A composite ceramide nano-composition, its preparation method and application

Abstract

The present invention belongs to the technical field of cosmetics, and discloses a composite ceramide nano-composition and its preparation and application. The preparation method of the composite ceramide nano-composition comprises the following steps: dissolving a polyoxyethylene polyoxypropylene ether block copolymer, a ceramide complex, and a stabilizer in a polyol, heating and mixing evenly to obtain an alcohol phase; dropping the alcohol phase into heated water, carrying out heat preservation and stirring treatment to obtain a mixed solution; subjecting the mixed solution to homogenization treatment to obtain the composite ceramide nano-composition. Compared with the compositions of the currently commonly used dosage forms, the present invention finds that the polyoxyethylene polyoxypropylene ether block copolymer has a higher encapsulation ability for the ceramide complex mainly composed of ceramide E, the nano-composition also enhances the stability through the stabilizer, and the prepared composite ceramide nano-composition has better water dispersibility, repair performance and stability.

Description

Technical Field

[0001] The present invention belongs to the technical field of cosmetics, and particularly relates to a composite ceramide nano-composition, a preparation method thereof, and an application thereof. Background Art

[0002] Ceramide is a class of lipid molecules composed of a sphingolipid group as the main chain and a fatty acid linked by an amide as the second chain. Ceramide exists in the stratum corneum of the skin and accounts for about 50% of the intercellular lipids in the stratum corneum. Ceramide plays an important regulatory role in life activities such as cell differentiation, proliferation, apoptosis, and aging. With age growth or skin aging, the synthesis amount of intracellular ceramide will decrease, the skin barrier function will decline, and the transdermal water loss will increase, resulting in skin dryness, chapping, and skin barrier defects. As the main component of the intercellular substance of skin stratum corneum cells, ceramide not only acts as a second messenger molecule in the sphingomyelin pathway, but also plays an important role in the process of forming the epidermal stratum corneum, and has functions such as maintaining skin barrier, moisturizing, and repairing.

[0003] Ceramide is an important active substance for maintaining normal skin metabolism, repairing skin barrier, and keeping skin moisture, and is widely used in cosmetics. However, ceramide has problems of low water solubility and poor water dispersibility, and it is difficult to be directly used in aqueous formulations. Therefore, at present, most related products only add a very small amount of ceramide, mostly belonging to conceptual addition, and it is difficult to truly play the skin care role of ceramide in cosmetics. Summary of the Invention

[0004] In order to overcome the problems of low water solubility and easy crystallization and precipitation of ceramide in the existing cosmetics formulations, the primary object of the present invention is to provide a preparation method of a composite ceramide nano-composition.

[0005] Another object of the present invention is to provide a composite ceramide nano-composition prepared by the above method.

[0006] Another object of the present invention is to provide an application of the above composite ceramide nano-composition.

[0007] The object of the present invention is achieved by the following solutions:

[0008] A preparation method of a composite ceramide nano-composition, which comprises the following steps:

[0009] (1) Dissolve a polyoxyethylene polyoxypropylene ether block copolymer, a ceramide complex, and a stabilizer in a polyol, heat and mix evenly to obtain an alcohol phase;

[0010] (2) Drop the alcohol phase into heated water, keep warm and stir to obtain a mixed solution;

[0011] (3) Homogenize the mixed solution to obtain a composite ceramide nano-composition.

[0012] In some embodiments, the polyoxyethylene polyoxypropylene ether block copolymer in step (1) is PEOx-PPOy-PEOz, where x = 10 - 113, y = 34 - 135, z = 10 - 113, and the molecular weight Mn = 3000 - 15000.

[0013] In some embodiments, the mass percentage of the polyoxyethylene polyoxypropylene ether block copolymer in the composite ceramide nano-composition in step (1) is 1 - 5%, preferably 2%.

[0014] In some embodiments, the mass percentage of the ceramide complex in the composite ceramide nano-composition in step (1) is 1 - 5%, preferably 2%.

[0015] In some embodiments, the ceramide complex in step (1) includes ceramide E (cetyldimonium hydroxypropyl PG - hydroxyethyl palmitamide) and other ceramides.

[0016] In some embodiments, the other ceramide is at least one of ceramide AP, ceramide AS, and ceramide NP, preferably ceramide NP.

[0017] In some embodiments, the mass ratio of ceramide E to the other ceramide is 2 - 6:1; preferably 4:1.

[0018] In some embodiments, the stabilizer in step (1) includes at least one of sodium cholate, cholesterol, and phytosterol; preferably sodium cholate.

[0019] In some embodiments, the mass percentage of the stabilizer in the composite ceramide nano-composition in step (1) is 0.1 - 1%; preferably 0.3%.

[0020] In some embodiments, the polyol in step (1) is at least one of 1,3 - propanediol, glycerol, 1,4 - butanediol, pentanediol, 1,2 - hexanediol, dipropylene glycol, diethylene glycol, and octyldodecanol; preferably 1,3 - propanediol.

