretion in patients with dry eyes was compared in an experiment.

[0087] 1. Purpose of the experiment

[0088] The dose-effect relationship of the effectiveness of menthol emulsions of different concentrations in promoting tear secretion in patients with dry eyes was evaluated; the efficacy was compared with that of a control drug; and the skin irritation of a single administration of the menthol emulsion of the present invention was investigated.

[0089] 2. Experimental Design

[0090] Since the menthol skin pharmaceutical composition of this test contains menthol, olive oil and / or essence, which are widely used in medicines and cosmetics, such as the concentration of menthol in Fengyoujing, is 0.32g / g, it can be considered that the safety of menthol at least within the range of 0.32g / g (i.e. 32%) and below is widely accepted and safe for human skin use.

[0091] 3. Experimental Methods

[0092] Recruit subjects with dry eye disease, the inclusion criteria are: (1) fully understand this trial study and sign the informed consent; (2) age>18 years old, regardless of gender; (3) complain of one of the subjective symptoms such as dry eyes, foreign body sensation, burning sensation, fatigue, discomfort, red eyes, and visual fluctuations; (4) The day before the trial, the Schirmer tear secretion was measured, and subjects with Schirmer tear secretion less than 5mm / 5min were included in the trial. On the day of the trial, all subjects were required not to wear makeup on their faces. At the beginning of the trial, the subjects were randomly divided into the following groups, 8 people / group, respectively:

[0093] Blank drug group (i.e., blank solvent group without menthol);

[0094] Experimental drug group 1 (experimental drug 1 in Example 1, an emulsion containing 1% menthol);

[0095] Experimental drug group 2 (experimental drug 2 in Example 1, an emulsion containing 1.5% menthol);

[0096] Experimental drug group 3 (experimental drug 3 in Example 1, an emulsion containing 2% menthol);

[0097] Experimental drug group 4 (experimental drug 4 in Example 1, an emulsion containing 3% menthol);

[0098] Experimental drug group 5 (experimental drug 5 in Example 1, an emulsion containing 4% menthol);

[0099] Experimental drug group 1 (experimental drug 6 in Example 1, an emulsion containing 5% menthol);

[0100] Experimental drug group 1 (experimental drug 7 in Example 1, an emulsion containing 6% menthol);

[0101] Experimental drug group 1 (experimental drug 8 in Example 1, an emulsion containing 7% menthol);

[0102] Oil-soluble control drug group 1 (oil-soluble control drug 1 in Example 1, containing 1% menthol);

[0103] Oil-soluble control drug group 2 (oil-soluble control drug 2 in Example 1, containing 2% menthol);

[0104] Oil-soluble control drug group 3 (oil-soluble control drug 3 in Example 1, containing 3% menthol);

[0105] Oil-soluble control drug group 4 (oil-soluble control drug 4 in Example 1, containing 4% menthol);

[0106] Oil-soluble control drug group 5 (oil-soluble control drug 5 in Example 1, containing 6% menthol);

[0107] Oil-soluble control drug group 6 (oil-soluble control drug 6 in Example 1, containing 8% menthol);

[0108] Oil-soluble control drug group 7 (oil-soluble control drug 7 in Example 1, containing 10% menthol);

[0109] Oil-soluble control drug group 8 (oil-soluble control drug 8 in Example 1, containing 12% menthol);

[0110] Solid-state control drug group 1 (solid-state control drug 1 in Example 1, containing 20% ​​of active ingredients such as menthol);

[0111] Solid-state control drug group 2 (solid-state control drug 2 in Example 1, containing 60% of active ingredients such as menthol);

[0112] Solid-state control drug group 3 (solid-state control drug 3 in Example 1, containing 6% of active ingredients such as menthol).

[0113] After grouping, each subject was given a skin 2cm-3cm away from the lower eyelid, horizontal to the eye, and the total weight of the pharmaceutical composition of the present invention was applied to the skin under the eye with a total weight of about 5 mg / eye, and the application area under each eye was about 2 square centimeters. After the application, each subject recorded the feeling of the eye and the feeling of the application site. The subjects in each group were randomly divided into two groups, 4 / group, and the Schirmer tear secretion was measured 5min and 30min after application. At the same time, the subjects were asked to score their compliance 30min after administration.

[0114] Schirmer tear secretion value is an important indicator of eye comfort for dry eye patients after treatment. Clinically, it is generally believed that if the Schirmer tear secretion value 5 minutes after medication can reach the normal value (i.e., Schirmer tear secretion value>15mm), and the Schirmer tear secretion value 30 minutes after medication can be>10mm, the patient's eyes will have better comfort after treatment.

[0115] The scoring criteria are as follows: 1 point (non-irritating); 2 points (slightly irritating but acceptable); 3 points (irritating); 4 points (strongly irritating, with a burning sensation, but no pain); 5 points (strongly irritating, with pain). An average score of 1 to 2 points (including 2 points) indicates good compliance, and below 2 points, the lower the score, the better the compliance. An average score of 2 to 5 points (excluding 2 points) indicates poor compliance, and the higher the score, the worse the compliance.

[0116] 4. Experimental Results

[0117] According to the above experimental method, the secretion of Schirmer tears after a certain period of administration was measured, and the test results are shown in Table 1 below.

[0118] Table 1 Tear secretion values ​​of the experimental group (*P<0.05 compared with before the experiment)

[0119]

[0120]

[0121] According to the tear secretion values ​​of each test group shown in Table 1, it can be seen that the pharmaceutical composition of the present invention is concentration-dependent in terms of the efficacy of promoting tear secretion within the concentration range of 1%-7%. The emulsion with a 1% menthol concentration has a tear secretion-promoting effect, but does not meet the Schirmer tear secretion value requirements for clinical treatment of dry eye comfort. The emulsion with 1.5% menthol has a significant tear secretion-promoting effect and can meet the Schirmer tear secretion value requirements for clinical treatment of dry eye comfort. As the concentration increases, the tear secretion-promoting effect is enhanced. After 5 minutes of use, the emulsion with a concentration of 4% reaches the maximum value of 30mm measured by the Schirmer tear test paper. When the concentration reaches 7%, the tear secretion-promoting effect reaches the maximum value of 30mm measured by the Schirmer tear test paper, and does not show irritation. See. Figure 1 The following are photos of the skin irritation of two groups of experimental drugs in the experiment of Example 2 (no skin irritation was found). Figure 2 The following are photos of skin irritation of 5 groups of experimental drugs in the experiment of Example 2 (no skin irritation was found). Figure 3 These are photos of skin irritation of 8 groups of experimental drugs in the experiment of Example 2 (no skin irritation was found). No skin irritation was found in the above.

