Penetration compositions based on polyglyceryl-10 myristate

Abstract

A kind of permeation composition based on polyglyceryl-10 myristate, it includes ergothioneine and polyglyceryl-10 myristate, the weight ratio of ergothioneine and polyglyceryl-10 myristate is 1:0.4-12, wherein, the content of polyglyceryl-10 myristate is 0.01wt%-2wt%.The permeation rate of the composition after 24h vertical percutaneous diffusion is 52.67-67.47%.The application of the aqueous dispersion system in skin external preparation is also disclosed.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of skin external agents, in particular to the directional penetration of ergothioneine in specific content by polyglyceryl-10 myristate, and more particularly to a penetration composition based on polyglyceryl-10 myristate, which can improve the penetration and absorption of ergothioneine in the skin, and has excellent stability. BACKGROUND

[0002] It is well known that the skin is the largest organ of our body, which has the functions of secretion, perspiration, perception, and temperature regulation, as well as protection and defense. The skin is the first defense system of the human body, which can prevent foreign invasion and bacterial infection. Due to the barrier function of the skin, the transdermal rate and absorption rate of most drugs or active ingredients, even low-dose high-efficiency ingredients, are difficult to achieve a very high ideal state.

[0003] The direct transdermal absorption pathway is divided into three types: intercellular pathway, transcellular pathway and appendage pathway. Each pathway has its own characteristics:

[0004] 1) Intercellular pathway: This pathway is the main path. The effective substance bends through the intercellular matrix of the keratinocytes. These intercellular matrices are composed of a large number of lipid bilayers, and the lipids in these keratin layers mainly contain ceramides, cholesterol, and free fatty acids. These lipids are lipophilic, so small molecular oil components are easy to pass through, but water-soluble components are not easy to pass through, such as ergothioneine.

[0005] 2) Transcellular pathway: The effective substance directly penetrates the keratinocytes and intercellular matrix. The permeability of keratinocytes is low, and it needs to pass through multiple hydrophilic / lipophilic barriers when passing through the transcellular pathway, so this process is very difficult, and this pathway only accounts for a very small part of skin absorption.

[0006] 3) Appendage pathway: The skin appendages include hair follicles, sebaceous glands and sweat glands. Large molecules or some ionic substances may pass through this pathway and directly reach the dermis. However, the area of the appendages on the skin surface is only about 0.1%, so it is not the main transdermal absorption pathway.

[0007] The transdermal absorption theory cannot be bypassed for the absorption of drugs or cosmetics through the skin, and the transdermal absorption theory mainly includes the following: diffusion theory, osmotic pressure theory, hydration theory, similar phase solubility theory and structure change theory.

[0008] 1) Transdermal absorption theory: to evaluate the passive transdermal ability of the material, generally using Fick's first law. The formula is R = K x A (cl-c2) / d, R: diffusion rate, K: diffusion constant of specific exogenous chemicals, A: skin area, (cl-c2): concentration gradient on both sides of the skin, d: the thickness of the stratum corneum. This theory comprehensively explains the influence of various factors on transdermal absorption, and can only roughly calculate the rate of transdermal absorption of chemicals, because the process of chemicals penetrating the skin consumes a long time and is difficult to reach equilibrium, which is a common theory.

[0009] 2) Osmotic pressure theory: the skin is regarded as a semi-permeable membrane, which separates solutions of different concentrations, and the solution penetrates the semi-permeable membrane from high concentration to low concentration, so that the active substance is absorbed. Two conditions must be met for the occurrence of osmotic phenomenon: one is that a semi-permeable membrane exists, and the other is that the two sides of the semi-permeable membrane must be two solutions of different concentrations. This theory can be used to explain why light tapping the face when applying cosmetic water, or massaging the application of cream and milk, can increase the osmotic pressure, so that the cosmetics are more easily absorbed.

[0010] 3) Hydration theory: when the hydration of keratin protein containing nitrogen in the keratinocyte is improved, the cell swells, reducing the compactness of the structure, and the permeability of the substance increases, making it easier for water-soluble and polar substances to penetrate the stratum corneum. Therefore, moisturizing agents (glycerol, etc.) are often added to cosmetics to improve the absorption of active ingredients; and patch masks make the local skin closed, increasing the degree of skin hydration. This method is more effective for water-soluble substances than for fat-soluble substances.

