Compound urea cream and preparation method thereof

Abstract

The invention provides a compound urea cream and a preparation method thereof, the core raw materials comprise 8-12 parts of urea, 0.5-1.2 parts of mannan oligosaccharide / fructo-oligosaccharide / inulin prebiotics in a specific proportion, and 0.3-0.8 part of a transdermal repair agent, the core raw materials are supplemented with bisabolol, allantoin, vitamin E acetate, dipotassium glycyrrhizinate and the like, and a hexadecanol / octadecanol mixed emulsifier and liquid paraffin are used as an oil phase. The preparation process comprises the following steps: encapsulating urea by using alhagi sparsifolia horny layer wax to form microcapsules; an oil phase and a water phase are uniformly dispersed by adopting pulse type homogeneous alternation, and a stable system with the particle size of 1-5 microns is formed; the cream inhibits urea crystal precipitation, controls the slow release rate, effectively enhances the hydration of cuticles, improves the moisturizing and water locking capabilities, has the functions of efficient moisturizing, anti-inflammation and barrier repair, and provides a new scheme for skin disease treatment.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceuticals, in particular to a compound urea cream and a preparation method thereof. Background Art

[0002] Urea cream is a commonly used preparation for the clinical treatment of dry skin, hyperkeratosis and other diseases. Its core function relies on the keratin softening, moisturizing and penetration-promoting functions of urea. Specifically, urea can bind to keratin in the stratum corneum of the skin, destroy its intermolecular hydrogen bonds, loosen and fall off the hardened stratum corneum cells, and achieve a keratin softening effect; at the same time, urea molecules have good hydrophilicity and can absorb moisture from the environment and lock it tightly, forming a moisturizing barrier on the skin surface; in addition, urea can also change the structure of the stratum corneum of the skin, reduce its density, and promote the transdermal penetration of drug molecules, thereby improving the therapeutic effect. However, the existing technology has the following significant deficiencies:

[0003] (1) In traditional urea creams, urea is directly dissolved or dispersed in the matrix. During storage, it is affected by temperature and humidity changes, and urea crystals (particle size > 50 μm) are easily precipitated. Crystallization not only leads to a decrease in the content of active ingredients and a noticeable granularity in the cream, but may also scratch the stratum corneum and cause irritation.

[0004] (2) Traditional urea creams only achieve moisturizing by softening the stratum corneum, but do not solve the fundamental problem of damaged stratum corneum barrier and lack systematic repair of the skin barrier.

[0005] (3) The transdermal efficiency is low, and free urea molecules have difficulty penetrating the dense stratum corneum.

[0006] Therefore, there is an urgent clinical need to develop a urea cream with high stability, precise transdermal penetration and barrier repair. Summary of the Invention

[0007] In view of this, the present invention provides a compound urea cream and a preparation method thereof to solve the above problems.

[0008] The technical solution of the present invention is achieved as follows: a compound urea cream: comprising the following raw materials in parts by weight: 8-12 parts of urea, 5-8 parts of glycerin, 0.1-0.5 parts of sodium hyaluronate, 0.2-0.8 parts of bisabolol, 0.5-1.5 parts of allantoin, 1-3 parts of vitamin E acetate, 0.4-0.9 parts of dipotassium glycyrrhizate, 0.5-1.2 parts of prebiotics, 0.3-0.8 parts of transdermal repair agent, 3-6 parts of hexadecanol / octadecanol mixed emulsifier, 4-8 parts of liquid paraffin, and 40-60 parts of deionized water; the molecular weight of the sodium hyaluronate is 800-1200 kDa.

[0009] Furthermore, the prebiotics are manno-oligosaccharides, fructo-oligosaccharides and inulin in a mass ratio of (5-7):(2-3):1.

[0010] Furthermore, the transdermal repair agent is panthenol, ceramide and leontopodium callus extract in a mass ratio of (0.3-0.5):(0.6-0.8):1.

[0011] Furthermore, the leontopodium callus extract is prepared by the following method: inducing callus in MS culture medium containing 5-Azacytosine, and using supercritical CO2 extraction combined with high pressure 1000-1500 bar homogenization to obtain active ingredients with a particle size of less than 100 nm.

