Ceramide nano-emulsion with good stability as well as preparation method and application of ceramide nano-emulsion

Abstract

The invention relates to a ceramide nanoemulsion with good stability as well as a preparation method and application of the ceramide nanoemulsion. The ceramide nanoemulsion accounts for 100% of the total mass of the nanoemulsion. The nano-emulsion comprises the following components in percentage by weight: 0.2%-2% of ceramide, 0.1332%-1.32% of cholesterol, 0.097%-0.97% of linoleic acid, 5%-15% of grease, 1%-2% of lecithin, 0.03%-0.2% of an antioxidant, 0.6%-9% of a nonionic surfactant and 3%-12% of polyol. According to the nano-emulsion disclosed by the invention, the lecithin and the nonionic surfactant are compounded, and the polyol has a synergistic effect, so that the nano-emulsion is good in stability under extreme environment conditions such as freezing and high temperature, and the particle size of the nano-emulsion is not obviously changed within 3 months. The ceramide nano-emulsion which is small in particle size, high in encapsulation efficiency and good in permeation enhancing effect is prepared through a high-pressure homogenization technology, transdermal absorption of ceramide is effectively promoted, and the physical stability of ceramide in a formula is improved.

Description

Technical Field

[0001] This application relates to the technical field of nanoemulsions, and particularly relates to a ceramide nanoemulsion with good stability, a preparation method thereof, and an application thereof. Background Art

[0002] Ceramide is a lipid naturally present in human skin, which is formed by the combination of a molecule of long-chain sphingosine and a molecule of long-chain free fatty acid through an amide bond. Since ceramide is a natural active ingredient with many functions, which meets the requirements of consumers for skin care needs, ingredient safety, and functionality, it is one of the active ingredients favored by many cosmetics manufacturers. However, due to ceramide: ① It is highly crystalline, has poor water dispersibility, low solubility in water and oil, and forms crystals at low temperatures, so it is difficult to ensure the long-term stability of cosmetics containing ceramide. To prepare a fine emulsion containing ceramide, usually, a large amount of surfactant is required, which damages safety and the feeling during use; ② It has poor transdermal performance, and it is difficult for ceramide to penetrate into keratinous substances (such as skin). The above two reasons greatly limit the application of ceramide in cosmetics. In order to improve the above two problems, improve the stability and transdermal performance of ceramide cosmetics, the nanoemulsion encapsulation technology is used to promote the application of ceramide in cosmetics.

[0003] Nanoemulsion refers to a multiphase colloidal dispersion system in which one phase is highly dispersed in another immiscible phase in the form of nanoscale droplets by using appropriate surfactants or external conditions, and the droplet size usually ranges from 50 to 500 nm. Compared with traditional emulsions, the nanoemulsion system is more suitable for active ingredient delivery. First of all, nanoemulsion has the ability to dissolve a large amount of lipophilic active ingredients, which can increase the drug loading capacity and improve the stability of the active ingredient in the formulation; secondly, due to the small droplet size and large specific surface area of nanoemulsion, its transdermal penetration and absorption are faster, and the transdermal absorption content is higher. After the transdermal absorption of skin active components is improved, the content of active components that can be utilized by the human body is also increased, thereby increasing the utilization rate of active ingredients.

[0004] However, nanoemulsion is a kinetically stable but thermodynamically unstable system. The nanoemulsion droplets are small, the gravitational force is weak, and the Brownian motion of its droplets can also offset the influence of the gravitational force, so it can prevent stratification or sedimentation; but because the droplets of nanoemulsion are nanoscale, they have a high interfacial energy, and small particles are prone to aggregate and fuse with larger particles, resulting in an increase in particle size and ultimately leading to emulsion instability. Therefore, how to ensure the stability of nanoemulsion during the shelf life and improve the stability of nanoemulsion to temperature changes is the challenge faced by current nanoemulsion technology.

[0005] At present, the prior art has adopted nanoemulsion technology to prepare ceramide nano-compositions, and their solubility, water dispersibility, and transdermal performance have all been improved. However, there are still obvious defects and deficiencies, such as:

[0006] A method for preparing a nanoemulsion, although nanoemulsion technology is adopted, the content of ceramide in the prepared nanoemulsion is 0.1%, and the content of active ingredients is very low, and the skin care effect is limited. Secondly, this invention patent only uses the naked eye to evaluate its stability in terms of whether it is turbid and precipitated, and it is impossible to determine the change in the particle size of the nanoemulsion under different conditions and whether it is still nano-sized droplets.

[0007] A nanoemulsion composition and its application, the prepared nanoemulsion has a particle size greater than 110 nm, and the skin penetration and skin retention effects are significantly deteriorated.

[0008] A nanoemulsion with good stability, although it significantly improves the stability of the nanoemulsion under high temperature and freezing conditions, the encapsulation amount of its active ingredients is relatively low, only 0.2% - 0.5%, and the preparation process is relatively cumbersome and complex, increasing the production cost. Summary of the Invention

[0009] Based on this, it is necessary for this application to provide a ceramide nanoemulsion and its preparation method, and to provide the application of the above nanoemulsion in the preparation of cosmetics. This nanoemulsion has the advantages of improving the stability of ceramide in the formula and its stability under extreme temperature conditions, as well as high encapsulation efficiency, small particle size, and good transdermal absorption performance.

[0010] The specific technical solution is as follows:

[0011] A ceramide nanoemulsion with good stability, the preparation raw materials of the nanoemulsion include phase A and phase B. Calculated as a percentage of the total mass of the nanoemulsion (calculated as 100% by mass), it contains the following components:

[0012] Phase A contains the following components in the following contents:

[0013]

[0014] Phase B contains the following components in the following contents:

[0015] Non-ionic surfactant 0.6% - 9%, and

[0016] Polyol 3% - 12%.