[0011] 4) Similarity theory: in transdermal absorption, when the active ingredient and the skin composition, structure and properties are similar, it is easy to be absorbed through the skin. Non-polar ingredients can easily penetrate the barrier through the lipid-rich intercellular space, while polar ingredients rely on the permeation of cells to cross the barrier. For example, the use of similar solubility theory in makeup removal oil to remove makeup.

[0012] 5) Structure change theory: penetration enhancers can promote the absorption of chemicals by destroying the ordered arrangement of intercellular lipids, or directly extracting stratum corneum lipid components, or destroying the compact structure of keratin proteins, or increasing the solubility of the stratum corneum. This is the penetration mechanism of many surfactants.

[0013] In the prior art, Chinese Patent Application CN116942590A discloses a four-dimensional acid Pickering nanoemulsion and a preparation method thereof. The average particle size of the four-dimensional acid Pickering nanoemulsion is 50-200 nm, and the four-dimensional acid Pickering nanoemulsion comprises the following raw materials by mass fraction: 10-30 wt% of salicylic acid; 5-10 wt% of mandelic acid; 2-5 wt% of azelaic acid; 0.1-1 wt% of glycyrrhizinate; 1-20 wt% of an emulsifier; 1-20 wt% of a liquid lipid; 1-10 wt% of a co-emulsifier; 1-20 wt% of a polyol; 0.5-5 wt% of a particle stabilizer; and the balance is water. The sum of the mass percentages of the above components is 100%. The emulsifier is selected from one or more of polyglyceryl 10 stearate, polyglyceryl 10 diisostearate, polyoxyethylene hydrogenated castor oil, cetyl stearyl alcohol polyether, coconut oil glucoside, polyethylene glycol laurate, lecithin, and polyglyceryl 10 myristate. The four-dimensional acid Pickering nanoemulsion prepared by the present application can effectively solve the application defects of the acid component in the prior art, such as high irritability, low solubility, and difficulty in being used in transparent formulations. The prepared four-dimensional acid Pickering nanoemulsion can make the active ingredient penetrate the skin, release and control in the stratum corneum, greatly improve the bioavailability of the active ingredient, and truly realize the acceleration of skin metabolism, help the aging stratum corneum to peel off, and achieve the effects of skin rejuvenation and brightening. In the application, polyglyceryl 10 myristate is used as an emulsifier, and since the entire system is at the nanoscale, the active ingredient can penetrate the skin. However, it does not suggest that polyglyceryl 10 myristate can be used as a penetration enhancer for ergothioneine.

[0014] As a common surfactant of polyglycerol, polyglyceryl-10 myristate is unexpectedly found to be able to increase the penetration of ergothioneine in the skin. Polyglyceryl-10 myristate is economical, practical and easy to obtain, and it is very meaningful to find such a raw material to help ergothioneine penetrate. SUMMARY

[0015] The present application aims to provide a combination of polyglyceryl-10 myristate, which can improve the penetration and absorption of ergothioneine in the skin, and the combination is stable.

[0016] The present application provides a penetration composition based on polyglyceryl-10 myristate, which comprises ergothioneine and polyglyceryl-10 myristate, and the weight ratio of the ergothioneine and the polyglyceryl-10 myristate is 1:0.4-12, wherein the content of the polyglyceryl-10 myristate is 0.01wt%-2wt%.

[0017] In a preferred embodiment, the content of the polyglyceryl-10 myristate is 0.01wt%-1wt%.

[0018] In a preferred embodiment, the weight ratio of ergothioneine and polyglyceryl-10 myristate is 1:0.5-10.

[0019] In a preferred embodiment, the composition can further comprise ≥97wt% of a carrier suitable for use in skin external agents.

[0020] Preferably, the carrier is selected from water. In a preferred embodiment, the composition has a permeation rate ≥50% after 24h vertical transdermal diffusion.

[0021] Preferably, the composition has a permeation rate of 52.67-67.47% after 24h vertical transdermal diffusion.

[0022] The present application also provides the use of polyglyceryl-10 myristate for promoting the permeation of ergothioneine.

[0023] In a preferred embodiment, the weight ratio of ergothioneine and polyglyceryl-10 myristate is 1:0.4-12,

[0024] Preferably, the weight ratio is 1:0.5-10.

[0025] The present application also provides the use of the permeation composition based on polyglyceryl-10 myristate in skin external agents.

[0026] In a preferred embodiment, the composition is used in skin external agents in an amount of 0.01wt%-20wt%.

[0027] In a preferred embodiment, the skin external agent is selected from cream, lotion, essence, gel, toner, mask, cleanser, bath agent, make-up remover, hair care, oil agent, floral water.