[0021] In some embodiments, the mass percentage of the polyol in the composite ceramide nano-composition in step (1) is 10 - 50%; preferably 25%.

[0022] In some embodiments, the heating temperature in step (1) is 40 - 100°C; preferably 80°C.

[0023] In some embodiments, the water in step (2) is supplemented to a total mass percentage of 100% of the composite ceramide nano - composition.

[0024] In some embodiments, the heating temperature of the water in step (2) is 40 - 100 °C; preferably 80 °C.

[0025] In some embodiments, the dropping rate in step (2) is 1 - 10 mL / min; preferably 5 mL / min.

[0026] In some embodiments, the speed of the heat - preservation stirring treatment in step (2) is 150 - 500 rpm; the time of the heat - preservation stirring treatment is 30 - 60 min; preferably, the speed of the heat - preservation stirring treatment is 350 rpm and the time of the heat - preservation stirring treatment is 40 min.

[0027] In some embodiments, the homogenization treatment in step (3) is high - pressure micro - jet homogenization treatment. Preferably, micro - jet homogenizer is used for homogenization, the homogenization pressure is 50 - 120 MPa, and the number of homogenization cycles is 1 - 8 times; further preferably, the homogenization pressure is 70 MPa and the number of homogenization cycles is 3 times.

[0028] A composite ceramide nano - composition prepared by the above method.

[0029] The application of the above - mentioned composite ceramide nano - composition in cosmetics, wherein the mass percentage of the composite ceramide nano - composition added in cosmetics is 0.1 - 30%.

[0030] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0031] The present invention provides a polyoxyethylene polyoxypropylene ether block copolymer for encapsulating a ceramide complex mainly composed of ceramide E. The polyoxyethylene polyoxypropylene ether block copolymer is an amphiphilic block polymer. When the solution of the polyoxyethylene polyoxypropylene ether block copolymer is added to the aqueous phase, the polyoxyethylene polyoxypropylene ether block copolymer can form micelles through self - assembly. Therefore, the nano - composition obtained by embedding the ceramide complex with the polyoxyethylene polyoxypropylene ether block copolymer is a nano - composition of the polymer micelle type. In the polyoxyethylene polyoxypropylene ether block copolymer, the polyoxyethylene block is a hydrophilic block polymer and the polyoxypropylene ether block is a hydrophobic block polymer. When the solution of the polyoxyethylene polyoxypropylene ether block copolymer is added to the aqueous phase, the polyoxypropylene ether block can provide a loading site for the ceramide complex through hydrophobic - hydrophobic interaction forces, playing a solubilizing and embedding role for the ceramide complex; the polyoxyethylene block, as the outer shell of the polymer micelle, can promote the dissolution of the polymer micelle while also serving as a protective layer to maintain the stability of the polymer micelle.

[0032] Compared with the nano - compositions of the currently commonly used dosage forms (liposomes and nano - emulsions), the polyoxyethylene - polyoxypropylene block copolymer of the present invention has a higher encapsulation ability for ceramide E complex. At the same time, the present invention also enhances the stability of the composite ceramide nano - composition through a stabilizer, and the composite ceramide nano - composition prepared after encapsulation has better water dispersibility, repair performance and stability. Detailed implementation mode

[0033] The present invention will be further described in detail below in conjunction with the embodiments, but the implementation modes of the present invention are not limited thereto. For those not specified in the embodiments, the conventional conditions or the conditions recommended by the manufacturer are followed. For the reagents or instruments not specified for the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0034] In the embodiments of the present invention, the amphiphilic polymer polyoxyethylene - polyoxypropylene block copolymer can be directly purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0035] Unless otherwise specified, the percentages mentioned in the present invention are all mass percentages.

[0036] Example 1

[0037] Add 2.0% by mass of polyoxyethylene - polyoxypropylene block copolymer (PEO 77 -PPO 75 -PEO 77 , Mn = 12232), 2.0% of ceramide complex (ceramide E and ceramide NP, mass ratio 4:1), and 0.3% of sodium cholate into 1,3 - propanediol with a mass percentage of 25%, heat to 80 °C, stir at 350 rpm for 40 min until the above - mentioned raw materials are fully mixed evenly to obtain an alcohol phase. Drop the alcohol phase into deionized water with a mass percentage of 70.7% and at 80 °C at a dropping rate of 5 mL / min, and after the dropping is completed, stir at a speed of 350 rpm for 40 min, and cool to room temperature (25 °C) to obtain a mixed solution. Treat the mixed solution by high - pressure micro - fluidization, with a homogenization pressure of 70 MPa and a homogenization times of 3 times to obtain a composite ceramide nano - composition. Specifically, the composite ceramide nano - composition is a polymer micelle encapsulating the composite ceramide.