[0017] In one embodiment, calculated as a percentage of the total mass of the nanoemulsion (calculated as 100% by mass), it contains the following components:

[0018] Phase A contains the following components in the following contents:

[0019]

[0020]

[0021] Phase B contains the following components in the following contents:

[0022] Non-ionic surfactant: 1% - 3%, and

[0023] Polyol: 6% - 10%.

[0024] The application of the ceramide nanoemulsion in the preparation of cosmetics. Optionally, the cosmetics include one or more of facial mask liquid, skin care lotion, essence, spray and emulsion.

[0025] The preparation method of the ceramide nanoemulsion includes the following steps:

[0026] Dissolve the lecithin in the oil, then add the ceramide and antioxidant and dissolve them to prepare Phase A; mix and dissolve the non-ionic surfactant, polyol and deionized water to prepare Phase B; homogenize Phase B, and slowly pour Phase A into Phase B, and then homogenize again to prepare the primary emulsion; and after the primary emulsion is cooled, perform high-pressure homogenization treatment to prepare the nanoemulsion.

[0027] An essence with good stability, containing the nanoemulsion.

[0028] Compared with the traditional technology, the present application has the following beneficial effects:

[0029] In the ceramide nanoemulsion provided by the present application, with the compounding of lecithin and non-ionic surfactant and the synergistic effect of polyol, it has good stability under extreme conditions such as high temperature and freezing, and the particle size has no significant change within 3 months; at the same time, the ceramide nanoemulsion provided by the present application has a high encapsulation rate, improves the stability of ceramide in the formulation, and has good transdermal performance.

[0030] The preparation method of the nanoemulsion of the present application is simple to operate. The nanoemulsion prepared by the high-pressure homogenization technology has a small particle size, good long-term stability and good permeation-promoting effect, and effectively promotes the transdermal absorption of ceramide. Brief Description of the Drawings

[0031] Figure 1 It is the particle size distribution diagram of the nanoemulsion prepared in Example 4;

[0032] Figure 2 It is the particle size distribution diagram of the nanoemulsion prepared in Example 6;

[0033] Figure 3 It is the transmission electron microscope image of the nanoemulsion prepared in Example 4;

[0034] Figure 4 Comparison of the results of the turbiscan lab stability analyzer for the samples of Example 7 and Comparative Example 6;

[0035] Figure 5 Micrographs of the samples of Example 7 and Comparative Example 6;

[0036] Figure 6 Graph for comparing the viscosity changes of the samples of Example 7 and Comparative Example 6;

[0037] Figure 7 Comparison of the results of in vitro skin cumulative permeation amount and retention amount for the samples of Example 4 and Comparative Example 1;

[0038] Figure 8 Comparison of the results of in vitro skin cumulative permeation amount and retention amount for the samples of Example 7 and Comparative Example 6;

[0039] Figure 9 Comparison of the results of in vivo relative percutaneous absorption amount of Raman confocal for the samples of Example 7 and Comparative Example 6. Detailed implementation manners

[0040] To make the above objects, features and advantages of the present application more obvious and understandable, the following will describe the detailed implementation manners of the present application in conjunction with the accompanying drawings. Many specific details are set forth in the following description in order to fully understand the present application. However, the present application can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without departing from the connotation of the present application. Therefore, the present application is not limited by the specific embodiments disclosed below.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which this application belongs. The terms used in the description of this application herein are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0042] The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0043] Ceramide is a type of polar substance with a relatively large molecular weight and is difficult to permeate through the skin; ceramide is also a type of highly crystalline substance, resulting in a small addition amount in the formulation and being extremely easy to crystallize and precipitate, thereby destabilizing the formulation.

[0044] As an excellent transport carrier, nanoemulsion has been widely used in the transport and delivery of ceramides. However, most of the existing ceramide nanoemulsions have a high content of emulsifiers and are prone to problems such as an increase in particle size and instability of the nanoemulsion under extreme temperature conditions such as high temperature and freezing, which pose great limitations on ensuring the stability of the nanoemulsion during storage and its use in different dosage forms of skin care products.

[0045] Therefore, an embodiment of the present application provides a ceramide nanoemulsion with good stability. The raw materials for preparing the nanoemulsion include phase A and phase B, and in terms of the percentage of the total mass of the nanoemulsion (calculated as 100% by mass), it contains the following components:

[0046] Phase A contains the following components in the following contents:

[0047]

[0048] Phase B contains the following components in the following contents:

[0049] Non-ionic surfactant 0.6% - 9%, and

[0050] Polyol 3% - 12%.

[0051] In a specific example, the mass percentage of ceramide in the nanoemulsion includes, but is not limited to, 0.2%, 0.4%, 0.6%, 0.8%, 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, or the range composed of any two values.

[0052] In a specific example, the mass percentage of oil in the nanoemulsion includes, but is not limited to, 5%, 7%, 9%, 11%, 13%, 15%, or the range composed of any two values.

[0053] In a specific example, the mass percentage of lecithin in the nanoemulsion includes, but is not limited to, 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, or the range composed of any two values.

[0054] In a specific example, the mass percentage of cholesterol in the nanoemulsion includes, but is not limited to, 0.132%, 0.396%, 0.665%, 0.924%, 1.188%, 1.32%, or the range composed of any two values.

[0055] In a specific example, the mass percentage of linoleic acid in the nanoemulsion includes, but is not limited to, 0.097%, 0.291%, 0.845%, 0.679%, 0.873%, 0.97%, or the range composed of any two values.

[0056] In a specific example, the mass percentage of the nonionic surfactant in the nanoemulsion includes, but is not limited to, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or a range composed of any two values.

[0057] In a specific example, the mass percentage of the polyol in the nanoemulsion includes, but is not limited to, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, or a range composed of any two values.

[0058] In a specific example, the nanoemulsion further contains a C phase, and the C phase contains p - hydroxyacetophenone and pentylene glycol; wherein, the mass percentage of p - hydroxyacetophenone in the nanoemulsion is 0.03% - 0.06%, and the mass percentage of pentylene glycol in the nanoemulsion is 0.05% - 2%. Optionally, the mass percentage of p - hydroxyacetophenone in the nanoemulsion is 0.04% - 0.05%, and the mass percentage of pentylene glycol in the nanoemulsion is 1% - 1.5%.

