Gradient targeting wrapping process for high-encapsulation-efficiency oil-soluble active matter

Abstract

The invention belongs to the technical field of collagen skin care products, and provides a high-encapsulation-efficiency oil-soluble active matter gradient targeting wrapping process which comprises the following steps: A, mixing an active matter, fatty acid and lipase Novozym 435 for reaction to obtain a hydrophobic modified active matter; b, preparing a blank liposome by adopting lipid to obtain a blank liposome suspension; adding the hydrophobic modified active matter into the blank liposome suspension to obtain an active liposome suspension; rGD peptide accounting for 0.2-0.5% of the mass of lipid is added into the active lipidosome suspension, ultrafiltration and centrifugation are performed, and RGD modified lipidosome suspension is obtained; the preparation method comprises the following steps: firstly adding an oily matrix I with a polarity value of more than 3 into RGD modified liposome suspension, then adding an oily matrix II with a polarity value of less than 2.5, finally adding a stabilizer, and homogenizing. According to the technical scheme, the problems that in the prior art, the encapsulation efficiency of oil-soluble active matter is low, the transdermal efficiency is poor, and the active matter is prone to inactivation are solved.

Description

Technical Field

[0001] This invention belongs to the field of collagen skincare technology and relates to a gradient-targeted encapsulation process for oil-soluble active ingredients with high encapsulation efficiency. Background Technology

[0002] Collagen is an important structural protein in the human body and has excellent skin care effects. However, traditional water-soluble collagen has disadvantages such as low water absorption, poor stability, and limited application scenarios. In traditional formulation systems, water-soluble components and oil phases are difficult to achieve stable miscibility, which prevents collagen from effectively integrating into the essential oil matrix, greatly limiting its application in multi-dosage cosmetics.

[0003] Superoxide dismutase (SOD) has various skin benefits, including antioxidant protection, anti-inflammatory effects, promoting wound healing, combating photoaging, and protecting the skin barrier. It is widely used in skincare products. Because SOD is water-soluble, it can be directly added to skincare products as an aqueous solution, such as toners and serums. However, water-soluble components are difficult to achieve stable miscibility with the oil phase, preventing SOD from effectively integrating into the essential oil matrix and significantly limiting its application in multi-form cosmetics.

[0004] In order for active ingredients to dissolve or be stably dispersed in the oil phase, such as SOD or collagen which need to be stably present in oily essences, creams, and sunscreens in cosmetics, they need to be modified or encapsulated to become oil-soluble active ingredients. This can broaden the application range of active ingredients and make it easier to add them to the formula.

[0005] A common physical method is to encapsulate them within water droplets of a W / O emulsion or within the hydrophilic core of liposomes / micelles. However, directly adding oil-soluble active ingredients to oily products presents the following problems: 1. Poor stability: Water-soluble active ingredients, especially natural collagen, have relatively large molecular weights. When encapsulated in water droplets or hydrophilic cores, they are prone to diffuse and leak from the carrier. Once leaked, the hydrophilic active ingredient immediately becomes incompatible with the surrounding oil phase, leading to aggregation, precipitation, inactivation, product stratification, or failure; 2. High water content requirement: W / O emulsions require a high proportion of aqueous phase to dissolve the active ingredient, which reduces the oil solubility or anhydrous properties of the final product, potentially failing to meet product formulation requirements, such as pure oil essences or anhydrous formulations.

[0006] By pre-lipophilizing the active ingredient, it can dissolve or be stably dispersed in the oil phase. When it is then encapsulated, since the active ingredient is already oil-soluble, the tendency to leak is greatly reduced when it is encapsulated in a hydrophobic environment, the system is more stable, and it can protect it from degradation, such as oxidation and enzymatic hydrolysis, thus solving the problem of long-term aggregation and oxidative inactivation of oil-soluble active ingredients; it also improves its targeting, such as its ability to penetrate the skin barrier.