[0122] According to the tear secretion values ​​of each group shown in Table 1, the oil-soluble control drug composition shows concentration dependence in the drug effect of promoting tear secretion within the concentration range of 1%-12%. The oil-soluble control drug compositions of 1% and 2% menthol have only a weak tear secretion effect, which does not meet the Schirmer tear secretion value requirements for clinical treatment of dry eye comfort. The oil-soluble control drug composition of 3% menthol has a significant tear secretion effect, which can meet the Schirmer tear secretion value requirements for clinical treatment of dry eye comfort. And as the concentration increases, the tear secretion effect is enhanced. After 5 minutes of use, the oil-soluble control drug composition with a concentration of 8% menthol reaches the maximum value of 30mm measured by the Schirmer tear test paper. However, when the concentration reaches 12%, although the tear secretion effect reaches the maximum value of 30mm measured by the Schirmer tear test paper, it shows weak irritation. It can be seen that compared with the emulsion of the present invention, the tear secretion effect of the oil-soluble control drug composition containing the same concentration of menthol is weaker. This may be because the emulsion composition preparation of the present invention contains a hydrophilic phase and a lipophilic phase, which is closer to the hydrophilicity and lipophilicity of the skin. After the emulsion is applied, it is thinner and refreshing, less likely to clog pores, more conducive to percutaneous absorption, and conducive to acting on facial nerves to promote tear secretion, and has a stronger efficacy.

[0123] See also Figure 4 , are photos of skin irritation of oil-soluble control drug group 3 (3% menthol), and no redness of the skin at the medication site was observed in the photos; Figure 5 The skin irritation photos of oil-soluble control drug group 7 (10% menthol) show that the skin at the medication site is slightly red. Figure 6 The skin irritation photos of the oil-soluble control drug group 8 (12% menthol) show obvious redness of the skin at the medication site. Figure 7 The skin irritation photos of solid control drug group 1 (containing 20% ​​of active ingredients such as menthol) are shown. Figure 8 The following are photos of the skin irritation of solid control drug group 2 (containing 60% of active ingredients such as menthol). It can be seen that high concentrations of menthol irritate the skin and cause large areas of redness and swelling at the medication site. This shows that menthol concentrations above 10% are irritating to the skin, and the irritation becomes stronger as the concentration increases. The greasiness brought by the oil-soluble type, the irritation to the skin at high concentrations, and the fact that the nose of the human body is prone to oil secretion, can easily cause local skin inflammation and acne problems. Considering that dry eyes are a chronic disease that requires long-term drug treatment, weak irritation will also significantly reduce patient compliance with treatment. Therefore, oil-soluble control drug groups 7 and 8 cannot be used as preferred options for the treatment of dry eyes.

[0124] The solid control drug group 1 (containing 20% ​​of active ingredients such as menthol) has a weak tear secretion effect. This may be because the control drug 1 is made of beeswax as a matrix and is made into a solid beeswax (different from it, the experimental drug 11 of the present invention is an emulsion with beeswax as an oil phase matrix), which blocks the skin from absorbing active drug ingredients such as menthol on the skin surface. Compared with each experimental group, the solid control drug group 1 has a higher concentration but a weaker tear secretion effect. The active ingredients such as menthol are volatile. The active ingredients such as menthol in the waxy substance applied around the eyes evaporate, which can easily make the patient unable to open his eyes and cause extreme discomfort, and the patient's compliance is poor. The solid control drug group 2 (containing 60% of active ingredients such as menthol) has a strong tear secretion effect, but the irritation is also extremely obvious. Although the solid control drug group 3 (containing 6% of active ingredients such as menthol) is non-irritating, the tear secretion effect is also very weak and cannot meet the treatment expectations.

[0125] In addition, the subjects in each group were studied according to the subjects' feelings in Table 2, and the subjects' feelings were summarized by observing the skin and understanding the feelings of taking the medicine. The specific experimental results are shown in Table 2.

[0126] Table 2 Specific results of subjects' feelings (8 subjects / group)

[0127]

[0128]

[0129]

[0130] As can be seen from Table 2, the menthol emulsion provided by the present invention can effectively promote the tear secretion of the subject within the concentration range of 1.5%-7%, and has no skin irritation. When the concentration of menthol is 1%, the effect of promoting the tear secretion of the subject is slightly weaker, and even when the concentration is further increased to 7%, the experimenters did not find skin irritation. After comparison, among the three dosage forms of emulsion, oil-soluble composition, and solid wax, the menthol emulsion of the present invention has a significant efficacy, and the activity of menthol is best exerted. When the concentration reaches 7%, it can fully meet the good treatment experience of dry eye patients. The menthol concentration is low, the amount of oily solvent used in the emulsion is small, and the water phase content is high, which can effectively reduce the greasy feeling of the skin and the phenomenon of acne after continuous and multiple uses, and improve the comfort of patients.

[0131] In summary, menthol oil-soluble control drugs for skin use can effectively promote the tear secretion of subjects within the concentration range of 3%-10%, without skin irritation; when the concentration of menthol is lower than 3%, the effect of promoting the tear secretion of subjects is not obvious, and when the concentration reaches 12%, some experimenters express mild skin irritation. The solid control drug group 1 has a weaker effect on promoting tear secretion and has weak skin irritation. The solid control drug group 2 has strong skin irritation. Although there is no skin irritation and other manifestations in the solid control drug group 3 (menthol 6%), the effect of promoting tear secretion is extremely weak. This may be because the solid control drugs 1-3 are solid beeswax, which blocks the skin from absorbing active drug ingredients such as menthol on the skin surface, so the activity is weaker, and the active ingredients such as menthol in the waxy substance applied around the eyes volatilize, which makes the patient extremely uncomfortable such as being unable to open his eyes, and the patient's compliance is poor.