[0038] Examples 2 - 11

[0039] The preparation method of the composite ceramide nano - composition provided in Example 2 - 11 is the same as that in Example 1, except that the types of polyoxyethylene - polyoxypropylene ether block copolymers, the addition amount of polyoxyethylene - polyoxypropylene ether block copolymers, the types of ceramide complexes, the mass ratio of ceramide E to other ceramides, and the types of stabilizers are different. The parameters changed in Example 2 - 11 are shown in Table 1.

[0040] Table 1

[0041]

[0042]

[0043] Example 12

[0044] Add polyoxyethylene - polyoxypropylene ether block copolymer (PEO 77 -PPO 75 -PEO 77 , Mn = 12232) with a mass percentage of 2.3%, ceramide complex (ceramide E and ceramide NP, mass ratio 3:1) with a mass percentage of 3.0%, and sodium cholate with a mass percentage of 0.2% into glycerol with a mass percentage of 30%. Heat to 85 °C and stir at 150 rpm for 60 min until the above - mentioned raw materials are fully mixed uniformly to obtain an alcohol phase. Drop the alcohol phase into deionized water with a mass percentage of 64.5% and at 85 °C at a dropping rate of 10 mL / min. After the dropping is completed, stir at a speed of 500 rpm for 30 min and cool to room temperature (25 °C) to obtain a mixed solution. Treat the mixed solution by high - pressure microfluidization, with a homogenization pressure of 120 MPa and a homogenization times of 1 time to obtain the composite ceramide nano - composition.

[0045] Example 13

[0046] Add polyoxyethylene - polyoxypropylene ether block copolymer (PEO 77 -PPO 75 -PEO 77 , Mn = 12232) with a mass percentage of 1.5%, ceramide complex (ceramide E and ceramide NP, mass ratio 5:1) with a mass percentage of 1%, and sodium cholate with a mass percentage of 1% into 1,2 - hexanediol with a mass percentage of 20%. Heat to 60 °C and stir at 50 rpm for 30 min until the above - mentioned raw materials are fully mixed uniformly to obtain an alcohol phase. Drop the alcohol phase into deionized water with a mass percentage of 76.5% and at 60 °C at a dropping rate of 1 mL / min. After the dropping is completed, stir at a speed of 150 rpm for 60 min and cool to room temperature (25 °C) to obtain a mixed solution. Treat the mixed solution by high - pressure microfluidization, with a homogenization pressure of 50 MPa and a homogenization times of 8 times to obtain the composite ceramide nano - composition.

[0047] Comparative Example 1

[0048] 2.0% by mass of soy lecithin, 2.0% by mass of ceramide complex (ceramide E and ceramide NP, mass ratio 4:1), and 0.3% by mass of sodium cholate were added to 25% by mass of 1,3 - propanediol, heated to 80 °C, and stirred at 350 rpm for 40 min until the above raw materials were fully and uniformly mixed to obtain an alcohol phase. The alcohol phase was uniformly added dropwise to deionized water at 80 °C with a mass percentage of 70.7% at a dropping rate of 5 mL / min. After the dropping was completed, it was stirred at 350 rpm for 40 min and cooled to room temperature (25 °C) to obtain a mixed solution. Then the mixed solution was treated by high - pressure microfluidization, with a homogenization pressure of 70 MPa and a homogenization number of 3 times to obtain a ceramide nano - composition.

[0049] In Comparative Example 1, 2.0% of the polyoxyethylene polyoxypropylene ether block copolymer in Example 1 was changed to 2.0% of soy lecithin, and the remaining steps were the same as in Example 1. What was prepared in Comparative Example 1 was a composite ceramide nano - composition encapsulated in liposomes.

[0050] Comparative Example 2

[0051] 2.0% by mass of ceramide complex (ceramide E and ceramide NP, mass ratio 4:1) and 15% by mass of caprylic / capric triglyceride were added to 25% by mass of 1,3 - propanediol, heated to 80 °C, and stirred at 350 rpm for 40 min until the above raw materials were fully and uniformly mixed to obtain an alcohol phase. The alcohol phase was uniformly added dropwise to deionized water at 80 °C with a mass percentage of 58% at a dropping rate of 5 mL / min. After the dropping was completed, it was stirred at 350 rpm for 40 min and cooled to room temperature (25 °C) to obtain a mixed solution. Then the mixed solution was treated by high - pressure microfluidization, with a homogenization pressure of 70 MPa and a homogenization number of 3 times to obtain a composite ceramide nano - composition.

[0052] What was prepared in Comparative Example 2 was a composite ceramide nano - composition of the nano - emulsion type.

[0053] Comparative Example 3

[0054] 2.0% of the polyoxyethylene polyoxypropylene ether block copolymer (PEO 77 -PPO 75 -PEO 77 , Mn = 12232) in Example 1 was replaced with 2.0% by mass of the polymer PCL 44 -b - mPEG 113 , and the remaining steps remained unchanged to prepare a composite ceramide nano - composition.