[0007] However, existing technologies for encapsulating oil-soluble active ingredients still have the following drawbacks: Insufficient encapsulation efficiency: Traditional liposome or emulsion technologies generally have encapsulation efficiency <85%, and the efficiency is even lower for large-molecule oil-soluble active ingredients; Some technologies, while improving transdermal permeability, sacrifice long-term storage stability. For example, the nanoemulsion spray-drying encapsulation process prepares nanoemulsions through high-pressure homogenization and combines it with spray drying technology to form microcapsules, improving the stability of active ingredients. This method can achieve an encapsulation efficiency of 80%-85%, but it is only suitable for lipophilic small molecules, such as essential oils. For large-molecule oil-soluble active ingredients, such as SOD and collagen, the encapsulation efficiency drops sharply to below 60%; High process energy consumption: High-temperature spray drying is required, which destroys the activity of heat-sensitive components; Simple carrier structure: Low loading capacity. For example, the existing biomimetic lipid layer encapsulation technology designs a multi-layer encapsulation system that simulates the lipid structure of the skin, using phospholipids and sphingolipids to improve transdermal permeability. The outer biomimetic lipid layer enhances permeability, but it has the following drawbacks: insufficient stability (lacking an antioxidant system, with an active ingredient retention rate of <80% during storage); and complex process (requiring precise control of the ratio of multiple lipid layers, making industrialization difficult).

[0008] For example, Chinese patent CN 118453442 A discloses an oil-soluble liquid composition containing recombinant collagen, its preparation method and application. By mass percentage, the raw materials include: 5%~15% recombinant collagen powder, 10%~30% oily matrix, 30%~60% dispersant, 20%~50% stabilizer, and 2%~10% moisturizing ingredients. This application achieves a stable and uniform recombinant collagen composition without precipitation or stratification by combining the various raw materials in the formula. However, this method does not address the issues of the activity stability and transdermal efficiency of recombinant collagen. Summary of the Invention

[0009] This invention proposes a gradient-targeted encapsulation process for oil-soluble active ingredients with high encapsulation efficiency, which solves the problems of low encapsulation efficiency, poor transdermal efficiency, and easy inactivation of active ingredients in the prior art.

[0010] The technical solution of this invention is implemented as follows: A gradient-targeted encapsulation process for oil-soluble active ingredients with high encapsulation efficiency includes the following steps: A. Mix the active ingredient, fatty acid, and lipase Novozym 435, and react at 55-60℃ for 4-7 hours to obtain a hydrophobically modified active ingredient; wherein the active ingredient is SOD, mussel adhesive protein, collagen, acetyl hexapeptide-8, or a snake venom-like peptide. B. Preparation of RGD-modified liposome suspension, including: B1. Blank liposomes were prepared using lipids to obtain a blank liposome suspension; B2. Add the hydrophobic modified active ingredient to the blank liposome suspension and stir to obtain the active liposome suspension; B3. Add RGD peptides to the active liposome suspension at 0.2-0.5% of the lipid mass, stir, ultrafilter and centrifuge to obtain RGD modified liposome suspension; C. First, add oily matrix I with a polarity value >3 to the RGD-modified liposome suspension and stir for the first time. Then, add oily matrix II with a polarity value <2.5 and stir for the second time. Finally, add the stabilizer and stir for the third time, and then homogenize. The amounts of oily matrix I, oily matrix II and stabilizer added are 12-28%, 3-12% and 0.8-1.5% of the RGD-modified liposome suspension, respectively.

[0011] Preferably, the first stirring is carried out at 30-40℃ and 100-200 rpm for 3-8 minutes.

[0012] Preferably, the second stirring is performed at 100-200 rpm for 3-8 minutes.

[0013] Preferably, the third stirring is performed at 100-200 rpm for 2-5 minutes.

[0014] Preferably, the process also includes step D: filtration and nitrogen filling and encapsulation.

[0015] Preferably, the fatty acid is decanoic acid, caprylic acid, or lauric acid.

[0016] Preferably, the amount of lipase Novozym 435 added is 4-6% of the active substance mass; the mass ratio of active substance to fatty acid is 1:0.3-1.2.

[0017] Preferably, the mass ratio of collagen to fatty acids is 1:0.5-0.6; Preferably, the mass ratio of collagen to decanoic acid is 1:0.54.

[0018] Preferably, the mass ratio of SOD to fatty acid is 1:0.2-0.4.

[0019] Preferably, the mass ratio of SOD to octanoic acid is 1:0.3.

[0020] Preferably, the mass ratio of acetyl hexapeptide-8 to fatty acid is 1:0.7-0.9.

[0021] Preferably, the mass ratio of acetyl hexapeptide-8 to lauric acid is 1:0.82.

[0022] Preferably, the mass ratio of the snake venom-like peptide to fatty acid is 1:1.1-1.3.

[0023] Preferably, the mass ratio of the snake venom-like peptide to octanoic acid is 1:1.2.