[0059] In a specific example, calculated as a percentage of the total mass of the nanoemulsion (counted as 100% by mass), it contains the following components:

[0060] Phase A contains the following components in the following contents:

[0061]

[0062] Phase B contains the following components in the following contents:

[0063] Nonionic surfactant 0.6% - 9%,

[0064] Polyol 3% - 12%,

[0065] Deionized water the balance;

[0066] Phase C contains the following components in the following contents:

[0067] p - Hydroxyacetophenone 0.03% - 0.06%,

[0068] Pentylene glycol 0.05% - 2%.

[0069] In a specific example, calculated as a percentage of the total mass of the nanoemulsion (counted as 100% by mass), it contains the following components:

[0070] Phase A contains the following components in the following contents:

[0071]

[0072] Phase B contains the following components in the following contents:

[0073] Nonionic surfactant 1% - 3%,

[0074] 6% - 10% of polyol,

[0075] The balance is deionized water;

[0076] Phase C contains each component with the following content:

[0077] 0.04% - 0.05% of p - hydroxyacetophenone,

[0078] 1% - 1.5% of pentanediol.

[0079] Optionally, calculated as a percentage of the total mass of the nano - emulsion (counted as 100% by mass), it contains the following components:

[0080] Phase A contains each component with the following content:

[0081]

[0082] Phase B contains each component with the following content:

[0083] 2% of non - ionic surfactant,

[0084] 7% of polyol,

[0085] The balance is deionized water;

[0086] Phase C

[0087] 0.05% of p - hydroxyacetophenone,

[0088] 1% of pentanediol.

[0089] In a specific example, in the ceramide nano - emulsion, the molar ratio of cholesterol, linoleic acid and ceramide is 1:1:1. Adding ceramide, cholesterol and linoleic acid in an equimolar ratio is beneficial to the transdermal absorption of ceramide and simultaneously accelerates the repair of the stratum corneum barrier.

[0090] In a specific example, the antioxidant is one or more of pentaerythritol tetra(bis - tert - butylhydroxyhydrocinnamate) and tocopherol.

[0091] In a specific example, the phosphatidylcholine content of lecithin is 45% - 90%. Preferably, the phosphatidylcholine content of lecithin is 45% - 75%.

[0092] In this application, lecithin, as a natural ingredient emulsifier, has good biocompatibility, can fuse with the stratum corneum lipids of the skin, disrupt its bilayer arrangement structure, and promote the transdermal absorption of ceramide.

[0093] In a specific example, the non-ionic surfactant is one or more of Tween 80, Steareth-21, Ceteth-25, Oleth-20, Beheneth-25, Sucrose Stearate, Polyglyceryl-10 Laurate, and Polyglyceryl-10 Myristate. In a preferred example, the non-ionic surfactant is one or more of Tween 80, Steareth-21, Ceteth-25, Oleth-20, and Beheneth-25.

[0094] In the present application, non-ionic surfactants such as Tween 80 can enhance the skin penetration ability, and they have the ability to fluidize the stratum corneum lipids, thereby enhancing the absorption of active ingredients.

[0095] In the present application, lecithin is used in combination with non-ionic surfactants. By selecting the type and adjusting the proportion of non-ionic surfactants, the strength and viscoelasticity of the interfacial film are improved, the fluidity of the interfacial film is reduced, the outward diffusion of surfactants from the interface is prevented, and at the same time, through steric hindrance and electrostatic repulsion, the collision between droplets is hindered, and the physical stability of the nanoemulsion is improved.

[0096] In a specific example, the polyol is one or several of glycerol, butanediol, and pentanediol. In a preferred example, the polyol is glycerol and / or pentanediol. In the present application, polyols with three or five carbon atoms have a synergistic effect with surfactants, can further reduce the interfacial tension, effectively reduce the Ostwald ripening rate of the system. At the same time, the polyol as a cryoprotectant can reduce the crystallization temperature of the aqueous phase, so as to have a nanoemulsion with good stability under high temperature and freezing conditions.

[0097] In a specific example, the oil is one or more of octyldodecanol, triglyceride caprylate / caprate, and dimethyl decanamide. Optionally, the oil is octyldodecanol and / or triglyceride caprylate / caprate.

[0098] The above nanoemulsion is a light yellow milky liquid with a faint blue opalescence, the particle size is 70 - 130 nm, and there is no obvious change in the particle size after being placed at -15°C and 45°C for 3 months.

[0099] The above ceramide nanoemulsion has a high encapsulation rate, improves the stability of ceramide in the formulation, and has good transdermal performance.

[0100] One embodiment of the present application also provides the application of the above nanoemulsion in the preparation of cosmetics. Optionally, the cosmetics include one or several of facial mask liquid, skin care lotion, essence, spray, and emulsion.

[0101] One embodiment of the present application also provides a preparation method of the above nanoemulsion, including the following steps a - d:

[0102] Step a: Dissolve the above-mentioned lecithin in the above-mentioned oil, and then add the above-mentioned ceramide and antioxidant and dissolve them to prepare Phase A.

[0103] Specifically, at a temperature of 55°C to 85°C, dissolve the lecithin in the oil. After the solution becomes clear and transparent, add the other components of Phase A: ceramide and antioxidant to prepare the Phase A solution.

[0104] Specifically, the selectable temperature range is 55°C to 65°C, 65°C to 75°C, or 75°C to 85°C. The specifically selectable temperatures are 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, or 85°C.

[0105] Step b: Mix and dissolve the above-mentioned non-ionic surfactant, polyol, and deionized water to prepare Phase B.

[0106] Specifically, mix and stir to dissolve at a temperature of 80°C to 85°C.

[0107] Specifically, stir until the solution becomes clear and transparent.

[0108] Step c: Homogenize Phase B, and slowly pour Phase A into Phase B, and then homogenize again to prepare the primary emulsion.