[0132] 5. Experimental Conclusion

[0133] The menthol skin pharmaceutical composition of the present invention can effectively promote the tear secretion of the test subject in the concentration range of 1.5%-7% without skin irritation. The menthol skin pharmaceutical composition of the present invention has better efficacy than the oil-soluble control drug of the same concentration.

[0134] Example 3: Experimental study on the efficacy of menthol emulsions prepared with different excipients in promoting tear secretion.

[0135] 1. Purpose of the experiment

[0136] To evaluate the effectiveness of menthol emulsions prepared with different excipients in promoting tear secretion in patients with dry eye and their skin irritation.

[0137] 2. Experimental Methods

[0138] Recruit subjects with dry eye disease, the inclusion criteria are: (1) fully understand this trial study and sign the informed consent; (2) age>18 years old, regardless of gender; (3) complain of one of the subjective symptoms such as dry eyes, foreign body sensation, burning sensation, fatigue, discomfort, red eyes, and visual fluctuations; (4) The day before the trial, the Schirmer tear secretion was measured, and subjects with Schirmer tear secretion less than 5mm / 5min were included in the trial. On the day of the trial, all subjects were required not to wear makeup on their faces. At the beginning of the trial, the subjects were randomly divided into the following groups, 8 people / group, namely:

[0139] Experimental drug group 4 (experimental drug 4 in Example 1, i.e., a 3% menthol drug group prepared with olive oil as the oil phase),

[0140] Experimental drug 10 group (experimental drug 10 in Example 1, i.e., 3% menthol drug group prepared with castor oil as the oil phase),

[0141] Experimental drug 12 group (experimental drug 12 in Example 1, i.e., 3% menthol drug group prepared with medium chain triglycerides as the oil phase),

[0142] Experimental drug 14 group (experimental drug 14 in Example 1, i.e., 6% menthol drug group prepared with polyoxyethylene (40) castor oil as emulsifier),

[0143] Experimental drug 16 group (experimental drug 16 in Example 1, i.e., 6% menthol drug group prepared with polyoxyethylene (35) castor oil as emulsifier),

[0144] Experimental drug 17 group (experimental drug 17 in Example 1, i.e., a 6% menthol drug group formulated with poloxamer 188 as an emulsifier).

[0145] After grouping, each subject was given a skin 2cm-3cm away from the lower eyelid, horizontal to the eye, and the total weight of the pharmaceutical composition of the present invention was applied to the skin under the eye with a total weight of about 5 mg / eye, and the application area under each eye was about 2 square centimeters. After the application, each subject recorded the feeling of the eye and the feeling of the application site. The subjects in each group were randomly divided into two groups, 4 / group, and the Schirmer tear secretion was measured 5min and 30min after application. At the same time, the subjects were asked to score their compliance 30min after administration.

[0146] The scoring criteria are as follows: 1 point (non-irritating); 2 points (slightly irritating but acceptable); 3 points (irritating); 4 points (strongly irritating, with a burning sensation, but no pain); 5 points (strongly irritating, with pain). An average score of 1 to 2 points (including 2 points) indicates good compliance, and below 2 points, the lower the score, the better the compliance. An average score of 2 to 5 points (excluding 2 points) indicates poor compliance, and the higher the score, the worse the compliance.

[0147] 3. Experimental results

[0148] According to the above experimental method, the Schirmer tear secretion after a certain period of administration was measured. The test results showed that the menthol skin pharmaceutical composition prepared with different excipients selected by the present invention all had a significant effect of promoting tear secretion. There was no significant difference in the tear secretion values ​​of the menthol skin pharmaceutical composition prepared with different excipients after 5 minutes and 30 minutes of use, and there was no significant difference in the compliance of each group. The results are shown in Table 3.

[0149] Table 3 Tear secretion values ​​of the test group

[0150]

[0151]

[0152] 4. Experimental Conclusion

[0153] The menthol skin pharmaceutical compositions prepared with different auxiliary materials selected by the present invention all have a significant tear secretion promoting effect, and there is no significant difference in the tear secretion promoting effect and irritation of each group at an appropriate concentration.

[0154] Example 4: Test on the tear secretion promotion of menthol emulsion at different application sites.

[0155] 1. Experimental purpose: To compare the efficacy of menthol emulsion applied to different parts of the skin

[0156] 2. Experimental Design

[0157] Recruit dry eye subjects. One day before the test, measure Schirmer tear secretion, and include subjects with Schirmer tear secretion less than 5mm in the test. At the beginning of the test, 8 subjects / group, and the subjects are randomly divided into the following groups:

[0158] Blank drug group (i.e., blank solvent group without menthol);

[0159] Experimental drug group 4 (experimental drug 4 in Example 1) was applied to the upper eyelid;

[0160] Experimental drug group 4 (experimental drug 4 in Example 1) was applied to the lower eyelid;

[0161] Experimental drug group 4 (experimental drug 4 in Example 1) was applied to the nose wing area;

[0162] Experimental drug group 6 (experimental drug 6 in Example 1) was applied to the upper eyelid;

[0163] Experimental drug group 6 (experimental drug 6 in Example 1) was applied to the lower eyelid;

[0164] Experimental drug group 6 (experimental drug 6 in Example 1) was applied to the nose wing area;

[0165] The blank drug group was applied to the upper eyelid, lower eyelid and nose wing at the same time.

[0166] After grouping, each subject was given the corresponding group of drugs to apply to the corresponding parts of the body, 5 mg / site / test. After application, each subject recorded the feeling of the eye and the feeling of the application site. The subjects in each group were randomly divided into two groups, 4 people / group, and the Schirmer tear secretion was measured 5 minutes and 30 minutes after application.