[0024] Preferably, the mass ratio of mussel agaric to fatty acids is 1:0.7-0.9.

[0025] Preferably, the mass ratio of mussel adhesive protein to lauric acid is 1:0.81.

[0026] Preferably, the mass ratio of the hydrophobic modified active ingredient to the lipid is 1:5 to 1:15.

[0027] Preferably, the molecular weight of the active ingredient is 368 Da-35 kDa.

[0028] Preferably, the molecular weight of the active ingredient is 5-20 kDa.

[0029] Preferably, step B2 stirring includes: constant temperature stirring at 40±2℃, stirring speed of 100-150rpm, and time of 20-45min.

[0030] Preferably, step B3, stirring, includes stirring at 50-55°C for 0.5-1.5 hours.

[0031] Preferably, the lipids comprise lecithin and cholesterol in a mass ratio of 3-9:1.

[0032] Preferably, the method for preparing the blank liposomes includes: dissolving lecithin and cholesterol in a solvent, stirring, removing the solvent, and preparing a lipid film; adding a buffer solution with a pH of 3.8-4.2 to the lipid film, shaking to hydrate and swell it, and then sonicating it with a probe to obtain blank liposomes.

[0033] Preferably, the oily matrix with a polarity value > 3 is isononyl isononanoate or isopropyl isostearate, and the oily matrix with a polarity value < 2.5 is caprylic / capric triglyceride or coconut oil alcohol-caprylic / capric ester.

[0034] Preferably, the stabilizer is polydimethylsiloxane or cyclopentadimethylsiloxane.

[0035] Preferably, the oily matrix with a polarity value > 3 is isononyl isononanoate, and the oily matrix with a polarity value < 2.5 is caprylic / capric triglyceride; the stabilizer is polydimethylsiloxane.

[0036] Preferably, the ultrafiltration centrifugation has a molecular weight cutoff of 90-110 kDa, a centrifugal force of 9000-11000 × g, and a centrifugation time of 25-35 min.

[0037] Preferably, step C, homogenization, includes homogenizing 2-3 times at 50-62°C and 500-800 bar pressure.

[0038] This invention also provides products prepared by the above-described high-encapsulation-rate oil-soluble active ingredient gradient targeted encapsulation process.

[0039] The beneficial effects of the present invention using the above technical solution are as follows: 1. This invention systematically solves the problems of low encapsulation efficiency, poor transdermal absorption, easy inactivation of activity, and unstable storage in the encapsulation of oil-soluble active ingredients through four core innovations: biomimetic multi-level encapsulation, RGD targeted modification, green low-temperature process, and polar gradient dispersion. Specific implementation data show that the encapsulation efficiency is >85%, the transdermal efficiency is improved, the activity retention rate is >90%, and the process is safe and compliant, possessing clear industrial application value.

[0040] 2. This invention significantly improves encapsulation efficiency and solves the problem of active ingredient leakage by combining thin-film dispersion with biomimetic lipid layer deposition. The invention uses Novozym 435 lipase to catalyze the reaction, avoiding damage from high temperatures / chemical reagents, and low-temperature homogenization reduces the risk of thermal denaturation, effectively protecting heat-sensitive active ingredients and preventing processing inactivation. This invention utilizes electrostatic adsorption of phospholipid amino groups and peptide carboxyl groups to achieve RGD modification. RGD peptide modification of liposomes reduces permeability barrier resistance, significantly improving transdermal efficiency and enhancing functional delivery. Nitrogen encapsulation blocks oxygen contact, inhibiting active ingredient oxidation. Step C involves the phased addition of oils, first high-polarity ININ, then low-polarity GTCC. This combination of two methods optimizes long-term storage stability and solves oxidation and stratification problems. It is compatible with a wide range of active ingredients, covering macromolecules to small molecules, such as SOD (32 kDa), mussel adhesive protein (17 kDa), collagen (16.6 kDa), acetyl hexapeptide-8 (888.9 Da), and snake venom-like peptides (496 Da), all with loadings >80 mg / mL. Attached Figure Description

[0041] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0042] Figure 1 The oil-soluble active ingredient products prepared according to the present invention are as follows: A represents oil-soluble collagen of Example 1, B represents oil-soluble SOD of Example 2, C represents oil-soluble acetyl hexapeptide-8 of Example 3, D represents oil-soluble snake venom peptide of Example 4, and E represents oil-soluble mussel adhesive protein of Example 5.