[0028] The present application has the following beneficial effects:

[0029] The polyglyceryl-10 myristate composition obtained according to the above scheme can not only ensure very stability, but also increase the transdermal absorption of ergothioneine in the skin. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 It is a working schematic diagram of the vertical diffusion cell used in the permeability test example;

[0031] Figure 2 It is a high performance liquid chromatogram of ergothioneine in Example 3 (3h);

[0032] Figure 3 It is a high performance liquid chromatogram of ergothioneine in Example 3 (24h). DETAILED DESCRIPTION

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, the preferred methods and materials are described. For the purposes of the present application, the following terms are defined below.

[0034] For the sake of providing a more concise description, some of the numerical descriptions given herein are not modified by the term "about". It is to be understood that every quantity given herein is intended to refer to both an actual given value and to an approximate value close to the actual given value, including values that would be obtained by rounding the given value to a reasonable number of significant figures in the context of the quantity. The term "about" is used in relation to a given value to indicate that the exact value need not be used, but that the approximate value is acceptable.

[0035] For the sake of providing a more concise description, some of the numerical descriptions given herein are recited as a range from about X amount to about Y amount. It is to be understood that when a range is recited, the range is not limited to the recited upper and lower values, but is intended to include the entire range of values between about X amount and about Y amount or any amount therebetween.

[0036] Carriers suitable for use in the field of topical skin preparations

[0037] The carrier suitable for the skin external agent of the present application is water, and the skin external agent can be selected from the group consisting of cream, emulsion, essence, jelly, lotion, pack, cleanser, bath agent, make-up remover, hair washing and hair care agent, oil agent, and floral water.

[0038] Permeation rate

[0039] The permeation rate of the present application is the permeation rate calculated from the amount of ergothioneine permeated through pigskin after 24 hours of vertical transdermal diffusion. In the present application, it is considered that the permeation rate has a permeation promoting effect if it is ≥ 50% after 24 hours of vertical transdermal diffusion.

[0040] Hereinafter, the technical solutions of the present application will be described in detail through preferred embodiments, but the scope of the present application is not limited to these embodiments, which are intended to illustrate the technical solutions of the present application rather than limit the scope of the present application. The test methods in the following examples are generally carried out under conventional conditions, or under the conditions recommended by the manufacturer, unless otherwise specified. All percentages and parts are by weight, unless otherwise specified.

[0041] The experimental materials used in the examples of the present application are as follows:

[0042] (I) Experimental materials

[0043] 1. Polyglyceryl-10 myristate (trade name NIKKOL Decaglyn 1-M, purchased from NIPPON SURFACTANT INDUSTRIES CO., LTD.)

[0044] 2. Ergothioneine (purchased from Shanghai Ergothioneine Biotechnology Group Co., Ltd.)

[0045] 3. Deionized water (self-made)

[0046] 4. Neosolue TM - Aqulio bis-diethoxydiglycol cyclohexane 1,4-dicarboxylate (purchased from NIPPON OIL & FAT CO., LTD.)

[0047] 5. 1,2-Pentanediol (trade name: effisin PG multifunctional, purchased from Ashland LLC) TM pg multifunctional, purchased from Ashland LLC)

[0048] 6. Laurocapram (purchased from TGI)

[0049] 7. RH 40 (trade name RH 40, purchased from BASF)

[0050] 8. 1,2-Hexanediol (trade name KMO-6, purchased from OSAKA ORGANIC CHEMICAL INDUSTRY LTD.)

[0051] 9. Propylene glycol (trade name Propylene Glycol USP / EP, purchased from DOW CHEMICAL)

[0052] 10. 0.9wt% physiological saline (self-made)

[0053] (B) Experimental instruments

[0054] 1. Fixed stirrer IKA RW20

[0055] 2. Weighing balance METTLER TOLEDO PL602-S

[0056] 3. Transdermal diffusion tester TK-12D, Shanghai Yuren Scientific Instrument Co., Ltd.

[0057] 4. Back skin of 1-2 month old miniature pigs Chongqing Meisheng Trading Co., Ltd.

[0058] 5. High-performance liquid chromatograph equipped with a diode array detector Waters ARC HPLC

[0059] 6. Incubator MMM Friocell 707

[0060] 7. Analytical balance METTLER TOLEDO XS205

[0061] 8. Digital ultrasonic cleaner Kunshan Ultrasonic Instrument Co., Ltd. KQ-800DE

[0062] Examples 1-14: Preparation of ergothioneine and polyglyceryl-10 myristate aqueous solutions with different proportions and concentrations

[0063] Sample preparation: Ergothioneine and polyglyceryl-10 myristate were weighed according to the mass fraction shown in Table 1, and deionized water was added to make up 100 mass parts. After stirring at room temperature until a transparent liquid was obtained, it was ready for use.