[0012] Furthermore, the supercritical CO2 extraction has an extraction pressure of 20-35 MPa, a temperature of 35-50°C, a CO2 flow rate of 15-30 L / h, and an extraction time of 2-4 hours.

[0013] Furthermore, the mass ratio of cetyl alcohol to octyl alcohol in the cetyl alcohol / octyl alcohol mixed emulsifier is (3:1)-(2:1), and polysorbate 80 accounting for 10-15% of the total amount of the emulsifier is added as a co-emulsifier.

[0014] Furthermore, the preparation method of the compound urea cream comprises the following steps:

[0015] S1. Urea pretreatment: Heat camel thorn stratum corneum wax to 60-70°C and melt it. Slowly add urea powder at a wax to urea mass ratio of 5-10:1 and stir at 200-300 rpm for 30-40 minutes to form a uniform mixture. Then, dropwise add the mixture into anhydrous ethanol at -10 to -20°C and stir at 500-800 rpm for 10-15 minutes to allow the wax to quickly solidify and encapsulate the urea. Finally, centrifuge and vacuum dry to obtain camel thorn stratum corneum wax-urea microcapsules with a urea encapsulation efficiency of ≥85%.

[0016] S2. Prepare the oil phase: Heat liquid paraffin and cetyl alcohol / octadecanol mixed emulsifier to 75-85° C. and melt, maintaining a stirring speed of 150-250 rpm to form an oil phase;

[0017] S3. Prepare the aqueous phase: Heat deionized water to 70-80°C, add glycerin and sodium hyaluronate in sequence, and stir at 300-500 rpm until the hyaluronic acid is completely swollen to form an aqueous phase;

[0018] S4. Colostrum formation: Slowly add the oil phase to the water phase under stirring at 200-400 rpm, and homogenize and emulsify at 2000-3000 rpm for 10-20 minutes to form colostrum;

[0019] S5. Prepare the cream: cool the colostrum to 50-60°C, add the camel thorn stratum corneum wax-urea microcapsules, vitamin E acetate, and dipotassium glycyrrhizate prepared in S1, stir at 150-250 rpm for 10-15 minutes, continue cooling to 40-50°C, add bisabolol, allantoin, and prebiotics, stir at a low speed of 100-200 rpm for 15-20 minutes, cool to 35-40°C, add the transdermal repair agent, stir at 80-150 rpm until uniform, and then homogenize and emulsify for a second time for 10-15 minutes to obtain the compound urea cream.

[0020] Furthermore, in step S1, the camel thorn cuticle wax is obtained by picking the 3rd to 5th sections of the upper part of the young stem at 5-7 am in the morning during the flowering period (June-August), washing, freeze-dried and crushed into 40-60 mesh camel thorn young stem powder, and ultrasonically extracting it at a material-liquid ratio of 1 g: (10-20) mL of petroleum ether-chloroform mixed solvent at 50-90° C., a power of 200-400 W, and an ultrasonic frequency of 40-60 kHz for 20-40 minutes. The extracted wax is then concentrated by rotary evaporation, precipitated with pre-cooled methanol, and vacuum dried to obtain purified wax.

[0021] Furthermore, in step S4, the rate of adding the oil phase to the water phase is controlled to be 2-5 mL / min to ensure a uniform and stable emulsification process and to form colostrum with a particle size distribution of 1-5 μm.

[0022] Furthermore, in step S5, the secondary homogenization and emulsification adopts a pulse homogenization mode: high-speed homogenization at 4500-5000 rpm for 10 seconds and then low-speed homogenization at 800-1000 rpm for 5 seconds are performed alternately.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The present invention adopts the idea of keratin softening, synergistic moisturizing and barrier repair, and multiple ingredients synergistically moisturize and lock in moisture for a long time. The prebiotic compound absorbs moisture through a hydrogen bond network and forms a moisturizing film. The transdermal repair agent synergistically inhibits the transepidermal water loss (TEWL) by 45.5%±3.3%. The long-chain fatty acids (C16-C18 account for 75%) in camel thorn wax form a bionic lipid film, which effectively softens and repairs the stratum corneum, allowing urea to be slowly released and absorbed through the skin, breaking through the limitation of traditional products that only moisturize but do not repair.