[0043] Figure 2 The images show the appearance of the oil-soluble collagen product prepared according to the present invention when added to essential oils, emulsions, or creams, where A represents essential oil, B represents emulsion, and C represents cream. Detailed Implementation

[0044] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0045] In the examples and comparative examples below, PDMS can be selected as a linear polydimethylsiloxane with a molecular weight of 28,000-65,000 Da and end-capped with trimethylsiloxy groups.

[0046] Cyclopentadimethylsiloxane (D5) is cosmetic grade with a purity of ≥98.5% and a kinematic viscosity (25℃) of 4-5 mm² / s.

[0047] Isononyl isononanoate: saponification value 185–205 mg KOH / g, ester content ≥ 98.0%, acid value ≤ 0.5 mg KOH / g.

[0048] Isopropyl isostearate: Saponification value 175–190 mg KOH / g, acid value ≤1.0 mg KOH / g, iodine value ≤5.0 gI2 / 100g.

[0049] Caprylic / capric triglycerides: saponification value 320–345 mg KOH / g, C8+C10 content ≥95.0%, acid value ≤0.3 mg KOH / g.

[0050] Cocoyl alcohol-caprylate / capric acid ester: saponification value 220–240 mg KOH / g, ester content ≥98.0%, fatty acid composition (C8: 55-70%, C10: 25-40%).

[0051] The oily matrix used in this invention includes, but is not limited to, isononyl isononanoate, isopropyl isostearate, caprylic / capric triglyceride and coconut oil alcohol-caprylate / capric acid ester, all of which are cosmetic or food grade products and their quality meets the requirements of the "Cosmetic Safety Technical Specifications" and relevant national standards.

[0052] RGD peptide (amino acid sequence GRGDSPK), purity ≥95%.

[0053] Collagen: Provided by Shandong Saiya Biotechnology Co., Ltd., brand name Jiaobeichu Col III.

[0054] SOD: Provided by Shandong Saiya Biotechnology Co., Ltd., brand name Cermein® SOD.

[0055] Snake venom-like peptide, Chinese name: Dipeptide Diaminobutyroyl Benzylamide Diacetate; English name: Dipeptide Diaminobutyroyl Benzylamide Diacetate; Sequence: H-β-Ala-Pro-Dab-NH-Bzl·2AcOH; CAS number: 823202-99-9; Molecular formula: C 19 H 29 N5O3 Example 1 A gradient-targeted encapsulation process for oil-soluble active ingredients with high encapsulation efficiency includes the following steps: A. Collagen (commercially available recombinant type III humanized collagen is sufficient; in this example, collagen with a molecular weight of 16.6 kDa, provided by Shandong Saiya Biotechnology Co., Ltd., brand name Col III), decanoic acid, and lipase Novozym 435 were mixed and reacted at 60°C for 6 hours. After the reaction, the mixture was centrifuged at 4°C and 8000×g for 15 minutes to gently remove lipase Novozym 435. The supernatant was collected to obtain the hydrophobically modified active product. The amount of lipase Novozym 435 added was 5% of the collagen protein mass; the mass ratio of collagen to decanoic acid was 1:0.54. B. Preparation of RGD-modified liposome suspension, including: B1. Preparation of blank liposome suspension 800 mg of lecithin and 200 mg of cholesterol were weighed as lipids and dissolved in 100 mL of a chloroform and methanol mixture (2:1 volume ratio). The mixture was stirred at 500 rpm for 30 min to ensure complete dissolution. Subsequently, the organic solvent was removed by rotary evaporation at 40 °C, 200 rpm, and -0.1 MPa vacuum to form a uniform lipid film. The film was then vacuum dried at -0.1 MPa and 25 °C for 24 h to completely remove any solvent residue. 10 mL of citrate buffer (containing 150 mM NaCl) at pH 4.0 was added to the lipid film, and the film was hydrated by shaking at 65 °C and 200 rpm for 30 min to allow it to fully expand. Finally, the film was subjected to ultrasonic treatment with a probe under the following conditions: 200 W power, 5 s working time followed by 5 s rest, repeated 20 times to obtain a blank liposome suspension. B2, Active ingredient loading Add 200 mg of the hydrophobic modified active ingredient prepared in step A to a blank liposome suspension, wherein the mass ratio of the hydrophobic modified active ingredient to lipid is 1:5, stir at 40℃ and 150 rpm for 30 min; then sonicate with a probe under the following conditions: 200W, 5s pulse / 5s interval, 20 cycles to obtain an active liposome suspension. B3, RGD modification Add 3 mg of RGD peptide powder to the active liposome suspension obtained in step B2, wherein the amount of RGD peptide added is 0.3% of the lipid mass, and stir at 55℃ for 1 h; then perform ultrafiltration centrifugation, retaining a molecular weight cutoff of 100 kDa, 10,000×g×30 min, and discard the filtrate to remove unbound RGD peptide; dilute the retentate obtained after centrifugation with pH 4.0 citrate buffer (containing 150 mM NaCl) and restore it to the original volume to obtain the purified RGD modified liposome suspension; C. Based on the mass of the RGD-modified liposome suspension obtained in step B3, at 35°C, first add 28% isononyl isononanoate (ININ, polarity > 3), and stir at 150 rpm for 5 minutes. Then add 12% caprylic / capric triglyceride (GTCC, polarity < 2.5), and continue stirring at 150 rpm for 5 minutes. Finally, add 1.0% polydimethylsiloxane (PDMS) as a stabilizer, stir for 3 minutes, and then homogenize twice at 50°C and 600 bar pressure to form a homogeneous encapsulation system. After each homogenization cycle, cool to below 40°C before proceeding to the next step. The polydimethylsiloxane is a trimethylsiloxy-terminated linear polydimethylsiloxane with a molecular weight of 60,000 Da and a kinematic viscosity of 1000 cSt. All percentages are mass percentages of the RGD-modified liposome suspension. D. The encapsulation system obtained in step C is filtered using a 0.22 μm microporous membrane. The total number of colonies is <10 CFU / g. The air inside the packaging container is replaced with nitrogen using a nitrogen filling device with a nitrogen flow rate of 5 L / min and an oxygen concentration of <0.5%. After sealing, it is stored in a brown glass bottle and protected from light.