[0064] Table 1: Components in ergothioneine and polyglyceryl-10 myristate aqueous solutions with different proportions and concentrations

[0065]

[0066]

[0067] Test Example 1: Permeability test

[0068] Test sample: Ergothioneine and polyglyceryl-10 myristate aqueous solutions with different proportions and concentrations prepared in Examples 1-14

[0069] Test steps:

[0070] 1) The frozen pigskin was taken out and after thawing, the subcutaneous fat and connective tissue were removed with scissors.

[0071] 2) The pigskin was immersed in physiological saline for 1 hour.

[0072] 3) The water bath of the transdermal diffusion instrument was turned on and heated (constant temperature 32°C).

[0073] 4) A magnetic stirrer was placed in the receiving pool, then the pigskin after cutting was fixed between the supply pool and the receiving pool, with the epidermis layer facing up and the dermis layer contacting the receiving pool. Physiological saline was added to the receiving pool as the receiving liquid, and the bubbles were discharged. A cover glass was placed on the supply pool, and the transdermal diffusion device was fixed in the transdermal diffusion device, and the temperature was kept constant (32°C) and stirred (440 r / min) for 1 hour.

[0074] 5) Each sample of the examples was added to the supply pool, i.e. the place where the raw material was located, and contacted with the pigskin, and the temperature was kept constant (32°C) and stirred (440 r / min). The receiving liquid was taken from the sampling tube at 3h and 24h, respectively, for measurement.

[0075] 6) The content of ergothioneine in the receiving liquid was determined by high performance liquid chromatography

[0076] a. Chromatographic conditions: the chromatographic column was Agilent HILIC Plus column (4.6 mm*100 mm, 3.5 μm), the mobile phase was 0.1% formic acid acetonitrile solution-0.1% formic acid water solution with a volume ratio of 80:20, the flow rate was 1 mL / min, the column temperature was 30 °C, the injection volume was 10 μL, and the detection wavelength was 262 nm.

[0077] b. Ergothioneine standard stock solution (0.5 g / L) preparation: 50 mg of ergothioneine standard was weighed (accurate to 0.01 mg), dissolved with water and made up to 100 mL. Stored at 4 °C.

[0078] c. Ergothioneine standard working solution preparation: a certain amount of ergothioneine standard stock solution was accurately transferred, and a series of standard working solutions (with mass concentrations of 5 μg / mL, 10 μg / mL, 25 μg / mL, 50 μg / mL and 100 μg / mL) were obtained by stepwise dilution with 0.1% formic acid methanol solution.

[0079] d. Standard curve preparation: the standard working solutions were determined according to the above chromatographic conditions, and the standard curve was drawn with the mass concentration of the standard working solution as the abscissa and the peak area as the ordinate.

[0080] e. Sample treatment and determination: 0.1-0.5 g (accurate to 0.1 mg) of sample was weighed into a 10 mL stoppered colorimetric tube, 8 mL of 0.1% formic acid methanol solution was added, and ultrasonic extraction was performed for 20 min. The sample was diluted with 0.1% formic acid methanol solution, shaken well, and part of the liquid was filtered through a 0.22 μm filter membrane. The sample was determined according to the above chromatographic conditions. The sample was quantified on the standard curve. The response value of the analyte in the sample solution should be within the linear range of the standard curve.

[0081] 7) Calculate the cumulative permeability

[0082] EGT permeability = (m 取样量 × C EGT ) / (m 上样量 × C EGT总 ) x 100%

[0083] Table 2 Permeability of ergothioneine and polyglycerol-10 myristate aqueous solution with different proportions and concentrations

[0084]

[0085]

[0086] The penetration rate of the composition sample prepared in Example 2 at 3h is 1.34%, which is less than the penetration rate of the composition sample prepared in Example 1 at 3h, and the penetration rate of the composition sample prepared in Example 2 at 24h is 25.37%, which is less than the penetration rate of the composition sample prepared in Example 1 at 24h, so it is considered that the composition sample prepared in Example 2 has no penetration effect.