[0167] 3. Experimental results:

[0168] The test results show that the same concentration of the drug, after applying to different parts, the effect is stronger in the lower eyelid than in the upper eyelid, and stronger in the upper eyelid than in the nose wing; but even if the three concentrations of the drug of the present invention are applied to the nose wing, it can significantly promote the tear secretion of the subjects. The tear secretion values ​​of each test group are detailed in Table 4.

[0169] Table 4 Tear secretion values ​​of the experimental group (*P<0.05 compared with before the experiment)

[0170]

[0171] 4. Experimental conclusion:

[0172] The same concentration of the drug, after being applied to different parts, has a stronger effect on the lower eyelid than on the upper eyelid, and on the upper eyelid than on the wing of the nose; but even on the wing of the nose, administration of 5% of the menthol emulsion of the present invention (experimental drug group 6) can significantly promote the tear secretion of the subjects.

[0173] Example 5: Test on the effect of menthol emulsion on tear secretion under closed eyes.

[0174] 1. Purpose of the experiment

[0175] Patients with dry eyes voluntarily participated in this test, and the test was conducted with eyes closed to determine whether the menthol emulsion of the present invention exerts its efficacy mainly through skin absorption, or whether it is mainly due to the volatilization of menthol, the volatile menthol fumigating the eyes and causing irritation tears, etc.

[0176] 2. Experimental Design

[0177] Recruit dry eye subjects. One day before the test, measure Schirmer tear secretion, and include subjects with Schirmer tear secretion less than 5mm in the test. At the beginning of the test, the subjects were randomly divided into the following groups, 4 people / group, respectively:

[0178] Blank drug group (i.e., drug group without menthol);

[0179] Experimental drug group 3 (experimental drug 3 in Example 1);

[0180] Experimental drug group 7 (experimental drug 7 in Example 1).

[0181] Self-adhesive transparent laser surgery postoperative protective light-transmitting monocular eye mask, use medical tape to block all the air holes on the eye mask. After grouping, cover both eyes of each subject with an eye mask, and then tell the subject to start gently closing their eyes when the drug is about to be applied, and they can open their eyes only after the tear secretion is measured. After the subject closes his eyes, start applying the drug. When applying the drug, apply the corresponding group of drugs to the lower eyelids of both eyes of each subject, and apply about 5mg / place / measurement. Repeatedly tell the subjects to gently close their eyes and rest without opening their eyes. After applying the drug, each subject records the feeling of the eye and the feeling of the application site after the experiment. The Schirmer tear secretion of the subjects in each group was measured 5min after application.

[0182] 3. Experimental results

[0183] The experimental results show that the menthol emulsion provided by the present invention can significantly promote the tear secretion of the subjects under the conditions of eye occlusion and eye closure, and the amount of tear secretion is not significantly different from the results recorded in Example 2. Menthol has a certain volatility, and the test results prove that the drug of the present invention does not promote tear secretion by stimulating the ocular surface through volatile menthol. The tear secretion values ​​of each test group are shown in Table 5.

[0184] Table 5 Tear secretion values ​​of the experimental group (*P<0.05 compared with before the experiment)

[0185]

[0186] 4. Experimental Conclusion

[0187] The drug of the present invention does not stimulate the ocular surface by volatile menthol to promote tear secretion, and it is speculated that it mainly exerts its pharmacological effect through skin absorption.

[0188] Example 6: Evaluation of the greasiness of the menthol skin pharmaceutical composition and the control drug

[0189] 1. Purpose of the experiment

[0190] Evaluation of skin greasiness after repeated use of menthol emulsion

[0191] 2. Experimental Design

[0192] Grease refers to the excessive greasy feeling of skin products during use, which is commonly referred to as "greasy". Excessive greasiness affects the compliance of product use. Dry eye subjects were recruited. One day before the test, they were required not to use any moisturizing cosmetics. One hour before the test on the same day, all subjects washed their faces. During the test, they were required not to wash their faces or use wet wipes to wipe the application area. 24 subjects (48 application areas on the lower eyelid) were included in the test. Experimental drug 3 (2% menthol, 8% olive oil) was applied to the lower eyelid, experimental drug 20 (4% menthol, 25% olive oil) was applied to the lower eyelid, and 4 groups of oil-soluble control drugs (4% menthol, olive oil dissolved) were applied to the lower eyelid. All of the above were applied once every two hours, and applied continuously for 6 times (dry eye patients usually use medication as needed, and the frequency of use is 6 times or more per day) to simulate the use of the emulsion of the present invention for one day. Two hours after the sixth application, the oiliness of the skin on the subjects' lower eyelids was observed, and the subjects were asked to rate the comfort level of the lower eyelids of both eyes, with 1 point being the most refreshing, with no greasy feeling at all, and 9 points being the most greasy feeling. The subjects were also allowed to freely choose which drug they would prefer to use subsequently.

[0193] 3. Experimental results

[0194] The subjects applied the oil-soluble control drug in Group 4, and the skin at the lower eyelid was oily and shiny. However, the skin at the lower eyelid where the emulsion of the present invention was applied was only slightly oily. The subjects reported that the skin at the oil-soluble control drug in Group 4 was very greasy, especially after the 5th and 6th application. The skin felt stuffy and had the urge to wash the face or wipe it with a wet wipe or rub it with hands. The greasy feeling score of the subjects was 8.5±0.5 (see Fig. 9 ).

[0195] The skin of the lower eyelid where the experimental drug 20 (containing 25% tea oil) of the present invention was applied felt slightly greasy, and the overall refreshing degree was much better than that of the oil-soluble control drug group 4 (containing 96% olive oil). The greasy feeling score of the subjects for experimental drug 20 was 2.9±0.5 (compared with the oil-soluble control drug group 4, P<0.05). The skin of the lower eyelid where the experimental drug 3 (containing 8% olive oil) of the present invention was applied did not feel greasy at all, and the overall refreshing degree was much better than that of the oil-soluble control drug group 4. The greasy feeling score of the subjects for experimental drug 3 was 1.8±0.8 (compared with the oil-soluble control drug group 4, P<0.05; compared with the experimental drug group 20, P<0.05). The order of use selected by all subjects was: experimental drug 3 was preferred, experimental drug 20 was the second choice, and the oil-soluble control drug 4 was the third choice.