[0056] Example 2 A gradient-targeted encapsulation process for oil-soluble active ingredients with high encapsulation efficiency includes the following steps: A. Mix 1.5 g SOD (commercially available ordinary SOD is fine; in this example, the SOD was provided by Shandong Saiya Biotechnology Co., Ltd., with a molecular weight of 32 kDa and brand name Cermein® SOD), 0.45 g caprylic acid, and 0.06 g lipase Novozym 435, and react at 55°C for 7 h. After the reaction, centrifuge at 4°C and 8000×g for 15 min to gently remove the lipase. Collect the supernatant to obtain the hydrophobic modified active product. B. Preparation of RGD-modified liposome suspension, including: B1. Preparation of blank liposome suspension: 750 mg of lecithin and 250 mg of cholesterol were weighed as lipids and dissolved in 100 mL of a 2:1 mixture of chloroform and methanol. The mixture was stirred at 500 rpm for 30 min to ensure complete dissolution. Subsequently, the organic solvent was removed by rotary evaporation at 40 °C, 200 rpm, and -0.1 MPa vacuum to form a uniform lipid film. The film was then vacuum dried at -0.1 MPa and 25 °C for 24 h to completely remove any solvent residue. 10 mL of citrate buffer (containing 150 mM NaCl) at pH 4.0 was added to the lipid film, and the film was hydrated by shaking at 65 °C and 200 rpm for 30 min to allow it to fully expand. Finally, the film was subjected to ultrasound treatment with a probe under the following conditions: 200 W power, 5 s working time followed by 5 s rest, repeated for 25 cycles to obtain a blank liposome suspension. B2. Active ingredient loading: The hydrophobic modified active ingredient prepared in step A was slowly added dropwise to the above blank liposome suspension, wherein the mass ratio of the hydrophobic modified active ingredient to lipid was 1:15. After stirring at 38℃ and 150 rpm for 40 min, the suspension was subjected to ultrasonic treatment with a probe. The ultrasonic conditions were: power 200 W, working for 5 s and resting for 5 s, repeated for 20 cycles to obtain the active liposome suspension. B3, RGD modification: 2.5 mg of RGD peptide powder was added to the active liposome suspension obtained in step B2, wherein the amount of RGD peptide added was 0.25% of the lipid mass, and the mixture was stirred at 50 °C for 1.5 h. Subsequently, ultrafiltration centrifugation was performed, with a molecular weight cutoff of 100 kDa, at 10,000 × g × 30 min, and the filtrate was discarded to remove unbound RGD peptides. The retentate obtained after centrifugation was diluted with pH 4.0 citrate buffer (containing 150 mM NaCl) and restored to its original volume to obtain the purified RGD modified liposome suspension. C. Based on the mass of the RGD-modified liposome suspension obtained in step B3, add 28% isopropyl isostearate (polarity > 3) at 30°C and stir at 100 rpm for 8 minutes. Then add 12% cocoyl alcohol-caprylate / caprylate and continue stirring at 200 rpm for 3 minutes. Finally, add 1.5% cyclopentamethoxysiloxane D5 as a stabilizer and stir for 2 minutes. Then homogenize and cycle twice at 50°C and 600 bar to form a homogeneous encapsulation system. After each homogenization cycle, cool to below 40°C before proceeding to the next step. All percentages are mass percentages of the RGD-modified liposome suspension. D. The encapsulation system obtained in step C is filtered using a 0.22 μm microporous membrane. The total number of colonies is <10 CFU / g. The air inside the packaging container is replaced with nitrogen using a nitrogen filling device with a nitrogen flow rate of 5 L / min and an oxygen concentration of <0.5%. After sealing, it is stored in a brown glass bottle and protected from light.