[0025] By physically encapsulating urea inside the microcapsule, it isolates it from direct contact with external moisture / temperature changes, inhibits the disordered arrangement and crystallization of urea molecules, and reduces the release rate of free urea. DETAILED DESCRIPTION

[0026] In order to better understand the technical content of the present invention, specific examples are provided below to further illustrate the present invention.

[0027] Unless otherwise specified, the experimental methods used in the examples of the present invention are all conventional methods.

[0028] Unless otherwise specified, the materials, reagents, etc. used in the examples of the present invention can be obtained from commercial sources.

[0029] Example 1

[0030] The compound urea cream includes the following raw materials in parts by weight: 8 parts of urea, 5 parts of glycerin, 0.1 parts of sodium hyaluronate (molecular weight 800kDa), 0.2 parts of bisabolol, 0.5 parts of allantoin, 1 part of vitamin E acetate, 0.4 parts of dipotassium glycyrrhizate, 0.5 parts of prebiotics (mannose oligosaccharide: oligofructose: inulin = 5:2:1), 0.3 parts of transdermal repair agent (panthenol: ceramide: leontopodium callus extract = 0.3:0.6:1), 3 parts of cetyl alcohol / octadecanol mixed emulsifier (cetyl alcohol: octadecanol = 3:1, containing 10% polysorbate 80), 4 parts of liquid paraffin, and 60 parts of deionized water;

[0031] The extract of Leontopodium edelweiss callus was prepared by the following method: callus was induced in MS medium containing 5-Azacytosine, and active ingredients with a particle size of less than 100 nm were obtained by supercritical CO2 extraction combined with high-pressure 1000 bar homogenization. The supercritical CO2 extraction pressure was 20 MPa, the temperature was 35°C, the CO2 flow rate was 15 L / h, and the extraction time was 2 h.

[0032] Preparation method:

[0033] S1. Urea pretreatment: Heat camel thorn cuticle wax to 60°C and melt it. Slowly add urea powder at a wax to urea mass ratio of 5:1 and stir at 200 rpm for 30 minutes to form a uniform mixture. Then, drop the mixture into -10°C anhydrous ethanol and stir at 500 rpm for 10 minutes to allow the wax to quickly solidify and encapsulate the urea. Finally, centrifuge and vacuum dry to obtain camel thorn cuticle wax-urea microcapsules with a urea encapsulation efficiency of ≥85%.

[0034] Camel thorn cuticle wax is prepared by washing, freeze-drying and crushing Camel thorn stemlets into powder of 40 mesh, extracting the powder with a petroleum ether-chloroform mixed solvent at a material-liquid ratio of 1 g:10 mL at 50°C, 200 W power and 40 kHz ultrasonic frequency for 20 minutes, concentrating the extract by rotary evaporation, precipitating the extract with pre-cooled methanol and drying the extract in vacuum to obtain the purified wax.

[0035] S2. Prepare the oil phase: Heat liquid paraffin and cetyl alcohol / octadecanol mixed emulsifier to 75°C to melt, maintain stirring speed at 150 rpm, to form an oil phase;

[0036] S3. Prepare the aqueous phase: Heat deionized water to 70°C, add glycerin and sodium hyaluronate in sequence, and stir at 300 rpm until the hyaluronic acid is completely swollen to form an aqueous phase;

[0037] S4. Colostrum formation: Slowly add the oil phase to the water phase at a stirring rate of 2 mL / min while stirring at 200 rpm, and homogenize and emulsify at 2000 rpm for 10 minutes to form colostrum with a particle size distribution of 1 μm;

[0038] S5. Prepare the cream: cool the colostrum to 50°C, add the camel thorn stratum corneum wax-urea microcapsules, vitamin E acetate, and dipotassium glycyrrhizate prepared in S1, stir at 150 rpm for 10 minutes, continue cooling to 40-50°C, add bisabolol, allantoin, and prebiotics, stir at a low speed of 100-200 rpm for 15 minutes, cool to 35°C, add the transdermal repair agent, stir at 80 rpm until uniform, homogenize and emulsify for a second time for 10 minutes, homogenize at a high speed of 4500 rpm for 10 seconds, and then homogenize at a low speed of 800 rpm for 5 seconds, alternating between the steps to obtain the compound urea cream.