[0196] 4. Experimental Conclusion

[0197] After continuous multiple uses of the menthol emulsion of the present invention, the greasy feeling of the subjects is weaker than that of the oil-soluble control drug, and the comfort and refreshing feeling are better than those of the oil-soluble control drug.

[0198] Example 7: Evaluation of the efficacy of menthol emulsion and oil-soluble control drug after multiple administration

[0199] 1. Purpose of the experiment

[0200] To evaluate whether the efficacy of menthol emulsion decreases after repeated use

[0201] 2. Experimental Design

[0202] Dry eyes are a chronic disease that requires long-term medication, and medication needs to be taken multiple times a day. Continuous and multiple use of oil-soluble liquid preparations gives patients a poor skin experience. Patients will have greasy skin after continuous and multiple use. After continuous and multiple administrations, the medication site is already covered with an oil layer, and the oil molecules clog the pores. Continuous and multiple use will reduce the efficacy. Dry eye subjects were recruited. The day before the test, they were required not to use any moisturizing cosmetics. One hour before the test on the same day, all subjects washed their faces. During the test, they were required not to wash their faces or use wet wipes to wipe the application area. Schirmer tear secretion was measured before the subjects were administered. Then the subjects were divided into 4 groups, 8 in each group, the first group was smeared with experimental drug 3 (2% menthol, 8% olive oil) on the lower eyelid, the second group was smeared with experimental drug 23 (3% menthol, 25% tea oil) on the lower eyelid, the third group was smeared with oil-soluble control drug 3 groups (3% menthol, 97% olive oil dissolved) on the lower eyelid, and the fourth group was smeared with oil-soluble control drug 3 groups (3% menthol, 97% olive oil dissolved) on the lower eyelid. The above groups 1, 2, and 3 were all smeared once every two hours, and smeared for 6 consecutive times (dry eye patients usually use medication as needed, and the frequency of use is 6 times or more per day) to simulate the use of the drug of the present invention for one day. The fourth group was smeared once every two hours, and from the second application, 30 minutes before application, the oil was gently wiped with the Heart-to-Heart Cleansing and Oil-Removing Wet Tissue (special for cleaning) to remove oil, and smeared for 6 consecutive times. Each of the above groups was further divided into two subgroups, and the Schirmer tear secretion was measured 5 minutes after the first application and 5 minutes after the sixth application.

[0203] 3. Experimental results

[0204] The Schirmer value of the subjects in group 3 (oil-soluble control drug group 3, 3% menthol, 97% olive oil dissolving) after the 6th application was lower than the Schirmer value after the first administration (P<0.05). However, the Schirmer value of the subjects in group 4 (oil-soluble control drug group 3, 3% menthol, 97% olive oil dissolving, plus wet wipes cleaning group) after the 6th application was equivalent to the Schirmer value after the first administration (P>0.05).

[0205] The Schirmer value of the subjects in group 2 (experimental drug 23, 3% menthol, 25% tea oil) after the 6th application was slightly lower than that after the first application, but there was no statistical difference (P>0.05). The Schirmer value of the subjects in group 1 (experimental drug 3, 3% menthol, 8% olive oil) after the 6th application was equivalent to that after the first application (P>0.05). The specific results are shown in Table 6.

[0206] Table 6: Tear secretion values ​​of the experimental group (*P<0.05 compared with 5 minutes after the first application)

[0207]

[0208] 4. Experimental Conclusion

[0209] It can be seen from the fourth group of tests in the third combination that the efficacy of oil-soluble liquid preparations will decrease after continuous multiple uses. If the efficacy is to be maintained, it is necessary to use wet wipes to clean the oil layer retained by multiple uses. However, the menthol emulsion prepared by the present invention does not show obvious problem of decreased efficacy after continuous multiple uses.

[0210] Example 8: Safety evaluation of long-term skin administration of menthol emulsion and control drugs.

[0211] 1. Purpose of the experiment

[0212] The safety of long-term administration (28 days) of the menthol emulsion of the present invention was evaluated by using a mouse animal experiment.

[0213] 2. Experimental Design

[0214] Female C57BL / 6 mice were randomly divided into the following groups, with 6 mice in each group, namely:

[0215] Healthy rat control group (administered blank solvent);

[0216] Experimental drug group 7 (experimental drug 7 in Example 1, menthol 6%, olive oil 25%);

[0217] Experimental drug group 8 (experimental drug 8 in Example 1, menthol 7%, olive oil 25%);

[0218] Oil-soluble control drug group 7 (oil-soluble control drug 7 in Example 1, menthol 10%);

[0219] Oil-soluble control drug group 8 (oil-soluble control drug 8 in Example 1, menthol 12%);

[0220] Solid-state control drug group 1 (solid-state control drug 1 in Example 1, menthol 20%);

[0221] Solid-state control drug group 2 (solid-state control drug 2 in Example 1, menthol 60%).

[0222] The corresponding drug of each group was applied to the skin of about 4mm below the lower eyelid of the mouse, and about 5 mg was applied to each lower eyelid each time. The healthy control group was given a blank solvent 6 times a day (8 o'clock, 11 o'clock, 13 o'clock, 15 o'clock, 17 o'clock, and 20 o'clock), and about 5 mg was applied to each lower eyelid each time. 30 minutes after the last administration on the 28th day, the skin irritation of the applied part of the mice in each group was detected and observed, and scored according to the skin irritation reaction scoring standard (see Table 7 for the scoring standard).

[0223] 3. Experimental results

[0224] Table 7 Skin irritation response scoring criteria

[0225]

[0226]

[0227] The healthy control mice were smeared with blank solvent under the eyelids for 28 consecutive days, and no abnormal redness or swelling or other irritation was observed on the skin. In addition, the mice in the oil-soluble control drug group 7 (10% menthol drug group) were also normal during the entire observation process.