[0109] Specifically, the homogenization rate is 4000 - 8000 rpm / min.

[0110] Step d: After the above-mentioned primary emulsion is cooled, it is subjected to high-pressure homogenization treatment to prepare the nanoemulsion.

[0111] Specifically, after the primary emulsion is cooled to room temperature, it is subjected to high-pressure homogenization treatment.

[0112] Specifically, the pressure of high-pressure homogenization is 500 bar to 700 bar, and the number of times of high-pressure homogenization is 5 to 7 times.

[0113] In this application, the high-pressure homogenization treatment makes the particle size of the nanoemulsion composition system smaller, more uniform and stable.

[0114] In a specific example, this preparation method further includes Step e: Add p-hydroxyacetophenone and pentylene glycol to the nanoemulsion prepared in Step d and disperse them evenly.

[0115] Specifically, p-hydroxyacetophenone and pentylene glycol can be mixed first to prepare the C-phase solution, and the C-phase solution is added to the nanoemulsion prepared in Step d and dispersed evenly.

[0116] One embodiment of this application also provides a serum with good stability, which contains the above-mentioned nanoemulsion or the nanoemulsion prepared by the above-mentioned preparation method.

[0117] In a specific example, the mass percentage of the nanoemulsion in the essence is 20% - 60%, and the specific optional mass percentages are 20%, 30%, 40%, 50% or 60%. Optionally, the mass percentage of the nanoemulsion in the essence is 30% - 50%.

[0118] In a specific example, the essence further includes one or more of a humectant, an ion chelating agent, a thickening agent, a preservative and an emollient.

[0119] In a specific example, by mass percentage, the essence contains the following components: 20% - 60% nanoemulsion, 3% - 5% glycerol, 3% - 5% butanediol, 0.5% - 2% pentanediol, 0.02% - 0.05% EDTA-2Na, 0.3% - 0.6% AVC (ammonium acryloyldimethyltaurate / VP copolymer), 0.5% - 2% polyglyceryl-10 myristate, 0.1% - 0.3% p-hydroxyacetophenone, and the balance is deionized water.

[0120] In a specific example, the preparation method of the above essence includes the following steps:

[0121] After dispersing AVC in 30% - 50% water, add glycerol, butanediol, pentanediol, p-hydroxyacetophenone, EDTA-2Na, and polyglyceryl-10 myristate, heat up to 80°C - 85°C, and keep warm (for example, keep warm for 25 min - 35 min); cool down (for example, cool down to room temperature), then add the above nanoemulsion and mix evenly, and make up the water to 100% after cooling to room temperature.

[0122] Next, the implementation schemes of the present application will be described in detail with reference to the examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. For the experimental methods without specific conditions in the following examples, the guidance given in the present application is preferably referred to, and it can also be carried out according to the experimental manuals or conventional conditions in the art, or according to the conditions recommended by the manufacturers, or referring to the experimental methods known in the art.

[0123] In the following specific examples, for the measurement parameters of the raw material components, if there is no special description, there may be slight deviations within the weighing accuracy range. For the temperature and time parameters, acceptable deviations caused by instrument test accuracy or operation accuracy are allowed.

[0124] Example 1

[0125] Prepare samples according to the raw material ratios in Table 1. Mix lecithin and oil, and mechanically stir at 85 °C until completely dissolved; then add antioxidants and ceramide, cholesterol, and linoleic acid in equimolar ratios until the solution is clear and transparent to obtain Phase A; mix Tween 80 surfactant, polyols (glycerol, pentylene glycol), and deionized water, and mechanically stir at 85 °C until completely dissolved to obtain Phase B; dissolve 0.05% p-hydroxyacetophenone in 1% pentylene glycol at room temperature to obtain Phase C; first homogenize Phase B at 4000 - 8000 rpm / min, and slowly pour Phase A into Phase B, then homogenize for 5 - 15 min to obtain the primary emulsion; after the primary emulsion cools to room temperature, perform high-pressure homogenization at 500 - 700 bar for 5 - 7 cycles to obtain the nanoemulsion; after the nanoemulsion cools to room temperature, add Phase C and disperse evenly.

[0126] Table 1

[0127]

[0128] Appropriate oils and their contents are required to provide sufficient oil-phase solubility to prevent ceramide leakage and system instability. When the ceramide content is 0.2% - 1%, 7 - 13% of GTCC is sufficient to dissolve ceramide, so the particle size can basically remain unchanged under the stability acceleration test. When the ceramide content is 1% - 2%, 10% - 15% of octyldodecanol is required as the oil.

[0129] Example 2

[0130] Prepare samples according to the raw material ratios in Table 2. Mix lecithin with different pc (phosphatidylcholine) contents (pc45, pc50, pc75, pc90, with phosphatidylcholine contents of 45%, 50%, 75%, and 90% respectively) and GTCC, and mechanically stir at 85 °C until completely dissolved; then add antioxidants and ceramide, cholesterol, and linoleic acid in equimolar ratios until the solution is clear and transparent to obtain Phase A; mix Tween 80 surfactant, polyols (glycerol, pentylene glycol), and deionized water, and mechanically stir at 85 °C until completely dissolved to obtain Phase B; dissolve 0.05% p-hydroxyacetophenone in 1% pentylene glycol at room temperature to obtain Phase C; first homogenize Phase B at 4000 - 8000 rpm / min, and slowly pour Phase A into Phase B, then homogenize for 5 - 15 min to obtain the primary emulsion; after the primary emulsion cools to room temperature, perform high-pressure homogenization at 500 - 700 bar for 5 - 7 cycles to obtain the nanoemulsion; after the nanoemulsion cools to room temperature, add Phase C and disperse evenly.