[0039] Example 2

[0040] The compound urea cream includes the following raw materials in parts by weight: 12 parts of urea, 8 parts of glycerin, 0.5 parts of sodium hyaluronate (molecular weight 1200kDa), 0.8 parts of bisabolol, 1.5 parts of allantoin, 3 parts of vitamin E acetate, 0.9 parts of dipotassium glycyrrhizate, 1.2 parts of prebiotics (mannose oligosaccharide: oligofructose: inulin = 7:3:1), 0.8 parts of transdermal repair agent (panthenol: ceramide: leontopodium callus extract = 0.5:0.8:1), 6 parts of cetyl alcohol / octadecanol mixed emulsifier (cetyl alcohol: octadecanol = 2:1, containing 15% polysorbate 80), 8 parts of liquid paraffin, and 40 parts of deionized water;

[0041] The extract of Leontopodium edelweiss callus was prepared by the following method: callus was induced in MS medium containing 5-Azacytosine, and active ingredients with a particle size of less than 100 nm were obtained by supercritical CO2 extraction combined with high-pressure 1500 bar homogenization. The supercritical CO2 extraction pressure was 35 MPa, the temperature was 50°C, the CO2 flow rate was 30 L / h, and the extraction time was 4 h.

[0042] Preparation method:

[0043] S1. Urea pretreatment: Heat camel thorn cuticle wax to 70°C and melt it. Slowly add urea powder at a wax to urea mass ratio of 10:1 and stir at 300 rpm for 40 minutes to form a uniform mixture. Then, drop the mixture into -20°C anhydrous ethanol and stir at 800 rpm for 15 minutes to allow the wax to quickly solidify and encapsulate the urea. Finally, centrifuge and vacuum dry to obtain camel thorn cuticle wax-urea microcapsules with a urea encapsulation efficiency of ≥85%.

[0044] Camel thorn cuticle wax is prepared by washing, freeze-drying and crushing Camel thorn stemlets into powder of 60 mesh, extracting the powder with a petroleum ether-chloroform mixed solvent at a material-liquid ratio of 1 g:20 mL at 90°C, 400 W power and 60 kHz ultrasonic frequency for 40 minutes, concentrating the extract by rotary evaporation, precipitating the extract with pre-cooled methanol and vacuum drying to obtain the purified wax.

[0045] S2. Prepare the oil phase: Heat liquid paraffin and cetyl alcohol / octadecanol mixed emulsifier to 85°C until melted, maintain stirring speed at 250 rpm, to form an oil phase;

[0046] S3. Prepare the aqueous phase: Heat deionized water to 80°C, add glycerin and sodium hyaluronate in sequence, and stir at 500 rpm until the hyaluronic acid is completely swollen to form an aqueous phase;

[0047] S4. Colostrum formation: Slowly add the oil phase to the water phase at a stirring rate of 5 mL / min while stirring at 400 rpm, and homogenize and emulsify at 3000 rpm for 20 minutes to form colostrum with a particle size distribution of 5 μm;

[0048] S5. Prepare the cream: cool the colostrum to 60°C, add the camel thorn stratum corneum wax-urea microcapsules, vitamin E acetate, and dipotassium glycyrrhizate prepared in S1, stir at 250 rpm for 15 minutes, continue to cool to 50°C, add bisabolol, allantoin, and prebiotics, stir at a low speed of 200 rpm for 20 minutes, cool to 40°C, add the transdermal repair agent, stir at 150 rpm until uniform, homogenize and emulsify for a second time for 15 minutes, homogenize at a high speed of 5000 rpm for 10 seconds, and then homogenize at a low speed of 1000 rpm for 5 seconds, alternating between the steps to obtain the compound urea cream.