[0055] Comparative Example 4

[0056] Replace the polyoxyethylene polyoxypropylene ether block copolymer (PEO 77 -PPO 75 -PEO 77 with a mass percentage of 2.0% in Example 1 (Mn = 12232) with a polyoxyethylene polyoxypropylene ether block copolymer (PEO 77 -PPO 75 -PEO 77 with a mass percentage of 5.0% (Mn = 12232), and keep the rest unchanged to obtain a composite ceramide nano - composition.

[0057] Comparative Example 5

[0058] Replace the ceramide complex (ceramide E and ceramide NP, mass ratio 4:1) with a mass percentage of 2.0% in Example 1 with 2.0% of ceramide E, and keep the rest unchanged to prepare a ceramide nano - composition.

[0059] Comparative Example 6

[0060] Replace the ceramide complex (ceramide E and ceramide NP, mass ratio 4:1) with a mass percentage of 2.0% in Example 1 with 2.0% of ceramide NP, and keep the rest unchanged to prepare a ceramide nano - composition.

[0061] Comparative Example 7

[0062] Replace the ceramide complex (ceramide E and ceramide NP, mass ratio 4:1) with a mass percentage of 2.0% in Example 1 with a ceramide complex (ceramide E and ceramide NP, mass ratio 1:1) with a mass percentage of 2.0%, and keep the rest unchanged to prepare a composite ceramide nano - composition.

[0063] Comparative Example 8

[0064] Replace the sodium cholate with a mass percentage of 0.3% in Example 1 with 0.3% of deionized water, and keep the rest unchanged to prepare a composite ceramide nano - composition.

[0065] Comparative Example 9

[0066] The polyoxyethylene polyoxypropylene ether block copolymer (PEO 77 -PPO 75 -PEO 77, 2.0% ceramide complex (ceramide E and ceramide NP, mass ratio 4:1), 0.3% sodium cholate were added to 1,3-propanediol at a mass percentage of 25%, stirred at 350 rpm for 40 min at room temperature (25 °C) until the above raw materials were fully mixed evenly to obtain an alcohol phase. At room temperature (25 °C), the alcohol phase was uniformly added dropwise to deionized water at a mass percentage of 70.7% at a dropping rate of 5 mL / min. After the addition was completed, it was stirred at a speed of 350 rpm for 40 min to obtain a mixed solution. The mixed solution was treated by high-pressure microfluidization, with a homogenization pressure of 70 MPa and a homogenization times of 3 times to obtain a composite ceramide nano-composition.

[0067] The difference between Comparative Example 9 and Example 1 is that the composite ceramide nano-composition in Comparative Example 9 was prepared at room temperature.

[0068] Comparative Example 10

[0069] 2.0% polyoxyethylene polyoxypropylene ether block copolymer (PEO 77 -PPO 75 -PEO 77 , Mn = 12232), 2.0% ceramide complex (ceramide E and ceramide NP, mass ratio 4:1), 0.3% sodium cholate were added to 1,3-propanediol at a mass percentage of 25%, heated to 80 °C, stirred at 350 rpm for 40 min until the above raw materials were fully mixed evenly to obtain an alcohol phase. At room temperature (25 °C), the alcohol phase was uniformly added dropwise to deionized water at a mass percentage of 70.7% at a dropping rate of 5 mL / min. After the addition was completed, it was stirred at a speed of 350 rpm for 40 min to obtain a mixed solution. The mixed solution was treated by high-pressure microfluidization, with a homogenization pressure of 70 MPa and a homogenization times of 3 times to obtain a composite ceramide nano-composition.

[0070] The difference between Comparative Example 10 and Example 1 is that in the step of preparing the composite ceramide nano-composition in Comparative Example 10, the step of mixing the alcohol phase and deionized water was carried out at room temperature.

[0071] Comparative Example 11

[0072] In Example 1, “the alcohol phase was uniformly added dropwise to deionized water at a mass percentage of 70.7% and 80 °C at a dropping rate of 5 mL / min” was changed to “the alcohol phase was uniformly added dropwise to deionized water at a mass percentage of 70.7% and 80 °C at a dropping rate of 12 mL / min” to prepare a composite ceramide nano-composition.

[0073] The difference between Comparative Example 11 and Example 1 is that the dropping rate of the alcohol phase in Comparative Example 11 is different from that in Example 1.

[0074] Test Example 1 - Particle Size Measurement

[0075] The particle sizes of the samples of Examples 1-13 and Comparative Examples 1-11 were characterized using a Malvern Nano-ZS90 dynamic light scattering particle size analyzer. The measurement angle was 90°, the measurement temperature was 25°C, and three parallel experiments were conducted for each group. The arithmetic mean of the experimental results was taken.