[0228] After each administration of the oil-soluble control drug group 8 (12% menthol drug group), the mice occasionally scratched the drug application site with their front paws, but this was only a transient reaction and the mice were not observed to scratch continuously. After 28 consecutive days of drug administration, no other abnormalities were observed except that the application site became red.

[0229] In the solid control drug group 1 (solid control drug 1 in Example 1, i.e., the total concentration of menthol and related mint components is about 20%), after each administration, the mice's front paws were seen scratching the drug-applied area, and occasionally the mice were seen scratching continuously. After 28 days of continuous administration, the application area became slightly red, and no other abnormalities were observed.

[0230] After the solid control drug 2 group (solid control drug 2 in Example 1, i.e., the group containing 60% of active ingredients such as menthol) was administered to mice, it was immediately found that the mice's front paws scratched the drug application site violently, and the application site became red and swollen after multiple administrations, reflecting the strong irritation of menthol at this concentration to the mouse lower eyelid. The specific irritation results of each group are summarized in Table 8.

[0231] Table 8 Evaluation of long-term administration irritation in mice

[0232]

[0233] 4. Experimental Conclusion

[0234] The 7% menthol emulsion of the present invention has no skin irritation when used for a long time. The 10% oil-soluble control drug has no long-term skin irritation, the 12% oil-soluble control drug has mild skin irritation when used for a long time, the solid control drug group 1 (solid control drug 1 in Example 1) has mild skin irritation when used for a long time, and the solid control drug group 2 (solid control drug 2 in Example 1) has strong skin irritation when used for a long time.

[0235] Example 9: Experiment on the effect of menthol emulsion on promoting tear secretion in dry eye model mice.

[0236] 1. Purpose of the experiment

[0237] The effectiveness of the menthol emulsion of the present invention in promoting tear secretion and treating dry eye was evaluated by using a mouse animal experiment.

[0238] 2. Experimental Design

[0239] (1) Grouping, modeling and treatment of experimental animals

[0240] The dry stress environment box was set to constant temperature (24±2°C), constant humidity (30±5%), and constant wind speed (2.5±0.5 km / s). Female C57BL / 6 mice were randomly divided into the following groups, with 6 mice in each group, namely:

[0241] Healthy rat control group (normal saline for modeling, blank solvent oil for treatment);

[0242] Blank group (a blank drug group without menthol was used after modeling);

[0243] Experimental drug group 2 (experimental drug 2 in Example 1, 1.5% menthol, was used after modeling);

[0244] Experimental drug group 3 (experimental drug 3 in Example 1, 2% menthol, was used after modeling);

[0245] Experimental drug group 5 (experimental drug 5 in Example 1, 4% menthol, was used after modeling);

[0246] Experimental drug 7 group (experimental drug 7 in Example 1, 6% menthol, was used after modeling);

[0247] Experimental drug 8 group (after modeling, experimental drug 8 in Example 1, 7% menthol, was used);

[0248] Oil-soluble control drug group 3 (after modeling, oil-soluble control drug 3, 3% menthol, was used);

[0249] Oil-soluble control drug group 4 (after modeling, oil-soluble control drug 4, 4% menthol, was used);

[0250] Oil-soluble control drug group 5 (after modeling, oil-soluble control drug 5, 6% menthol was used);

[0251] Oil-soluble control drug group 6 (after modeling, oil-soluble control drug 6, 8% menthol was used);

[0252] Oil-soluble control drug group 7 (after modeling, oil-soluble control drug 7, 10% menthol, was used);

[0253] Oil-soluble control drug group 8 (after modeling, oil-soluble control drug 8, 12% menthol, was used);

[0254] Solid control drug group 1 (solid control drug 1, 20% menthol, was used after modeling);

[0255] Solid-state control drug group 2 (solid-state control drug 2, 60% menthol, was used after modeling).

[0256] Mice in the healthy mouse control group were subcutaneously injected with 0.2 mL of normal saline in the hind limbs 4 times a day (9 o'clock, 12 o'clock, 15 o'clock, and 18 o'clock), and were placed in a normal environment with a relative humidity of 55% ± 10% for 5 days, for 5 consecutive days. Mice in other groups except the healthy mouse control group were subcutaneously injected with 2.5 mg / mL scopolamine solution in the hind limbs 6 times a day (8 o'clock, 11 o'clock, 13 o'clock, 15 o'clock, 17 o'clock, and 20 o'clock), 0.2 mL each time, and placed in a dry stress environment for 5 consecutive days. At the same time as modeling, the corresponding drug of each group was applied to the skin about 4 mm of the lower eyelid of the mouse, and about 5 mg was applied to each lower eyelid each time. The healthy control group was given a blank solvent, 6 times a day, and about 5 mg was applied to each lower eyelid each time. 30 minutes after the last administration on the 5th day, the various indicators of mice in each group were detected.

[0257] (2) Tear secretion measurement

[0258] Phenol red cotton thread is a common indicator for detecting tear secretion. The length of time that the phenol red cotton thread turns red can be used to quantify the tear secretion of mice. The tear secretion of mice in each group was measured on the fifth day of modeling. At the same time, under gas anesthesia, the lower eyelid of the mouse was gently pulled up with ophthalmic forceps, and the phenol red cotton thread was inserted into the inner side of the inferior conjunctival fornix. After 20 seconds, it was removed and the length of the red cotton thread was measured with a ruler and recorded.

[0259] (3) Fluorescein sodium staining

[0260] Corneal fluorescein staining was used to observe the damage of corneal epithelial barrier function. Mice were anesthetized with gas, and then 2.5 microliters of 0.25% sodium fluorescein dye solution was topically applied to the cornea. Blink manually 5 times, draw 1 mL of saline with a 1 mL syringe to rinse, and take gross photos under cobalt blue light of a slit microscope. For the grading of fluorescein staining, the cornea was divided into four quadrants and scored separately. The 4 scores were added to obtain the final score for each eye (the minimum value is 0 and the maximum value is 16). The fluorescein score for each quadrant is as follows: none, 0; mild punctate staining less than 30 spots, 1; dense punctate staining more than 30 spots, 2; severe diffuse staining, no positive plaques, 3; fluorescein-positive plaques, 4.