[0131] Table 2

[0132]

[0133] The content of PC in lecithin and the type and content of antioxidants will affect the pH stability and particle size stability of nanoemulsions, while high-temperature conditions will accelerate the changes in the pH and particle size of the nanoemulsion system. When the PC content of lecithin is 45% - 50%, the pH and particle size of the nanoemulsion remain relatively stable after 30 days of high-temperature storage. When the antioxidant is pentaerythritol tetra(bis-tert-butylhydroxyhydrocinnamate) at 0.03% - 0.05%, the pH and particle size of the nanoemulsion remain relatively stable after 30 days of high-temperature storage.

[0134] Example 3

[0135] Prepare the sample according to the raw material ratio in Table 2. Mix lecithin (PC50) and GTCC, and stir mechanically at 85°C until completely dissolved; then add the antioxidant and equimolar ratios of ceramide, cholesterol, and linoleic acid until the solution is clear and transparent to obtain Phase A; mix the surfactant (except lecithin), polyols (glycerol, pentylene glycol, and / or butylene glycol), and deionized water, and stir mechanically at 85°C until completely dissolved to obtain Phase B; dissolve 0.05% p-hydroxyacetophenone in 1% pentylene glycol at room temperature to obtain Phase C; first homogenize Phase B at 4000 - 8000 rpm / min, and slowly pour Phase A into Phase B, and homogenize for 5 - 15 min to obtain the primary emulsion; after the primary emulsion cools to room temperature, perform high-pressure homogenization treatment at 500 - 700 bar for 5 - 7 cycles to obtain the nanoemulsion; after the nanoemulsion cools to room temperature, add Phase C and disperse evenly.

[0136] Table 3

[0137]

[0138] According to the content of ceramide, adjust the type and proportion of surfactants and polyols to provide sufficient interfacial film strength to stabilize the nanoemulsion system. When the ceramide content is 1% - 2%, the surfactant is a compound of 1% - 2% lecithin and 1% - 3% Tween 80 or polyether surfactant, and when the polyol content is 6% - 9% glycerol, the particle size of the nanoemulsion remains basically unchanged within 30 days of the accelerated stability experiment, showing good physical stability.

[0139] Example 4

[0140] This example provides a nanoemulsion containing the following raw materials in mass percentages:

[0141] Lecithin pc50: 1%

[0142] Ceramide: 1%

[0143] Glycerol trioctanoate / decanoate: 10%

[0144] Cholesterol: 0.665%

[0145] Linoleic acid: 0.485%

[0146] Pentaerythritol tetra(bis-tert-butyl hydroxydrocinnamate): 0.03%

[0147] Tween 80: 2%

[0148] Glycerol: 6%

[0149] Pentylene glycol: 2%

[0150] p-Hydroxyacetophenone: 0.05%

[0151] Water up to 100%.

[0152] At 80 °C to 85 °C, under stirring, dissolve lecithin in caprylic / capric triglyceride (GTCC), then add ceramide, cholesterol, linoleic acid and pentaerythritol tetra(bis-tert-butyl hydroxydrocinnamate) to obtain Phase A; mix Tween 80, glycerol, 1% pentylene glycol and deionized water, heat to 80 °C to 85 °C, and stir until the solution is clear and transparent to obtain Phase B; dissolve p-hydroxyacetophenone in 1% pentylene glycol at room temperature to obtain Phase C; first homogenize Phase B at 4000 - 8000 rpm / min, and slowly pour Phase A into Phase B, then homogenize for 5 min to obtain the primary emulsion; after the primary emulsion cools to room temperature, perform high-pressure homogenization treatment at 500 - 700 bar for 5 - 7 cycles to obtain the nanoemulsion; after the nanoemulsion cools to room temperature, add Phase C and disperse evenly.

[0153] The obtained ceramide nanoemulsion is a light yellow emulsion with a faint blue opalescence. The particle size measured by a nano particle size analyzer is 103.1 nm, and the polydispersity index (PDI) is 0.178. Transmission electron microscopy shows as Figure 3 shown, the particle size distribution of the nanoemulsion is as Figure 1 shown.

[0154] Example 5

[0155] This example provides a nanoemulsion containing the following raw materials in mass percentages:

[0156] Lecithin pc50: 1%

[0157] Ceramide: 2%

[0158] Caprylic / capric triglyceride: 10%

[0159] Cholesterol: 1.3%

[0160] Linoleic acid: 0.97%

[0161] Pentaerythritol tetra(bis-tert-butyl hydroxydrocinnamate): 0.03%

[0162] Tween 80: 2%

[0163] Glycerin: 9%

[0164] Pentylene glycol: 2%

[0165] p-Hydroxyacetophenone: 0.05%

[0166] Water up to 100%.

[0167] At 80 °C to 85 °C under stirring, dissolve lecithin in caprylic / capric triglyceride, and then add ceramide, cholesterol, linoleic acid, and pentaerythrityl tetra(bis-tert-butylhydroxyhydrocinnamate) to obtain Phase A; mix Tween 80, glycerin, 1% pentylene glycol, and deionized water, heat to 80 °C to 85 °C, and stir until the solution is clear and transparent to obtain Phase B; dissolve p-hydroxyacetophenone in 1% pentylene glycol at room temperature to obtain Phase C; first homogenize Phase B at 4000 - 8000 rpm / min, and slowly pour Phase A into Phase B, and homogenize for 5 min to obtain the primary emulsion; after the primary emulsion cools to room temperature, perform high-pressure homogenization treatment at 500 - 700 bar for 5 - 7 cycles to obtain the nanoemulsion; after the nanoemulsion cools to room temperature, add Phase C and disperse evenly.

[0168] The obtained ceramide nanoemulsion is a light yellow emulsion with a faint blue opalescence. The particle size measured by a nano particle size analyzer is 122.6 nm, and the polydispersity index (PDI) is 0.228.

[0169] Example 6

[0170] This example provides a nanoemulsion containing the following raw materials in mass percentages:

[0171] Lecithin pc50: 1%

[0172] Ceramide: 1%

[0173] Caprylic / capric triglyceride: 10%

[0174] Cholesterol: 0.665%

[0175] Linoleic acid: 0.485%

[0176] Pentaerythrityl tetra(bis-tert-butylhydroxyhydrocinnamate): 0.03%

[0177] Ceteareth-25: 2%

[0178] Glycerin: 6%

[0179] Pentylene glycol: 2%

[0180] p-Hydroxyacetophenone: 0.05%

[0181] Water up to 100%.