[0076] Test Example 2 - Encapsulation Efficiency

[0077] The encapsulation efficiencies of ceramide E and / or other ceramides in the samples of Examples 1-13 and Comparative Examples 1-11 were determined as follows: 200 μL of the nano-composition was taken, ultrafiltration centrifugation was performed (9000 rpm, 30 min), and 5 μL of the filtrate was taken to measure the content of ceramide E and / or other ceramides using a high performance liquid chromatograph (HPLC, Shimadzu, Japan), thereby obtaining the content of unencapsulated ceramide E and / or other ceramides in the nano-composition. Another portion of the above nano-composition was taken, methanol was added, and ultrasonic demulsification was performed at a sample:methanol ratio of 1:9 (v / v) for 30 min. After filtration through a 0.45 μm organic filter membrane, 5 μL of the sample solution was taken to measure the content of ceramide E or other ceramides using a high performance liquid chromatograph (HPLC, Shimadzu, Japan), thereby obtaining the total content of ceramide E and / or other ceramides in the nano-composition. The encapsulation efficiency (EE) of ceramide E and / or other ceramides in the nano-composition was calculated according to formula (1). The analytical column used in the HPLC system was a non-polar C 18 column, the mobile phase was ethanol, the flow rate was 1.0 mL / min, the column temperature of the chromatographic column was 30°C, and three parallel experiments were conducted for each group. The arithmetic mean of the experimental results was taken.

[0078]

[0079] Among them, C1 represents the concentration of unencapsulated ceramide E and / or other ceramides in the sample; C0 represents the total concentration of ceramide E and / or other ceramides in the sample after demulsification with methanol.

[0080] Table 2 Results of particle sizes and encapsulation efficiencies of the samples of Examples 1-13 and Comparative Examples 1-11

[0081]

[0082]

[0083] The test results show that the nano-compositions of the examples of the present invention have smaller particle sizes and better encapsulation efficiencies.

[0084] Comparing Example 1 with Comparative Examples 1-2, it can be seen that the type of the prepared nano-composition has an impact on the particle size and encapsulation efficiency of the final product. The nano-composition of complex ceramide encapsulated by liposome was prepared in Comparative Example 1, and the nano-composition of complex ceramide of the nano-emulsion type was prepared in Comparative Example 2. Compared with liposomes and nano-emulsions, it is more suitable to encapsulate the ceramide complex with an amphiphilic polyoxyethylene polyoxypropylene ether block copolymer. The nano-composition of the polymer micelle type prepared has a small particle size and a high encapsulation efficiency.

[0085] Comparing Examples 1-3 with Comparative Example 3, it can be seen that different types of polymers selected for encapsulation result in different particle sizes and encapsulation efficiencies of the prepared nano-compositions. In the present invention, using an amphiphilic polyoxyethylene polyoxypropylene ether block copolymer has the best encapsulation effect on the ceramide complex, and the finally prepared nano-composition has a small particle size and a high encapsulation efficiency.

[0086] Furthermore, comparing Examples 1-3, it can be seen that the type of polyoxyethylene polyoxypropylene ether block copolymer also has an impact on the encapsulation effect of the nano-composition. The present invention preferably selects PEO 77 -PPO 75 -PEO 77 to prepare the nano-composition, and the obtained product has the smallest particle size and the highest encapsulation efficiency.

[0087] Comparing Examples 1, 4, 5 with Comparative Example 4, it can be seen that the addition amount of the polyoxyethylene polyoxypropylene ether block copolymer has an impact on the particle size and encapsulation efficiency of the final product. When the addition amount of the polyoxyethylene polyoxypropylene ether block copolymer is small, the particle size of the final product decreases with the increase of the polyoxyethylene polyoxypropylene ether block copolymer, and the encapsulation efficiency also increases. When the addition amount of the polyoxyethylene polyoxypropylene ether block copolymer reaches 2%, the smallest particle size and the largest encapsulation efficiency are obtained. Further, with the increase of the addition amount of the polyoxyethylene polyoxypropylene ether block copolymer, the particle size of the final product becomes larger and the encapsulation efficiency becomes smaller. In the present invention, the addition amount of the polyoxyethylene polyoxypropylene ether block copolymer should be selected as 1-3%, preferably 2%.

[0088] Comparing Examples 1, 8, 9 with Comparative Examples 5-7, it can be seen that different interactions between ceramide and polyoxyethylene polyoxypropylene ether block copolymer affect the particle size and encapsulation efficiency of the final product. In the present invention, the nano-composition containing ceramide E has a smaller particle size and a higher encapsulation efficiency. Among them, adding a small amount of other ceramides will further reduce the particle size of the nano-composition and increase the encapsulation efficiency (such as Examples 1, 8, 9, Comparative Example 7), but the addition amount of other ceramides should not be too large, otherwise it will also further cause an increase in particle size and a decrease in encapsulation efficiency. In the present invention, the mass ratio of ceramide E to other ceramides should be controlled at 2-6:1, and further preferably 4:1.

[0089] Comparing Example 1, Example 10, Example 11 with Comparative Example 8 shows that whether a stabilizer is added and the type of stabilizer affect the particle size and encapsulation efficiency of the final product. In the present invention, adding a stabilizer can reduce the particle size of the final product and increase the encapsulation efficiency, and among them, using sodium cholate as the stabilizer has the best effect.