[0087] The penetration rate of the composition sample prepared in Example 2 at 3h is 1.34%, which is less than the penetration rate of the composition sample prepared in Example 1 at 3h, and the penetration rate of the composition sample prepared in Example 2 at 24h is 25.37%, which is less than the penetration rate of the composition sample prepared in Example 1 at 24h, so it is considered that the composition sample prepared in Example 2 has no penetration effect.

[0088] The penetration rate of the composition sample prepared in Example 3 at 3h is 5.80%, which is greater than the penetration rate of the composition sample prepared in Example 1 at 3h, and the penetration rate of the composition sample prepared in Example 3 at 24h is 61.21%, which is greater than the penetration rate of the composition sample prepared in Example 1 at 24h, so it is considered that the composition sample prepared in Example 3 has a synergistic penetration effect.

[0089] The penetration rate of the composition sample prepared in Example 4 at 3h is 10.9%, which is greater than the penetration rate of the composition sample prepared in Example 1 at 3h, and the penetration rate of the composition sample prepared in Example 4 at 24h is 60.23%, which is greater than the penetration rate of the composition sample prepared in Example 1 at 24h, so it is considered that the composition sample prepared in Example 4 has a synergistic penetration effect.

[0090] The penetration rate of the composition sample prepared in Example 5 at 3h is 15.37%, which is greater than the penetration rate of the composition sample prepared in Example 1 at 3h, and the penetration rate of the composition sample prepared in Example 5 at 24h is 63.78%, which is greater than the penetration rate of the composition sample prepared in Example 1 at 24h, so it is considered that the composition sample prepared in Example 5 has a synergistic penetration effect.

[0091] In summary, by comparing the penetration rates at 3h and 24h, it can be seen that when the content of ergothioneine in the composition is 1wt%, and the content of polyglyceryl-10 myristate is 0.5-2wt% (i.e. ergothioneine: polyglyceryl-10 myristate = 2:1, 1:1, 1:2), the composition exhibits a synergistic penetration effect. However, when the content of polyglyceryl-10 myristate is 0.3wt% (i.e. ergothioneine: polyglyceryl-10 myristate = 10:3), the composition has no penetration effect.

[0092] The sample of the composition prepared in Example 7 had a 3 h permeation rate of 5.35% which was less than the 10.46% permeation rate of the sample of the composition prepared in Example 6, and the sample of the composition prepared in Example 7 had a 24 h permeation rate of 25.08% which was less than the 47.01% permeation rate of the sample of the composition prepared in Example 6, and the sample of the composition prepared in Example 7 was considered to have no permeation effect;

[0093] The sample of the composition prepared in Example 8 had a 3 h permeation rate of 10.44% which was less than the 10.46% permeation rate of the sample of the composition prepared in Example 6, and the sample of the composition prepared in Example 8 had a 24 h permeation rate of 49.34% which was greater than the 47.01% permeation rate of the sample of the composition prepared in Example 6, and the sample of the composition prepared in Example 8 was considered to have no synergistic permeation effect;

[0094] The sample of the composition prepared in Example 9 had a 3 h permeation rate of 13.32% which was greater than the 10.46% permeation rate of the sample of the composition prepared in Example 6, and the sample of the composition prepared in Example 9 had a 24 h permeation rate of 48.45% which was greater than the 47.01% permeation rate of the sample of the composition prepared in Example 6, and the sample of the composition prepared in Example 9 was considered to have a synergistic permeation effect;

[0095] The sample of the composition prepared in Example 10 had a 3 h permeation rate of 17.76% which was greater than the 10.46% permeation rate of the sample of the composition prepared in Example 6, and the sample of the composition prepared in Example 10 had a 24 h permeation rate of 52.67% which was greater than the 47.01% permeation rate of the sample of the composition prepared in Example 6, and the sample of the composition prepared in Example 10 was considered to have a synergistic permeation effect;

[0096] The sample of the composition prepared in Example 11 had a 3 h permeation rate of 20.64% which was greater than the 10.46% permeation rate of the sample of the composition prepared in Example 6, and the sample of the composition prepared in Example 11 had a 24 h permeation rate of 49.74% which was greater than the 47.01% permeation rate of the sample of the composition prepared in Example 6, and the sample of the composition prepared in Example 11 was considered to have a synergistic permeation effect;

[0097] The sample of the composition prepared in Example 12 had a 3 h permeation rate of 6.01% which was less than the 10.46% permeation rate of the sample of the composition prepared in Example 6, and the sample of the composition prepared in Example 12 had a 24 h permeation rate of 21.98% which was less than the 47.01% permeation rate of the sample of the composition prepared in Example 6, and the sample of the composition prepared in Example 12 was considered to have no synergistic permeation effect;