[0182] At 80 °C to 85 °C, under stirring conditions, dissolve lecithin in caprylic / capric triglyceride, then add ceramide, cholesterol, linoleic acid and pentaerythrityl tetra(bis-tert-butylhydroxyhydrocinnamate) to obtain Phase A; mix cetostearyl alcohol polyether-25, glycerol, 1% pentylene glycol and deionized water, heat to 80 °C to 85 °C, and stir until the solution is clear and transparent to obtain Phase B; dissolve hydroxyacetophenone in 1% pentylene glycol at room temperature to obtain Phase C; first homogenize Phase B at 4000 - 8000 rpm / min, and slowly pour Phase A into Phase B, then homogenize for 5 min to obtain the primary emulsion; after the primary emulsion cools to room temperature, perform high-pressure homogenization treatment at 500 - 700 bar for 5 - 7 cycles to obtain the nanoemulsion; after the nanoemulsion cools to room temperature, add Phase C and disperse evenly.

[0183] The obtained ceramide nanoemulsion is a light yellow emulsion with a faint blue opalescence. The particle size measured by a nanoemulsion particle size analyzer is 94.9 nm, and the polydispersity index (PDI) is 0.172. The particle size distribution of the nanoemulsion is as Figure 2 shown.

[0184] Example 7

[0185] This example provides an essence containing the nanoemulsion prepared in Example 4, and its ingredient ratio is shown in Table 4.

[0186] Table 4

[0187] Component Mass percentage (%) Efficacy component Example 4 nanoemulsion 40％ Ceramide nanoemulsion Glycerol 3 Humectant Butylene glycol 4 Humectant Pentylene glycol 1 Humectant EDTA-2Na 0.03 Ion chelating agent AVC (ammonium acryloyldimethyltaurate / VP copolymer) 0.4 Polymer thickener p-Hydroxyacetophenone 0.2 Preservative Polyglycerol-10 myristate 1 Emollient Water To 100 Deionized water

[0188] Preparation method:

[0189] First disperse AVC in 50% water, then add glycerol, butylene glycol, pentylene glycol, hydroxyacetophenone, EDTA-2Na, and polyglyceryl-10 myristate, heat to 85 °C and hold for 30 min; after cooling to room temperature, add the ceramide nanoemulsion and mix evenly, then make up the water to 100%.

[0190] Comparative Example 1

[0191] Comparative Example 1 provides a nanoemulsion and its preparation method, which is substantially the same as that of Example 4, except that it is not subjected to high-pressure homogenization treatment.

[0192] This emulsion is a milky yellow viscous liquid with a particle size of 660 nm. After standing for three days, it shows upper and lower layers. The upper layer is milky white, and the lower layer is a light yellow turbid liquid.

[0193] Comparative Example 2

[0194] Comparative Example 2 provides a nanoemulsion, which is substantially the same as that of Example 4, except that Tween 80 is replaced by sucrose stearate.

[0195] The nanoemulsion is a pale yellow emulsion with a faint blue opalescence. Its particle size is 82.4 nm. After one freeze-thaw cycle, the sample state changes to a milky white viscous liquid, without the faint blue opalescence, and flocculation occurs.

[0196] Comparative Example 3

[0197] Comparative Example 3 provides a nanoemulsion, which is substantially the same as Example 4, except that Tween 80 is replaced by polyglyceryl-10 myristate.

[0198] The nanoemulsion is a milky white liquid with a faint blue opalescence. Its particle size is 85.5 nm. After one freeze-thaw cycle, the sample state changes to a milky white viscous liquid, without the faint blue opalescence, and the particle size increases significantly.

[0199] Comparative Example 4

[0200] Comparative Example 4 provides a nanoemulsion, which is substantially the same as Example 4, except that the content of Tween 80 is increased from 2% to 9%.

[0201] The nanoemulsion is a pale yellow emulsion with a particle size of 75.9 nm. After being stored at -15°C for 30 days, the particle size increases to 742.0 nm and the viscosity increases.

[0202] Comparative Example 5

[0203] Comparative Example 5 provides a nanoemulsion, which is substantially the same as Example 4, except that the polyol is changed from 6% glycerol to 6% glycerol + 3% butanediol.

[0204] The nanoemulsion is a pale yellow emulsion with a particle size of 104.9 nm and a PDI of 0.160. After being stored at -15°C for 30 days, the particle size and PDI increase to 1048 nm and 0.519 respectively. After being stored at 45°C for 30 days, the particle size and PDI increase to 643 nm and 0.710 respectively. This nanoemulsion has poor stability under freezing and high-temperature storage conditions.

[0205] Comparative Example 6

[0206] This comparative example provides a serum, which is different from Example 7 in that the nanoemulsion in Example 4 is replaced by 0.4% ceramide powder.

[0207] Experimental Example 1 Investigation of the Stability of Nanoemulsion

[0208] The samples of Example 4 and Example 6 were respectively placed under the conditions of daily, light, dark, 4°C, 45°C, -15°C, and freeze-thaw cycle (one freeze-thaw cycle is to place at -15°C for 24 hours and then at 45°C for 24 hours), and their particle size stability was measured. The results are shown in Table 5.

[0209] Table 5

[0210]

[0211]

[0212] Experimental Example 2 Comparative Investigation on the Stability of Essence

[0213] Absorb a certain amount of the samples of Example 7 and Comparative Example 6 into the sample bottles of the Turbiscan Lab stability analyzer, and measure the dynamic changes in the stability of the essence. The parameter settings are to scan once every 30 min, and the scanning time is 24 h. See the experimental results in Figure 4 . In terms of the kinetic stability index (TSI) of the two, the smaller the TSI index, the better the stability. It can be seen from this that the ceramide essence encapsulated by nanoemulsion has significantly better stability than the unencapsulated ceramide essence, thus indicating that nanoemulsion can improve the physical stability of ceramide in the formulation.