[0261] 3. Experimental results

[0262] Five days after modeling, sodium fluorescein was dripped onto the mouse ocular surface, and then macroscopic photos were taken under a slit lamp using cobalt blue light, and the photos were clinically scored. The results showed that the corneal fluorescein score of the blank control group increased (12.37±2.64VS 0.57±0.21), indicating obvious defects in the corneal epithelium. However, in comparison, the corneal fluorescein staining scores of the experimental drug treatment groups decreased significantly after 5 days of treatment ( Fig.10 and Fig.11 ), tear secretion also increased significantly ( Fig.12 ). After the blank solvent was applied under the eyelids of healthy control mice, the corneal epithelial score was no different from that before the experiment. And after the five groups of menthol emulsions provided by the present invention were administered, no symptoms reflecting drug irritation such as scratching the drug application site with the front paws were found in the mice.

[0263] After the mice were administered with the oil-soluble control drug 8 group (oil-soluble control drug 8 in Example 1, i.e., the 12% oil-soluble menthol drug group), the mice were occasionally seen scratching the drug application site with their front paws, reflecting that this concentration of menthol slightly irritates the mouse lower eyelids. After the mice were administered with the solid control drug 1 group (containing menthol and other active ingredients at 20%), the mice were seen scratching the drug application site with their front paws, reflecting that this concentration of menthol irritates the mouse lower eyelids. After the mice were administered with the solid control drug 2 group (containing menthol and other active ingredients at 60%), the mice were immediately found scratching the drug application site with their front paws, reflecting that this concentration of menthol strongly irritates the mouse lower eyelids.

[0264] 4. Experimental Conclusion

[0265] Based on the above experimental results, it can be seen that the menthol emulsion provided by the present invention can have a significant therapeutic effect of promoting tear secretion in dry eye model mice within the menthol concentration range of 1.5%-7%, and will not cause discomfort reactions such as irritation in mice, and has good safety in use.

[0266] Example 10: Study on the mechanism of menthol emulsion in promoting tear secretion.

[0267] 1. Purpose of the experiment

[0268] The mechanism of the menthol emulsion of the present invention in promoting tear secretion was revealed by using mouse animal experiments.

[0269] 2. Experimental Design

[0270] Female C57BL / 6 mice were randomly divided into the following groups, with 8 mice in each group, namely:

[0271] Healthy rat control group;

[0272] Healthy mouse treatment group (experimental drug 5 in Example 1, i.e., 4% menthol drug group);

[0273] blank treatment group (i.e., blank solvent group without menthol);

[0274] Experimental drug group 2 (experimental drug 2 in Example 1, i.e., 1.5% menthol drug group);

[0275] Experimental drug group 5 (experimental drug 5 in Example 1, i.e., 4% menthol drug group);

[0276] Experimental drug group 8 (experimental drug 8 in Example 1, i.e., 7% menthol drug group).

[0277] Principle of nerve block mouse modeling: Compound lidocaine and carbamazepine are nerve blockers. When the two are administered together, they block the nerves in the skin around the eyes. After nerve blockade, tear secretion will be reduced compared with normal mice.

[0278] The healthy mice control group and the healthy mice treatment group were intraperitoneally injected with 0.2 mL of normal saline once a day (9 am) for 5 consecutive days. The other groups of mice were intraperitoneally injected with carbamazepine once a day (9 am) at a dose of 30 mg / kg, and 5% compound lidocaine cream (National Medicine Standard No. 2063466, produced by Tongfang Pharmaceutical Group Co., Ltd.) was applied to the periocular area twice a day (9 am and 18 pm), 250 mg / time. The area where the compound lidocaine was applied should include the area where the menthol skin pharmaceutical composition was applied, and the application area should be at least twice the area of ​​the menthol skin pharmaceutical composition applied, every day for 5 consecutive days. On the fourth day of the experiment, the tear secretion of all mice was measured.

[0279] On the fifth day of the experiment, 1 hour after the second application of compound lidocaine, the area where the compound lidocaine was applied was gently wiped with a cotton swab soaked in saline. 15 minutes after the end of wiping, each group of mice was given the corresponding experimental drugs, and each group of mice was randomly divided into two groups, each with 4 mice. 5 minutes and 30 minutes after the drug administration, one group was randomly selected, and the tear secretion of mice was measured with phenol red cotton thread. On the fifth day of the experiment, the healthy mice control group mice were smeared with blank solvent solution, and the healthy mice treatment group mice were smeared with experimental drugs 5. The other groups of mice were given drugs according to the experimental groups, and then each group of mice was randomly divided into two groups, each with 4 mice. 5 minutes and 30 minutes after the drug administration, one group was randomly selected, and the tear secretion of mice was measured with phenol red cotton thread.

[0280] 3. Experimental results

[0281] The experimental results are as follows Fig.13 As shown, after the blank solvent was applied to the eyelids of healthy control mice, there was no significant change in tear secretion, while after the healthy mice were treated with drug 5 (4% ​​menthol emulsion), the tear secretion increased significantly. The compound lidocaine and carbamazepine are nerve blockers that block the nerves in the skin around the eyes, and the tear secretion of mice is reduced compared with normal mice. Even if different concentrations of the menthol emulsion of the present invention are given, the tear secretion of mice does not increase significantly. This shows that the menthol composition of the present invention promotes tear secretion mainly by acting on the facial nerves of animals.

[0282] 4. Experimental Conclusion

[0283] The drug of the present invention promotes tear secretion mainly by acting on facial nerves.

[0284] Example 11: Comparison of menthol emulsion in promoting tear secretion and commonly used drugs on the market.

[0285] 1. Purpose of the experiment

[0286] Through a mouse experiment, the difference in efficacy between the menthol emulsion of the present invention and a commonly used drug for treating dry eye on the market was compared.