[0098] In summary, by comparing the 3h permeation rate with the 24h permeation rate, it can be seen that when the content of ergothioneine in the composition is 0.1wt%, the content of polyglyceryl-10 myristate is 0.04-1.2wt% (i.e. ergothioneine: polyglyceryl-10 myristate = 1:0.4-12), the composition exhibits synergistic penetration effect. When the content of polyglyceryl-10 myristate is 0.01wt% or 2wt% (i.e. ergothioneine: polyglyceryl-10 myristate = 10:1 or 1:20), the composition has no penetration effect.

[0099] The 3h permeation rate of the composition sample prepared in Example 14 is 14.70%, which is greater than the 11.41% of the composition sample prepared in Example 13, and the 24h permeation rate of the composition sample prepared in Example 14 is 67.47%, which is greater than the 59.70% of the composition sample prepared in Example 13, and it is considered that the composition sample prepared in Example 14 has synergistic penetration effect;

[0100] In summary, by comparing the 3h permeation rate with the 24h permeation rate, it can be seen that when the content of ergothioneine in the composition is 0.001wt%, the content of polyglyceryl-10 myristate is 0.01wt% (i.e. ergothioneine: polyglyceryl-10 myristate = 1:10), the composition exhibits synergistic penetration effect.

[0101] Test Example 2: Stability test

[0102] Test sample: aqueous solution of ergothioneine and polyglyceryl-10 myristate with different proportions and concentrations prepared in Examples 1-14

[0103] Stability evaluation method: place the sample in a constant temperature oven at room temperature (25°C) and high temperature (48°C) respectively, and observe whether the sample has color change, crystal or particle precipitation, odor change problem at each time point after the sample is restored to room temperature for 1 week, 4 weeks.

[0104] No color change, represented by ○; color change or other changes, represented by ×.

[0105] Odor index: no change in odor (acceptable) is 0 points;

[0106] There is a slight unpleasant odor (still acceptable) for 1-2 points;

[0107] There is a similar sulfur smell (unacceptable) for 3-4 points;

[0108] There is a significant increase in sulfur smell, and the odor is unpleasant (unacceptable) for 5 points.

[0109] Table 3 Stability of aqueous solution of ergothioneine and polyglyceryl-10 myristate with different proportions and concentrations

[0110]

[0111]

[0112] After 1 week stability, the samples of the compositions prepared in Examples 1-14 all had no change in color, and none of them precipitated crystals or particles, and none of them had odor change at room temperature. The sample of the composition prepared in Example 1-12 had slight unpleasant odor at high temperature. The samples of the compositions prepared in Examples 13-14 had no odor change at high temperature.

[0113] Therefore, it can be concluded that after 1 week stability test, when the content of ergothioneine in the composition is 1wt% and 0.1wt%, high temperature can make it have unpleasant odor, and room temperature is better. When the content of ergothioneine in the composition is 0.001wt%, there is no odor change at room temperature and high temperature.

[0114] After 4 weeks stability, the samples of the compositions prepared in Examples 1-14 all had no change in color, and none of them precipitated crystals or particles. The sample of the composition prepared in Example 1-12 had slight unpleasant odor at room temperature and high temperature. The samples of the compositions prepared in Examples 13-14 had no odor change at room temperature and high temperature.

[0115] Therefore, it can be concluded that after 4 weeks stability test, when the content of ergothioneine in the composition is 1wt%, compared with the stability test results at 1 week, the odor is heavier at room temperature; the odor at high temperature has no change. When the content of ergothioneine in the composition is 0.1wt%, compared with the stability test results at 1 week, the odor is heavier at room temperature; the odor at high temperature has no change. When the content of ergothioneine in the composition is 0.001wt%, compared with the stability test results at 1 week, there is no odor change at room temperature and high temperature.

[0116] Comparative Examples 1-5: Preparation of aqueous solutions of ergothioneine and different penetration enhancers

[0117] Sample preparation: Ergothioneine and different penetration enhancers were weighed according to the mass fraction shown in Table 4, deionized water was added to make up 100 mass parts, and then stirred at room temperature until a transparent liquid was obtained for standby.