[0090] Comparing Example 1 with Comparative Example 9 and Comparative Example 10 shows that the control of temperature during the preparation of the nano-composition has a great influence on the encapsulation efficiency of the final product. In Comparative Example 9, the composite ceramide nano-composition was prepared at room temperature, and the particle size of the finally obtained product was slightly larger than that of Example 1, and the encapsulation efficiency was only 36.8%, far lower than that of Example 1. When the composite ceramide nano-composition was prepared at room temperature, the ceramide complex could not be well dissolved in the polyol at this time, and a large amount of the ceramide complex precipitated, resulting in a low encapsulation efficiency of the final product. In the steps of preparing the composite ceramide nano-composition in Comparative Example 10, the step of mixing the alcohol phase and deionized water was carried out at room temperature, and the ceramide complex dissolved in the polyol was likely to precipitate during the mixing process, resulting in a low encapsulation efficiency of the final product.

[0091] Comparing Example 1 with Comparative Example 11 shows that the rate of dropping the alcohol phase into the water phase during the preparation of the nano-composition has a great influence on the particle size and encapsulation efficiency of the final product. If the dropping rate of the alcohol phase is too fast, it will lead to insufficient hydration of the alcohol phase and the water phase, and it is easy to cause the precipitation of the ceramide complex. Within a suitable dropping range, the alcohol phase and the water phase can be fully mixed and contacted, which will not cause the precipitation of the ceramide complex, and also enables the preparation of a composite ceramide nano-composition with a small particle size and a high encapsulation efficiency during the subsequent homogenization process. In the present invention, the dropping rate of the alcohol phase is 1-10 mL / min; preferably 5 mL / min.

[0092] Test Example 3 - Stability

[0093] Test method: Respectively take 10 mL of the samples of Example 1-13 and Comparative Example 1-11 and place them in colorless transparent PE sample bottles. The above samples are respectively placed at 4°C, 25°C, and 45°C, and the color and layering phenomenon of the samples are observed at the 0th month, 1st month, and 3rd month.

[0094] Table 3 Color conditions of the nano-compositions of Example 1-13 and Comparative Example 1-11

[0095]

[0096]

[0097] Table 4 Layering conditions of the nano-compositions of Example 1-13 and Comparative Example 1-11

[0098]

[0099]

[0100] As shown in Table 3 and Table 4, the composite ceramide nano-composition of the present invention was placed at 4°C - 45°C for 3 months, and its color did not change, and there was no delamination phenomenon, indicating that the composite ceramide nano-composition of the present invention has good stability. The nano-compositions of Comparative Examples 1 - 11 showed different degrees of changes when placed at 4°C - 45°C for 3 months, indicating that the preparation process of the nano-composition, the type of copolymer, the addition amount of the copolymer, the type of ceramide added and its ratio, and the addition of the stabilizer will all affect the stability of the final product.

[0101] Test Example 4 - Water Dispersibility

[0102] Samples of Examples 1 - 13 and Comparative Examples 1 - 11 with a mass percentage of 20% were respectively added to deionized water with a mass percentage of 80%. After mixing evenly, the appearance of the samples was observed respectively after standing at room temperature for 1 month, 2 months, and 3 months to investigate the water dispersibility of the samples. In addition, an aqueous solution of a ceramide complex with a mass percentage of 0.4% was set as a control group (the ceramide complex is ceramide E and ceramide NP, with a mass ratio of 4:1).

[0103] Table 5 Test Results of Water Dispersibility of Samples in the Control Group, Examples 1 - 13 and Comparative Examples 1 - 11

[0104]

[0105]

[0106] As shown in Table 5, the composite ceramide nano-composition of the present invention has good water dispersibility and can be stably placed in water for more than 3 months when dispersed in water in an amount of 20% by mass. During the 3-month placement process of the nano-compositions prepared in Comparative Examples 1 - 11, precipitation and separation phenomena occurred to varying degrees, indicating that the preparation process of the nano-composition, the type of copolymer, the addition amount of the copolymer, the type of ceramide added and its ratio, and the addition of the stabilizer will all affect the water dispersibility of the final product, and thus easily affect its application in aqueous formulations.

[0107] Test Example 5 - Repair Efficacy

[0108] The samples of Examples 1 - 13 and Comparative Examples 1 - 11 were subjected to human efficacy evaluation to test the repair efficacy of the ceramide nano-composition of the present invention.

[0109] Test samples: Dilute the nano-compositions of Examples 1-13 and Comparative Examples 1-11 with deionized water to prepare 10% aqueous solutions, 0.2% aqueous ceramide complex solutions (the mass ratio of ceramide E to ceramide NP is 4:1, and 10% propylene glycol is added as a solubilizer), and deionized water (as a blank control).