[0049] Example 3

[0050] The compound urea cream includes the following raw materials in parts by weight: 10 parts of urea, 6 parts of glycerin, 0.3 parts of sodium hyaluronate (molecular weight 1000kDa), 0.5 parts of bisabolol, 1.0 parts of allantoin, 2 parts of vitamin E acetate, 0.6 parts of dipotassium glycyrrhizate, 0.8 parts of prebiotics (mannose oligosaccharide: oligofructose: inulin = 6:2.5:1), 0.5 parts of transdermal repair agent (panthenol: ceramide: leontopodium callus extract = 0.4:0.5:1), 4.5 parts of cetyl alcohol / octadecanol mixed emulsifier (cetyl alcohol: octadecanol = 2.5:1, containing 12% polysorbate 80), 6 parts of liquid paraffin, and 50 parts of deionized water;

[0051] The extract of Leontopodium edelweiss callus was prepared by the following method: callus was induced in MS medium containing 5-Azacytosine, and active ingredients with a particle size of less than 100 nm were obtained by supercritical CO2 extraction combined with high-pressure 1200 bar homogenization. The supercritical CO2 extraction was performed at an extraction pressure of 30 MPa, a temperature of 40°C, a CO2 flow rate of 25 L / h, and the extraction time was 3 h.

[0052] Preparation method:

[0053] S1. Urea pretreatment: Heat camel thorn cuticle wax to 65°C and melt it. Slowly add urea powder at a wax to urea mass ratio of 8:1, and stir at 250 rpm for 35 minutes to form a uniform mixture. Then, dropwise add the mixture into -15°C anhydrous ethanol and stir at 700 rpm for 12 minutes to allow the wax to quickly solidify and encapsulate the urea. Finally, centrifuge and vacuum dry to obtain camel thorn cuticle wax-urea microcapsules with a urea encapsulation efficiency of ≥85%.

[0054] Camel thorn cuticle wax is prepared by extracting Camel thorn stem powder with a petroleum ether-chloroform mixed solvent at a material-liquid ratio of 1 g:(10-20) mL at 70° C., 300 W power, and 50 kHz ultrasonic frequency for 30 minutes, followed by rotary evaporation concentration, pre-cooled methanol precipitation, and vacuum drying to obtain purified wax.

[0055] S2. Prepare the oil phase: heat liquid paraffin and cetyl alcohol / octadecanol mixed emulsifier to 80°C to melt, maintain stirring speed at 200 rpm, to form an oil phase;

[0056] S3. Prepare the aqueous phase: Heat deionized water to 75°C, add glycerin and sodium hyaluronate in sequence, and stir at 400 rpm until the hyaluronic acid is completely swollen to form an aqueous phase;

[0057] S4. Colostrum formation: Slowly add the oil phase to the water phase at a stirring rate of 3 mL / min while stirring at 300 rpm. Homogenize and emulsify at 2500 rpm for 15 minutes to form colostrum with a particle size distribution of 3 μm.

[0058] S5. Prepare the cream: cool the colostrum to 55°C, add the camel thorn stratum corneum wax-urea microcapsules, vitamin E acetate, and dipotassium glycyrrhizate prepared in S1, stir at 200 rpm for 12 minutes, continue cooling to 45°C, add bisabolol, allantoin, and prebiotics, stir at a low speed of 150 rpm for 18 minutes, cool to 38°C, add the transdermal repair agent, stir at 120 rpm until uniform, homogenize and emulsify for a second time for 13 minutes, homogenize at a high speed of 4800 rpm for 10 seconds, and then at a low speed of 900 rpm for 5 seconds, alternating between the steps to obtain the compound urea cream.

[0059] Comparative Example 1

[0060] The difference between this comparative example and Example 3 is that the raw material composition does not contain prebiotics.

[0061] Preparation method S5 does not add prebiotics, and other steps are the same as Example 3.

[0062] Comparative Example 2

[0063] The difference between this comparative example and Example 3 is that the raw material composition does not contain a transdermal repair agent.

[0064] Preparation method S5 does not add a transdermal repair agent, and the other steps are the same as Example 3.

[0065] Comparative Example 3

[0066] The difference between this comparative example and Example 3 is that the transdermal repair agent is replaced with panthenol and ceramide in a mass ratio of 0.4:0.5.

[0067] Comparative Example 4

[0068] The difference between this comparative example and Example 3 is that the transdermal repair agent is replaced by panthenol and leontopodium callus extract in a mass ratio of 0.4:1.