[0118] Table 4: Content of each component in aqueous solutions of ergothioneine and different penetration enhancers

[0119]

[0120] Note: The weight ratio of laurocapram: RH40 in the table is 3:7

[0121] Test Example 3: Penetration test

[0122] Test sample: ergothioneine prepared in Comparative Examples 1-5 and aqueous solutions of different penetration enhancers

[0123] Test procedure:

[0124] 1) The frozen pigskin was taken out and after thawing, the subcutaneous fat and connective tissue were removed with scissors.

[0125] 2) The pigskin was immersed in physiological saline for 1 hour.

[0126] 3) The water bath of the transdermal diffusion instrument was opened and heated (constant temperature 32°C).

[0127] 4) A magnetic stirrer was placed in the receiving pool, then the pigskin after cutting was fixed between the supply pool and the receiving pool, with the epidermis layer facing upwards and the dermis layer contacting the receiving pool. Physiological saline was added into the receiving pool as the receiving liquid, and the bubbles were discharged. The cover glass was placed on the supply pool, and the transdermal diffusion device was fixed and incubated (32°C) with stirring (440 r / min) for 1 hour.

[0128] 5) The sample of each example was added to the supply pool, i.e. where the raw material was located, to contact the pigskin, and incubated (32°C) with stirring (440 r / min). The receiving liquid was taken from the sampling tube at 3 hours and 24 hours, respectively, for determination.

[0129] 6) The content of ergothioneine in the receiving liquid was determined by high performance liquid chromatography

[0130] a. Chromatographic conditions: the chromatographic column was Agilent HILIC Plus chromatographic column (4.6 mm*100 mm, 3.5 μm), the mobile phase was 0.1% formic acid acetonitrile solution-0.1% formic acid water solution at a volume ratio of 80:20, the flow rate was 1 mL / min, the column temperature was 30°C, the injection volume was 10 μL, and the detection wavelength was 262 nm.

[0131] b. Preparation of ergothioneine standard stock solution (0.5 g / L): 50 mg of ergothioneine standard was weighed (accurate to 0.01 mg), dissolved with water and diluted to 100 mL. It was stored at 4°C.

[0132] c. Preparation of ergothioneine standard working solution: a certain amount of ergothioneine standard stock solution was accurately transferred, and a series of standard working solutions (mass concentrations were 5 μg / mL, 10 μg / mL, 25 μg / mL, 50 μg / mL, 100 μg / mL) were obtained by stepwise dilution with 0.1% formic acid methanol solution.

[0133] d. Standard curve preparation: the standard working solution was determined according to the above chromatographic conditions, and the standard curve was drawn with the mass concentration of the standard working solution as the abscissa and the peak area as the ordinate.

[0134] e.Sample treatment and determination: 0.1-0.5 g (accurate to 0.1 mg) of sample was weighed into a 10 mL stoppered colorimetric tube, 8 mL of 0.1% formic acid methanol solution was added, and ultrasonic extraction was performed for 20 min. The sample was diluted with 0.1% formic acid methanol solution, shaken well, and part of the liquid was filtered through a 0.22 μm filter membrane, and then determination was performed according to the above chromatographic conditions. The sample was quantified on the standard curve. The response value of the analyte in the sample solution should be within the linear range of the standard curve.

[0135] 7) Calculate the cumulative permeation rate

[0136] EGT permeation rate = (m 取样量 × C EGT ) / (m 上样量 × C EGT总 ) x 100%

[0137] Table 5 Permeation rate of ergothioneine and aqueous solution of different penetration enhancers

[0138]

[0139] In this application, when the sample of the composition under investigation has a permeation rate of more than 50% in 24 h, it is considered to have a penetration enhancing effect.

[0140] There are many common penetration enhancement techniques in the industry, one of which is chemical penetration enhancement, which is mostly a surfactant or a polyol raw material. Neosolue TM Aqulio, 1,2-pentanediol, 1,2-hexanediol, propylene glycol, RH40 are all chemical penetration enhancers. Laurocapram is one of the most commonly used penetration enhancers in the pharmaceutical field, which also belongs to the category of chemical penetration enhancers.

[0141] Therefore, the sample of the composition prepared in Comparative Example 1-2 and Comparative Example 5 has a permeation rate of more than 50% in 24 h, i.e. the sample of the composition prepared in Comparative Example 1-2 and Comparative Example 5 has a penetration enhancing effect.

[0142] The sample of the composition prepared in Comparative Examples 3 and 4 has no penetration enhancing effect; according to the permeability data of the sample of the composition prepared in Example 14 in Table 2, i.e. the aqueous solution of ergothioneine and polyglycerol-10 myristate has the highest permeation rate of 67.47%, and the highest penetration enhancing efficiency.