[0110] Test method: Select 250 eligible and healthy subjects aged 18-60 years, randomly and evenly distribute them into 25 experimental groups, with 10 valid cases in each group and an equal male-female ratio. Set 3 sample test areas and 1 blank control area on the arms of each subject (divide 2 areas on the inner side of each forearm). Use a 3×3 cm tape to repeatedly stick 8 times on the test areas to establish a physical damage model. Dip a disposable medical cotton swab into 0.1-0.2 g of the test sample and evenly apply it 5 times back and forth on the test areas. Repeat the application operation 1 time with a clean cotton swab. Do not apply any sample to the blank control group area, and measure the transdermal water loss and skin pigment of the skin in this area at different times.

[0111] Detect the transdermal water loss of the test areas through a three-probe skin water loss test probe Tewameter TM330T. Measure each area once, with each measurement lasting 30 s, and take the average value of the last 20 s as the measurement value.

[0112] Detect the skin heme content of the test areas through a skin pigment test probe Mexameter MX18. Detect each area 3 times, and take the average value of the 3 detection values as the measurement value.

[0113] The time points for detecting transdermal water loss and skin pigment of the skin are before tape damage (original value, denoted as D0), after tape damage (damage value, denoted as D1), and 2 days after using the sample (repair value after 2 days, denoted as D3).

[0114] Take the value after tape damage as the starting value, calculate the change rates of transdermal water loss and skin pigment values 2 days after using the sample, and evaluate the repair effects of the nano-compositions of Examples 1-13 and Comparative Examples 1-11.

[0115] The calculation formula is as follows

[0116]

[0117] Among them, X Tn represents the average value of the parameter detected at the nth time point after use, and X T0 represents the average value of the parameter detected before use.

[0118]

[0119] Among them, XT0 The average value of the parameters detected before use is shown, and the change rate represents the degree of change in the average value relative to the initial value.

[0120] The transdermal water loss value refers to the rate of water loss from the skin per unit time and per unit area. The greater the transdermal water loss, the more water the skin loses per unit time, indicating a poorer skin barrier. If the change rate of the skin's transdermal water loss is negative, it indicates that the skin barrier has been repaired, and the greater the negative value, the better the repair effect.

[0121] The skin pigment value reflects the degree of skin flushing. The greater the skin pigment value, the more severe the skin flushing. If the change rate of the skin pigment value is negative, it indicates that the skin flushing has improved and the skin barrier has been repaired, and the greater the negative value, the better the repair effect.

[0122] Table 6 Test results of the skin repair conditions of Examples 1-13 and Comparative Examples 1-11

[0123]

[0124]

[0125] As shown in Table 6, the repair effects of the nano-compositions of Examples 1-13 and Comparative Examples 1-11 on the skin are better than those of the composite ceramide aqueous solution, indicating that although the composite ceramide is dissolved in water through a solubilizer, its transdermal absorption effect is still poor. Among them, the repair effect of the composite ceramide nano-composition of Examples 1-13 is better than that of the nano-composition of Comparative Examples 1-11.

[0126] Comparing Example 1 with Comparative Examples 1-2, it can be seen that the type of the prepared nano-composition has an impact on the repair effect of the final product. The nano-composition of composite ceramide encapsulated by liposomes was prepared in Comparative Example 1, and the nano-composition of composite ceramide of the nano-emulsion type was prepared in Comparative Example 2. Compared with liposomes and nano-emulsions, the nano-composition prepared by the amphiphilic polymer selected in the present invention has a small particle size, which can further promote the transdermal absorption of the composite ceramide, thereby enhancing the repair effect of the composite ceramide nano-composition.

[0127] Comparing Examples 1-3 with Comparative Example 3, it can be seen that different types of polymers selected for encapsulation result in different repair effects of the prepared nano-compositions. In the present invention, the amphiphilic polyoxyethylene polyoxypropylene ether block copolymer has the best encapsulation effect on the ceramide complex, and the finally prepared nano-composition has the best repair effect.

[0128] Furthermore, comparing Examples 1-3, it can be seen that the type of polyoxyethylene polyoxypropylene ether block copolymer also has an impact on the repair effect of the nano-composition. The present invention preferably selects PEO77 -PPO 75 -PEO 77 Prepare a nano - composition, and the repair effect of the final product is optimal.

[0129] Comparing Example 1, 4, 5 with Comparative Example 4, it can be seen that the addition amount of the polyoxyethylene - polyoxypropylene ether block copolymer affects the repair effect of the final product. When the addition amount of the polyoxyethylene - polyoxypropylene ether block copolymer is small, the repair effect of the final product gets better as the amount of the polyoxyethylene - polyoxypropylene ether block copolymer increases. When the addition amount of the polyoxyethylene - polyoxypropylene ether block copolymer is 2%, the optimal repair effect is achieved. Further, as the addition amount of the polyoxyethylene - polyoxypropylene ether block copolymer increases, the particle size of the final product becomes larger and the repair effect becomes worse. In the present invention, the polyoxyethylene - polyoxypropylene ether block copolymer should be selected as 1 - 3%, preferably 2%.