[0214] Experimental Example 3 Investigation on the Improvement of Ceramide Recrystallization Phenomenon

[0215] Take a certain amount of Example 7 and Comparative Example 6 and place them on a glass slide on a microscope (magnification: 1.6×10), and observe the crystallization phenomenon of ceramide. See the experimental results in Figure 5 . Among them, Figure 5 a and b in are the microscope photos of the sample of Example 7, Figure 5 c and d in are the microscope photos of the sample of Comparative Example 6. It can be seen from the microscope results that nanoemulsion encapsulation can significantly inhibit the recrystallization of ceramide, thus improving the stability of ceramide in the formulation.

[0216] Experimental Example 4 Viscosity Comparison of Essence

[0217] Test the viscosity changes of Example 7 and Comparative Example 6 after 0, 3, 7, and 15 freeze-thaw cycles (-15°C for 24 h and then 45°C for 24 h is one freeze-thaw cycle) respectively. See the experimental results in Figure 6 . The recrystallization phenomenon of ceramide will increase the viscosity of the formulation. It can be seen from the viscosity changes of the essence that the viscosity change of Example 7 is significantly smaller than that of Comparative Example 6, indicating that nanoemulsion encapsulation can significantly inhibit the recrystallization phenomenon of ceramide, thus improving the stability of ceramide in the formulation.

[0218] Experimental Example 5 Comparative Analysis of In Vitro Skin Permeability and Retention

[0219] The transdermal experiment was carried out in a Franz diffusion cell device. The abdominal skin of guinea pigs was fixed between the receiving cell and the supply cell (the inner layer of the skin faced the receiving cell). The effective permeation area of the skin was 1.77 cm 2, the volume of the receiving pool is 12 ml, and the magnetic stirring speed in the receiving chamber is 300 r / min. Fill the receiving pool with the release medium 2% SDS - 20% ethanol - normal saline to remove air bubbles, turn on the stirring, and keep the temperature constant at (37.0 ± 0.5) °C. Apply the samples (with the same ceramide content in the samples) evenly on the skin surface. After 24 h, take 1 ml of the sample with a sampling needle and put it into an ep tube. Then, first use a non - porous puncture needle to draw air bubbles in the receiving pool, and then supplement 1 ml of isothermal receiving liquid to the receiving pool. Measure the concentration of ceramide in the receiving liquid filtered through a 0.22 μm filter membrane by HPLC. Calculate the cumulative permeation amount of ceramide in 24 h.

[0220] Calculate the cumulative transdermal amount of ceramide per unit area according to the following formula:

[0221]

[0222] In the formula: Q n : The cumulative permeation amount per unit area at the nth time point (μg / ml);

[0223] C n : The concentration of ceramide in the receiving liquid when sampling at the nth time point (μg / ml);

[0224] C n-1 : The concentration of ceramide in the receiving liquid when sampling at the (n - 1)th time point (μg / ml);

[0225] V0: The volume of the receiving liquid in the receiving pool (ml);

[0226] S: The effective area of the diffusion cell (cm 2 );

[0227] V: The volume of each sampling (1 ml).

[0228] After 24 h, remove the skin, wash the residual sample liquid on the surface of the mouse skin with ultrapure water, then cut the mouse skin into pieces and place them in a 10 ml ep tube. Add 3 ml of methanol and sonicate for 30 min. After sonication, centrifuge at 5000 rpm for 10 min. Take the supernatant and measure the content of ceramide by HPLC, which is the retention amount of the active substance in the skin (Q s ).

[0229] Q s = VC / A

[0230] In the formula: A is the effective diffusion area (1.76625 cm 2 ), V is the total volume of the skin extraction solution (3 ml), and C is the concentration of ceramide in the skin extraction solution.

[0231] Conduct transdermal tests on the samples of Example 4 and 7 and Comparative Example 1 and 6 of the present invention. See the test results inFigure 7 , 8 . From Figure 7 the in vitro skin cumulative permeation amount and skin retention amount of the samples of Example 4 and Comparative Example 1, it can be seen that the skin permeation amount per unit area of the samples of Example 4 and Comparative Example 1 at 24 h are respectively: ceramide nanoemulsion 1.45 μg / cm 2 , ceramide coarse emulsion 0.72 μg / cm 2 . The skin retention amount per unit area at 24 h are respectively: ceramide nanoemulsion 9.55 μg / cm 2 , ceramide coarse emulsion 5.99 μg / cm 2 . It can be seen that both the permeation amount and retention amount of ceramide in the ceramide nanoemulsion prepared by high-pressure homogenization technology are higher than those of the ceramide emulsion prepared by ordinary homogenization, which are increased by 1.6 times and 2.0 times respectively. From Figure 8 it can be seen that when ceramide nanoemulsion and free ceramide are respectively added to the essence formula, after 24 h, the ceramide permeation amounts are 2.78 μg / cm 2 and 0.99 μg / cm 2 respectively, an increase of 2.8 times. The skin retention amount of the former is 3.1 times that of the latter after 24 h, which are 6.76 μg / cm 2 and 2.21 μg / cm 2 respectively.

[0232] Experimental Example 6 Comparative Analysis of the Relative Percutaneous Absorption Amount of Skin Efficacy Ingredients in Vivo

[0233] The determination of the relative percutaneous absorption amount of the efficacy ingredient in vivo skin was detected by Raman confocal microscopy.

[0234] ① Test parameters: Sample application amount: 200 μL / cm 2 , excitation light source wavelength: 638 nm, acquisition range 4000 - 400 cm -1 , acquisition time 6 s, integration times 1 time, grating 600 gr / mm, hole value 300 nm, detection exposure time: 2 s, scanning depth: from 0 μm on the skin surface to 30 μm under the skin layer, scanning step 2 μm, randomly select 6 points for scanning in each test area.