[0143] Test Example 4: Stability test

[0144] Test sample: aqueous solution of ergothioneine and different penetration enhancers prepared in Comparative Examples 1-5

[0145] Stability evaluation method: The samples were placed in a constant temperature oven at room temperature (25°C) and high temperature (48°C) for 1 week and 4 weeks, respectively. At each time point, the samples were returned to room temperature, and whether the samples had color changes, crystal or particle precipitation, or odor changes was observed.

[0146] No color change, represented by o; color change to yellow or other changes, represented by x.

[0147]

[0148] After 1 week of stability, the color of the compositions prepared in Comparative Examples 1-5 did not change, and no crystals or particles were precipitated.

[0149] After 4 weeks of stability, the color of the compositions prepared in Comparative Examples 1-5 did not change, and no crystals or particles were precipitated.

[0150] In summary, after 1-4 weeks of stability testing, when the ergothioneine content in the composition was 0.001 wt%, there was no color change or crystal precipitation at room temperature and high temperature.

[0151] Application Examples

[0152] The compositions of polyglyceryl-10 myristate and ergothioneine in Examples 1-14 were used to prepare skin external agents. The skin external agents are preferably cosmetic compositions, such as cosmetic water, serum, cream, mask, jelly, facial cleanser, shampoo, bath, makeup remover, etc. The weight percentage of the polyglyceryl-10 myristate composition in Examples 1-14 in the skin external agent is 0.01%-20% (w / w). The preferred weight percentage is 0.01%-10% (w / w). The more preferred weight percentage is 0.01%-5% (w / w).

[0153] The following are specific application examples of the polyglyceryl-10 myristate composition in Examples 1-14 in skin external agents, as well as the formulations and preparation methods of these dosage forms. In the following tables, "-" indicates no addition.

[0154] Application Example 1: Preparation of a cream

[0155]

[0156] Application Example 2: Preparation of an emulsion

[0157]

[0158]

[0159] Application Example 3: Preparation of a jelly

[0160]

[0161] Preparation Example 4: Preparation of a toner

[0162]

[0163] Preparation Example 5: Preparation of an essence

[0164]

[0165]

[0166] Preparation Example 6: Preparation of a pack

[0167]

[0168] Preparation Example 7: Preparation of an eye cream

[0169]

[0170]

[0171] Preparation Example 8: Preparation of an aerosol (cleansing foam)

[0172]

[0173] Preparation Example 9: Preparation of a spray

[0174]

[0175] Preparation Example 10: Preparation of a shower

[0176]

[0177] Preparation Example 11: Preparation of a facial cleanser

[0178]

[0179]

[0180] Preparation Example 12: Preparation of an essence

[0181]

[0182] In all of the above specific application examples of skin external agents, the polyglyceryl-10 myristate composition of Examples 1 to 14 can be used in the formulations either partially or wholly in place of deionized water or directly as a formulation.

Claims

1. A penetrant composition based on polyglyceryl- 10 myristate consisting of ergothioneine, polyglyceryl- 10 myristate and water, wherein, The content of the polyglyceryl-10 myristate is 0.01wt%-2wt%, the content of the ergothioneine is 0.001wt%-1wt%, and the weight ratio of the ergothioneine and polyglyceryl-10 myristate is 1:0.5-10.

2. The composition of claim 1, wherein The content of the polyglyceryl-10 myristate is 0.01wt%-1wt%.

3. The composition according to any one of claims 1 to 2, wherein The penetration rate of the composition after 24h vertical transdermal diffusion is ≥50%.

4. The composition of claim 3, wherein The penetration rate of the composition after 24h vertical transdermal diffusion is 52.67-67.47%.

5. Use of polyglyceryl-10 myristate to promote the penetration of ergothioneine, characterized in that, The content of the ergothioneine is 0.001wt%-1wt%, the weight ratio of the ergothioneine and polyglyceryl-10 myristate is 1:0.5-10, and the content of the polyglyceryl-10 myristate is 0.01wt%-2wt%.

6. The use of the composition of claim 4 in a non-therapeutic skin external preparation.

7. The use of claim 6, wherein the content of the composition in the non-therapeutic skin external preparation is 0.01wt%-20wt%.

8. Use according to claim 7, wherein The non-therapeutic skin external preparation is selected from the group consisting of cream, emulsion, essence, jelly, lotion, mask, cleanser, bath agent, make-up remover, hair washing and conditioning agent, oil agent, and floral water.

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