[0069] Comparative Example 5

[0070] Step S1 is omitted, urea powder is directly added in step S5, and the remaining steps are the same as those in Example 3.

[0071] 1. Effect Test

[0072] 1. Franz Diffusion Cell Experiment

[0073] (1) Experimental conditions

[0074] Receptor solution: pH 7.4 PBS buffer (containing 0.1% sodium azide for preservation)

[0075] Skin model: fresh pig skin (stratum corneum thickness 30-50 μm, degreased with acetone)

[0076] Diffusion cell parameters: effective diffusion area 3.14cm 2 , the water bath temperature was controlled at 32±0.5℃, and the stirring speed was 200rpm

[0077] (2) Operation process

[0078] The pigskin was fixed between the supply and receiving cells of a Franz diffusion cell, with the stratum corneum facing the supply cell. 0.2 g of compound urea cream (Examples 1-3 and Comparative Examples 1-5) was evenly applied to the stratum corneum of the pigskin, and an equal amount of blank cream matrix was applied to the control group.

[0079] 1 mL of receiving solution was taken from the receiving pool at 0 h, 2 h, 4 h, 6 h, and 8 h after smearing the sample, and 1 mL of phosphate buffered saline (PBS, pH 7.4) preheated to 32°C was added at the same time.

[0080] The water content in the receiving solution was determined by Karl-Fischer water determination, and the amount of water absorbed per unit area through the skin was calculated to evaluate the transdermal moisturizing ability of the cream.

[0081] (3) Test results

[0082] Table 1: Franz diffusion cell experiment (8h cumulative moisturizing amount)

[0083]

[0084] 2. Transepidermal water loss (TEWL) test

[0085] (1) Experimental preparation

[0086] Skin sample: Fresh pig skin (obtained within 24 hours after slaughter, subcutaneous fat removed, cut into 5cm×5cm squares, with the stratum corneum facing upwards)

[0087] Experimental apparatus: Homemade TEWL measurement chamber (size: 3 cm diameter, 2 cm height, internal humidity 50 ± 5%, temperature 25 ± 1°C)

[0088] Test instruments: Dew point humidity sensor (accuracy ±0.1% RH), electronic balance (accuracy 0.0001g)

[0089] (2) Operation process

[0090] ① Baseline value determination: Place the pigskin sample in the measurement chamber for 30 minutes and weigh it every 10 minutes. When the weight change is less than 0.1% for three consecutive times, record the initial TEWL0 = Δm / (A×Δt) (Δm is the mass change, A is the exposure area, and Δt is the time interval)

[0091] ② Sample treatment: 0.2g cream (Example 3 / Comparative Examples 1-5) was evenly applied on the surface of the pig skin stratum corneum, and the control group was smeared with the same mass of blank matrix.

[0092] ③ Dynamic monitoring: 0.5h, 1h, 2h, 4h, and 8h after treatment, weigh the cavity and calculate the real-time TEWL t , and calculate TEWL inhibition rate = (TEWL0-TEWL t ) / TEWL0×100%

[0093] (3) Test results

[0094] Table 2: Comparison of transepidermal water loss (TEWL)

[0095]

[0096] Note: * indicates P < 0.01 compared with the blank group; the higher the inhibition rate, the better the barrier protection effect.

[0097] 3. Stratum corneum water content detection

[0098] (1) Loss on drying method (reference method)

[0099] Sampling: Use a 2 cm diameter puncher to take samples from the stratum corneum area of the treated pigskin sample and accurately weigh the wet weight (W wet)

[0100] Drying: Place the sample in a vacuum drying oven at 60°C (pressure <10 mmHg) and dry for 24 hours, then weigh the dry weight (Wdry).

[0101] Calculation: Moisture content (%) = (W wet - W dry) / W dry × 100%

[0102] (2) Test results

[0103] Table 3: Loss on drying method (after 8 hours of treatment)

[0104]

[0105] Note: * indicates P < 0.01 compared with the blank group;

[0106] As shown in the results of Tables 1-3 above, Examples 1-3 all performed excellently in terms of moisturizing performance, skin barrier protection, and improvement of stratum corneum water content, among which Example 3 had the best indicators.