[0287] 2. Experimental Design

[0288] Three drugs commonly used in the treatment of dry eye disease, including 0.3% sodium hyaluronate eye drops (trade name: Aili), 0.4% polyethylene glycol eye drops (trade name: Siran), and 3% diquafosol sodium eye drops (trade name: Li Ai Si), were selected as control drugs.

[0289] The dry stress environment box was set to constant temperature (24±2°C), constant humidity (30±5%), and constant wind speed (2.5±0.5 km / s). Female C57BL / 6 mice were randomly divided into the following groups, with 6 mice in each group, namely:

[0290] Healthy rat control group;

[0291] Blank group (i.e., blank solvent group without menthol);

[0292] Experimental drug group 5 (experimental drug 5 in Example 1, i.e., 4% menthol emulsion);

[0293] Control drug group 4 (0.3% sodium hyaluronate eye drops group);

[0294] Control drug group 5 (0.4% polyethylene glycol eye drops);

[0295] 6 groups of control drugs (3% diquafosol sodium eye drops).

[0296] The healthy mouse control group was injected with 0.2 mL of normal saline subcutaneously in the hind limbs 4 times a day (9 o'clock, 12 o'clock, 15 o'clock, and 18 o'clock), and was placed in a normal environment with a relative humidity of 55% ± 10% for 5 days, for 5 consecutive days. The other groups of mice, except the healthy mouse control group, were injected with 2.5 mg / mL scopolamine solution subcutaneously in the hind limbs 6 times a day (8 o'clock, 11 o'clock, 13 o'clock, 15 o'clock, 17 o'clock, and 20 o'clock), 0.2 mL each time, and placed in a dry stress environment for 5 consecutive days. At the same time as the modeling, the applied drug was applied to the skin about 4 mm below the lower eyelid of the mouse, and about 5 mg was applied each time on the lower eyelid of each eye. The healthy control group was given a blank solvent 4 times a day, and about 5 mg was applied each time on the lower eyelid of each eye. Control drug group 4 (0.3% sodium hyaluronate eye drops group), control drug group 5 (0.4% polyethylene glycol eye drops), and control drug group 6 (3% diquafosol sodium eye drops) were administered 4 times a day, with each eye drop of about 5 μL (about 5 mg). Tear secretion and corneal fluorescein staining of mice in each group were measured 30 minutes after the last administration on the 5th day, and tear secretion of mice in each group was measured 2h and 4h.

[0297] 3. Experimental results

[0298] The results showed that the corneal fluorescein score of the blank control group increased, indicating obvious defects in the corneal epithelium. However, in comparison, there was no obvious corneal defect in the experimental drug treatment group and the control drug group after 5 days of treatment, and the fluorescein staining score decreased significantly ( Fig.14 and Fig.15 ). In tear secretion ( Fig.16 ), the tear secretion values ​​measured at 30min, 2h, and 4h after administration of the experimental drug 5 groups showed that as time went on, the tear secretion amount showed a downward trend, but compared with the blank treatment group, the tear secretion amount increased significantly, indicating that the menthol emulsion of the present invention has the effect of stimulating and promoting the recovery of the tear function of the dry eye model mice to a certain extent. However, the tear secretion of the three control drugs at the three time points after administration did not increase significantly, indicating that the three control drugs did not have a significant effect on the recovery of the tear secretion function of the dry eye mice themselves, and their mechanism of action was mainly to play the role of an exogenous tear-like supplement; after eye drops, the ocular surface was supplemented with exogenous liquid, and the measured ocular surface tear-like liquid (strictly speaking, it should be the exogenously added eye drops) increased, but as time went on, the exogenously added tear-like liquid was lost on the ocular surface, and the ocular surface began to become "dry" again. This experiment fully demonstrates that the low-concentration menthol drug of the present invention has a different treatment mechanism from the existing artificial tear eye drops for treating dry eyes. The present invention acts on the facial nerves to promote the body's own tear production, and the drug treatment effect of the present invention is more significant.

[0299] 4. Experimental Conclusion

[0300] The low-concentration menthol drug of the present invention has a different treatment mechanism from the existing artificial tear type eye drops for treating dry eye, and the drug treatment effect of the present invention is more significant. The drug of the present invention has the effect of stimulating the tear function of dry eye model mice to achieve a certain degree of recovery, while the three drugs widely used in clinical practice have no such effect.

[0301] 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 replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. Use of low-concentration menthol as the sole active ingredient in the preparation of a transdermal emulsion for facial administration for treating dry eye, wherein the transdermal emulsion contains low-concentration menthol as the sole active ingredient and an oil phase matrix, an emulsifier and an aqueous phase, wherein the mass proportion of menthol is 1.5%-7%, the mass proportion of the oil phase matrix is ​​3%-25%, the mass proportion of the emulsifier is 0.05%-3%, and the balance is an aqueous phase; The oil phase matrix is ​​one or more selected from tea oil, olive oil, soybean oil, coconut oil, sunflower oil, corn oil, avocado oil, shea butter, grape seed oil, almond oil, castor oil and jojoba oil, lanolin, beeswax, medium chain triglycerides, isopropyl palmitate, safflower oil, stearyl alcohol, stearic acid, cetyl alcohol, cholesterol, silicone oil, liquid paraffin; The emulsifier is at least one selected from lecithin, polyoxyethylene 35 castor oil, polyoxyethylene 40 castor oil, polyoxyethylene 40 hydrogenated castor oil, Tween 80, Span 80, poloxamer 188, poloxamer 407, sodium stearate, potassium stearate, sodium lauryl sulfate, sodium hexadecyl sulfate, cetyl alcohol, polyoxyethylene 40 stearate, polyoxyethylene lauryl ether, and sucrose fatty acid ester.

2. The use according to claim 1, characterized in that: The menthol is natural menthol or synthetic menthol.

3. The use according to claim 1, characterized in that: The emulsion consists of 2%-6% menthol, 5%-20% oil phase matrix, 0.05%-3% emulsifier and the balance water phase.

4. The use according to claim 1, characterized in that: The aqueous phase is water, or an aqueous solution in which a water-soluble auxiliary agent is dissolved.

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