[0235] ② Test method: Before the test, the subjects cleaned both forearms with clear water, exposed the forearms in a constant temperature and humidity environment (temperature: (24 ± 1) °C, relative humidity: 55% ± 5%) and balanced for 30 min. During the balancing process, three 2 cm × 2 cm areas were marked on the inner sides of both forearms of the subjects, 3 - 5 cm away from the wrist, as the test areas. Samples with the same content of the active substance were applied to the skin respectively. The penetration depth and penetration amount of the active substance within 30 μm under the skin of the test areas of the subjects were detected before application, 30 min after application, and 2 h after application.

[0236] The samples of Example 7 and Comparative Example 6 of the present invention were tested by Raman confocal microscopy. See the experimental results in Figure 9 . From Figure 9 After 2 h of use in Example 7 and Comparative Example 6, at each depth within 30 μm of the skin, the penetration amount of the ceramide nanoemulsion essence was higher than that of the free ceramide essence. After 30 min and 2 h of using the samples, the retention amounts of ceramide in the stratum corneum were: ceramide nanoemulsion essence: 2.97, 4.38; free ceramide essence: 1.13, 1.59. After being encapsulated by the nanoemulsion, the retention amounts of ceramide in the stratum corneum at 30 min and 2 h increased by 2.6 times and 2.8 times respectively. It shows that the nanoemulsion has excellent permeability in the deep layer of the skin and can promote the penetration of lipophilic active substances into the deeper layer of the skin.

[0237] The technical features of the above - mentioned embodiments can be combined arbitrarily. For the sake of concise description, not all possible combinations of the technical features in the above - mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope recorded in this specification.

[0238] The above - mentioned embodiments only represent several implementation manners of the present application. Their descriptions are relatively specific and detailed, but they should not be construed as limitations on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several modifications and improvements can still be made, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application should be subject to the appended claims, and the specification and the drawings can be used to explain the content of the claims.

Claims

1. A ceramide nanoemulsion with good stability, characterized in that, The raw materials for preparing the nanoemulsion include phase A and phase B, and in terms of the percentage of the total mass of the nanoemulsion (counted as 100% by mass), it contains the following components: Phase A contains the following components in the following contents: Phase B contains the following components in the following contents: Nonionic surfactant 0.6% - 9%, and, Polyol 3% - 12%.

2. The nanoemulsion according to claim 1, wherein, In terms of the percentage of the total mass of the nanoemulsion (counted as 100% by mass), it contains the following components: Phase A contains the following components in the following contents: Phase B contains the following components in the following contents: Nonionic surfactant 1% - 3%, and Polyol 6% - 10%.

3. The nanoemulsion according to claim 1 or 2, characterized in that, The nanoemulsion further contains phase C, and phase C contains p - hydroxyacetophenone and pentylene glycol; wherein, the mass percentage of p - hydroxyacetophenone in the nanoemulsion is 0.03% - 0.06%, and the mass percentage of pentylene glycol in the nanoemulsion is 0.05% - 2%; Optionally, the mass percentage of p - hydroxyacetophenone in the nanoemulsion is 0.04% - 0.05%, and the mass percentage of pentylene glycol in the nanoemulsion is 1% - 1.5%.

4. The nanoemulsion according to claim 1 or 2, characterized in that, In the nanoemulsion, the molar ratio of cholesterol, linoleic acid and ceramide is 1:1:

1.

5. The nanoemulsion according to claim 1 or 2, characterized in that, The nanoemulsion satisfies one or more of the following conditions: (1) The antioxidant is one or more of pentaerythritol tetra(bis - tert - butylhydroxyhydrocinnamate) and tocopherol; and, (2) The nonionic surfactant is one or more of Tween 80, steareth - 21, ceteareth - 25, oleth - 20, beheneth - 25, sucrose stearate, polyglyceryl - 10 laurate and polyglyceryl - 10 myristate; Optionally, the nonionic surfactant is one or more of Tween 80, steareth - 21, ceteareth - 25, oleth - 20 and beheneth - 25.

6. The nanoemulsion according to claim 1 or 2, characterized in that, The nanoemulsion satisfies one or more of the following conditions: 1) The polyol is one or several of glycerol, butylene glycol and pentylene glycol; preferably, the polyol is glycerol and / or pentylene glycol; And, 2), the oil is one or more of octyldodecanol, triglyceride of caprylic / capric acid and dimethyldecanamide; Optionally, the oil is octyldodecanol and / or triglyceride of caprylic / capric acid.

7. The nanoemulsion according to claim 1 or 2, characterized in that, The phosphatidylcholine content of the lecithin is 45% - 90%; Optionally, the phosphatidylcholine content of the lecithin is 45% - 75%.

8. Use of the nanoemulsion according to any one of claims 1 - 7 in the preparation of cosmetics; Optionally, the cosmetics include one or several of facial mask liquid, skin care lotion, essence, spray and emulsion.

9. The preparation method of the nanoemulsion according to any one of claims 1 to 7, characterized in that, Comprising the following steps: Dissolve the lecithin in the oil, and then add and dissolve the fat - soluble active ingredient and the antioxidant to prepare phase A; Mix and dissolve the nonionic surfactant, polyol and deionized water to prepare phase B; Homogenize phase B, and slowly pour phase A into phase B, and then homogenize again to prepare the primary emulsion; and After the primary emulsion is cooled, it is subjected to high - pressure homogenization treatment to prepare the nanoemulsion; Optionally, the preparation method further includes a step of adding p-hydroxyacetophenone and pentanediol into the nanoemulsion and dispersing them evenly; Optionally, the homogenization rate is 4000-8000 rpm / min; Optionally, the pressure of high-pressure homogenization is 500 bar to 700 bar, and the number of high-pressure homogenization is 5 to 7 times.

10. An essence with good stability, characterized in that, Comprising the nanoemulsion according to any one of claims 1 to 7.

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