[0107] Comparison with Comparative Example 1 demonstrates that the prebiotics prepared from mannooligosaccharides, oligofructose, and inulin of the present invention can delay urea release and enhance its hydration capacity, absorbing water to form a moisturizing film, while promoting the orderly arrangement of lipids between stratum corneum cells and reducing water loss. Furthermore, the prebiotics can promote the synthesis of ceramides and cholesterol in the stratum corneum, enhancing the stability of the lipid bilayer; inhibit urease activity, reduce the irritants produced by urea decomposition, and mitigate the risk of barrier damage.

[0108] Compared with Comparative Examples 2, 3, and 4, it is shown that the transdermal repair agent can improve the permeability of the stratum corneum of the skin, helping active ingredients such as urea and sodium hyaluronate to penetrate deeper into the skin more efficiently; at the same time, through the synergistic mechanism of "keratin softening + cell repair", the skin barrier function is strengthened: ceramide directly replenishes stratum corneum lipids and enhances the stability of the barrier structure; Leontopodium callus extract stimulates keratinocyte proliferation and differentiation, accelerating barrier repair; panthenol promotes cell metabolism, improves skin barrier function, effectively reduces water loss, and protects the skin from external stimuli. Taking the detection of stratum corneum water content as an example, the water content of Example 3 reached 33.6±2.2% after 8 hours of treatment. In contrast, the transdermal repair agent optimizes the skin penetration environment, allowing the active ingredients to fully exert their moisturizing, anti-inflammatory and other effects, thereby enhancing the overall effect of the cream.

[0109] Compared with Comparative Example 5, camel thorn wax can penetrate into the intercellular spaces to replenish barrier lipids, reduce the irritation caused by direct contact of urea with the skin, and slowly melt to release urea after contact with the skin, so that the TEWL inhibition rate of urea in the stratum corneum reaches 45.5±3.3% and the water content is 33.6±2.2% after 8 hours.

[0110] 2. Urea crystal precipitation rate test

[0111] 1. Sample Processing

[0112] Take 0.5 g of each of the cream samples of Example 3 and Comparative Example 5, add 5 mL of methanol and ultrasonically dissolve for 10 min, centrifuge at 10000 rpm for 15 min, and take the supernatant to pass through a 0.45 μm filter membrane for testing;

[0113] At the same time, prepare urea standard solution (0.1-1 mg / mL) and draw the standard curve (R 2 >0.999)

[0114] 2. Testing conditions

[0115] HPLC column: C18 (250×4.6mm, 5μm)

[0116] Mobile phase: water-acetonitrile (95:5, v / v), flow rate 1.0 mL / min

[0117] Detection wavelength: 214 nm, column temperature 30 °C, injection volume 20 μL;

[0118] 3. Observation Methods

[0119] Samples stored in a 45°C incubator were collected on days 0, 7, and 14. After smearing, the crystal morphology was observed under a 100x optical microscope, and the number of crystals in the field of view was counted (n = 5 fields). The free urea content in the cream was determined by high-performance liquid chromatography (HPLC).

[0120] 4. Result Data

[0121]

[0122] From the above results, it can be seen that the present invention rapidly solidifies the camel thorn stratum corneum wax in low-temperature ethanol to form a hydrophobic barrier, and wraps urea inside the microcapsule by physical embedding, isolating it from direct contact with external moisture / temperature changes, inhibiting the disordered arrangement and crystallization of urea molecules, and reducing the release rate of free urea.

[0123] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A compound urea cream, characterized in that: The invention comprises the following raw materials in parts by weight: 8-12 parts of urea, 5-8 parts of glycerin, 0.1-0.5 parts of sodium hyaluronate, 0.2-0.8 parts of bisabolol, 0.5-1.5 parts of allantoin, 1-3 parts of vitamin E acetate, 0.4-0.9 parts of dipotassium glycyrrhizate, 0.5-1.2 parts of prebiotics, 0.3-0.8 parts of transdermal repair agent, 3-6 parts of hexadecanol / octadecyl alcohol mixed emulsifier, 4-8 parts of liquid paraffin, and 40-60 parts of deionized water; the molecular weight of the sodium hyaluronate is 800-1200 kDa.