[0130] Comparing Example 1, 6 - 9 with Comparative Example 5 - 7, it can be seen that the type and addition ratio of ceramides affect the repair effect of the nano - composition. Comparing Example 1 with Comparative Example 5 and 6, it can be seen that compared with the encapsulation of a single ceramide, when the nano - composition contains ceramide E and other ceramides, the repair effect of the nano - composition is better. Further, comparing Example 1, 6, 7, it can be seen that when ceramide E is compounded with other ceramides, the type of other ceramides also affects the repair effect of the final product. The compounding effect is: ceramide E and ceramide NP > ceramide E and ceramide AS > ceramide E and ceramide AP. Comparing Example 1, 8, 9 with Comparative Example 7, it can be seen that the mass ratio of ceramide E to ceramide NP further affects the compounding effect, and thus affects the repair effect of the nano - composition. In the present invention, the mass ratio of ceramide E to other ceramides should be controlled at 2 - 6:1, further preferably 4:1.

[0131] Comparing Example 1, 10, 11 with Comparative Example 8, it can be seen that the addition of the stabilizer and the type of the stabilizer affect the repair effect of the final product. In the present invention, adding a stabilizer can reduce the particle size of the final product, thereby improving the repair effect, and among them, using sodium cholate as the stabilizer has the best repair effect.

[0132] Comparing Example 1 with Comparative Example 9 and 10, it can be seen that the control of the temperature during the preparation of the nano - composition has a great impact on the repair effect of the final product. Comparative Example 9 prepares the composite ceramide nano - composition at room temperature, and in the steps of preparing the composite ceramide nano - composition in Comparative Example 10, the step of mixing the alcohol phase and deionized water is carried out at room temperature. The preparation steps of Comparative Example 9 and 10 easily lead to a large amount of precipitation of the ceramide complex, resulting in a poor repair effect of the final product.

[0133] Comparing Example 1 with Comparative Example 11, it can be seen that the rate of dropping the alcohol phase into the aqueous phase during the preparation of the nano-composition affects the repair effect of the final product. If the dropping rate of the alcohol phase is too fast, it will lead to insufficient hydration of the alcohol phase and the aqueous phase, easily resulting in the precipitation of the ceramide complex, and further leading to a poor repair effect of the final product.

[0134] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A preparation method of a composite ceramide nano-composition, characterized in that It includes the following steps: (1) Dissolve polyoxyethylene polyoxypropylene ether block copolymer, ceramide complex, and stabilizer in polyol, heat and mix evenly to obtain an alcohol phase; (2) Drop the alcohol phase into the heated water, keep warm and stir to obtain a mixed solution; (3) Homogenize the mixed solution to obtain a composite ceramide nano-composition; The ceramide complex in step (1) includes ceramide E and other ceramides; The other ceramides are at least one of ceramide AP, ceramide AS, and ceramide NP; The polyoxyethylene polyoxypropylene ether block copolymer in step (1) is PEOx-PPOy-PEOz, where x = 10 - 113, y = 34 - 135, z = 10 - 113, and the molecular weight Mn = 3000 - 15000; The mass percentage of the polyoxyethylene polyoxypropylene ether block copolymer in the composite ceramide nano-composition in step (1) is 1 - 3%; 2. The method for preparing the composite ceramide nano-composition according to claim 1, characterized in that: The mass percentage of the ceramide complex in the composite ceramide nano-composition in step (1) is 1 - 5%; The mass percentage of the stabilizer in the composite ceramide nano-composition in step (1) is 0.1 - 1%; The mass percentage of the polyol in the composite ceramide nano-composition in step (1) is 10 - 50%; The water in step (2) is supplemented to make the total mass percentage of the composite ceramide nano-composition 100%; 3. The method for preparing the composite ceramide nano-composition according to claim 1, characterized in that: The mass ratio of ceramide E to the other ceramides is 2 - 6:1; 4. The method for preparing the composite ceramide nano-composition according to claim 1, characterized in that: The stabilizer in step (1) includes at least one of sodium cholate, cholesterol, and phytosterol; The polyol in step (1) is at least one of 1,3-propanediol, glycerol, 1,4-butanediol, pentanediol, 1,2-hexanediol, dipropylene glycol, diethylene glycol, and octyldodecanol; 5. The method for preparing the composite ceramide nano-composition according to claim 1, characterized in that: The heating temperature in step (1) is 40 - 100 °C; The heating temperature of the water in step (2) is 40 - 100 °C; The dropping rate in step (2) is 1 - 10 mL / min; The stirring speed during the heat preservation and stirring treatment in step (2) is 150 - 500 rpm; the time of the heat preservation and stirring treatment is 30 - 60 min; The homogenization treatment in step (3) is high-pressure microfluidic jet homogenization treatment, the homogenization pressure is 50 - 120 MPa, and the number of homogenization cycles is 1 - 8 times; 6. A composite ceramide nano-composition prepared by the method according to any one of claims 1 - 5.

7. The application of the composite ceramide nano-composition according to claim 6 in cosmetics.

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