2. A compound urea cream as claimed in claim 1, characterized in that: The prebiotics are mannooligosaccharides, oligofructose and inulin in a mass ratio of (5-7):(2-3):

1.

3. A compound urea cream as claimed in claim 1, characterized in that: The transdermal repair agent comprises panthenol, ceramide and leontopodium callus extract in a mass ratio of (0.3-0.5):(0.6-0.8):

1.

4. A compound urea cream as claimed in claim 3, characterized in that: The leontopodium callus extract is prepared by the following method: inducing callus in MS culture medium containing 5-Azacytosine, and adopting supercritical CO2 extraction combined with high pressure 1000-1500 bar homogenization and crushing to obtain active ingredients with a particle size of less than 100 nm.

5. A compound urea cream according to claim 4, characterized in that: The supercritical CO2 extraction has an extraction pressure of 20-35 MPa, a temperature of 35-50°C, a CO2 flow rate of 15-30 L / h, and an extraction time of 2-4 hours.

6. A compound urea cream according to claim 1, characterized in that: The mass ratio of cetyl alcohol to stearyl alcohol in the cetyl alcohol / stearyl alcohol mixed emulsifier is (3:1)-(2:1), and polysorbate 80 accounting for 10-15% of the total amount of the emulsifier is added as a co-emulsifier.

7. A method for preparing the compound urea cream according to any one of claims 1 to 6, characterized in that: The following steps are involved: S1. Urea pretreatment: Heat camel thorn stratum corneum wax to 60-70°C and melt, then slowly add urea powder at a wax to urea mass ratio of 5-10:1, and stir at 200-300 rpm for 30-40 minutes to form a uniform mixture; then dropwise add the mixture into anhydrous ethanol at -10 to -20°C and stir at 500-800 rpm for 10-15 minutes to allow the wax to rapidly solidify and encapsulate the urea; finally, centrifuge and vacuum dry to obtain camel thorn stratum corneum wax-urea microcapsules with a urea encapsulation efficiency of ≥85%; S2. Prepare the oil phase: Heat liquid paraffin and cetyl alcohol / octadecanol mixed emulsifier to 75-85° C. and melt, maintaining a stirring speed of 150-250 rpm to form an oil phase; S3. Prepare the aqueous phase: Heat deionized water to 70-80°C, add glycerin and sodium hyaluronate in sequence, and stir at 300-500 rpm until the hyaluronic acid is completely swollen to form an aqueous phase; S4. Colostrum formation: Slowly add the oil phase to the water phase under stirring at 200-400 rpm, and homogenize and emulsify at 2000-3000 rpm for 10-20 minutes to form colostrum; S5. Prepare the cream: cool the colostrum to 50-60°C, add the camel thorn stratum corneum wax-urea microcapsules, vitamin E acetate, and dipotassium glycyrrhizate prepared in S1, stir at 150-250 rpm for 10-15 minutes, continue cooling to 40-50°C, add bisabolol, allantoin, and prebiotics, stir at a low speed of 100-200 rpm for 15-20 minutes, cool to 35-40°C, add the transdermal repair agent, stir at 80-150 rpm until uniform, and then homogenize and emulsify for a second time for 10-15 minutes to obtain the compound urea cream.

8. The preparation method according to claim 7, wherein: The camel thorn horny layer wax in step S1 is prepared by washing, freeze-drying and crushing camel thorn stem powder to 40-60 mesh, and ultrasonically extracting it in a petroleum ether-chloroform mixed solvent at a material-liquid ratio of 1 g: (10-20) mL at 50-90° C., a power of 200-400 W, and an ultrasonic frequency of 40-60 kHz for 20-40 minutes, then concentrating it by rotary evaporation, precipitating it with pre-cooled methanol, and vacuum drying it to obtain purified wax.

9. The preparation method according to claim 7, wherein: In step S4, the rate of adding the oil phase to the water phase is controlled to be 2-5 mL / min, forming colostrum with a particle size distribution of 1-5 μm.

10. The preparation method according to claim 7, wherein: In step S5, the secondary homogenization and emulsification adopts a pulse homogenization mode: high-speed homogenization at 4500-5000 rpm for 10 seconds and then low-speed homogenization at 800-1000 rpm for 5 seconds are performed alternately.

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