[0057] Example 3 A gradient-targeted encapsulation process for oil-soluble active ingredients with high encapsulation efficiency includes the following steps: A. Mix 1.0 g acetyl hexapeptide-8 (molecular weight 888.9 Da), 0.82 g lauric acid and 0.06 g lipase Novozym 435 and react at 60℃ for 5 h. After the reaction, centrifuge at 4℃ and 8000×g for 15 min to gently remove the lipase. Collect the supernatant to obtain the hydrophobic modified active product. B. Preparation of RGD-modified liposome suspension, including: B1. Preparation of blank liposome suspension: 850 mg of lecithin and 150 mg of cholesterol were weighed as lipids and dissolved in 100 mL of a 2:1 mixture of chloroform and methanol. The mixture was stirred at 500 rpm for 30 min to ensure complete dissolution. The organic solvent was then removed by rotary evaporation at 40 °C, 200 rpm, and -0.1 MPa vacuum to form a uniform lipid film. The film was then vacuum dried at -0.1 MPa and 25 °C for 24 h to completely remove any solvent residue. 10 mL of citrate buffer (containing 150 mM NaCl) at pH 4.0 was added to the lipid film, and the film was hydrated by shaking at 65 °C and 200 rpm for 30 min to allow it to fully expand. Finally, the film was subjected to ultrasonic treatment with a probe under the following conditions: 200 W power, 5 s working time followed by 5 s rest, repeated for 18 cycles to obtain a blank liposome suspension. B2. Active ingredient loading: The hydrophobic modified active ingredient prepared in step A was added to the above blank liposome suspension, wherein the mass ratio of the hydrophobic modified active ingredient to lipid was 1:10, and the mixture was stirred at 40°C and 150 rpm for 30 min. Since small molecules are easy to diffuse, no ultrasonic treatment is required, and the active liposome suspension is obtained directly. B3, RGD modification: Add 5 mg of RGD peptide powder to the active liposome suspension obtained in step B2, wherein the amount of RGD peptide added is 0.5% of the lipid mass, and stir at 55℃ for 0.5 h; then perform ultrafiltration centrifugation, retaining a molecular weight cutoff of 100 kDa, 10,000×g×30 min, and discard the filtrate to remove unbound RGD peptide; dilute the retentate obtained after centrifugation with pH 4.0 citrate buffer (containing 150 mM NaCl) and restore it to the original volume to obtain the purified RGD modified liposome suspension; C. Based on the mass of the RGD-modified liposome suspension obtained in step B3, 16% of isononyl isononanoate (ININ) was added at 35°C and stirred at 150 rpm for 5 minutes. Then, 4% of caprylic / capric triglyceride (GTCC) was added and stirred at 150 rpm for another 5 minutes. Finally, 0.8% of polydimethylsiloxane (PDMS) was added as a stabilizer and stirred for 3 minutes. The mixture was then homogenized and cycled three times at 60°C and 800 bar to form a homogeneous encapsulation system. After each homogenization cycle, the mixture was cooled to below 40°C before proceeding to the next step. The polydimethylsiloxane was a trimethylsiloxy-terminated linear polydimethylsiloxane with a molecular weight of 60,000 Da and a kinematic viscosity of 1000 cSt. All percentages are mass percentages of the RGD-modified liposome suspension. D. The encapsulation system obtained in step C is filtered using a 0.22 μm microporous membrane. The total number of colonies is <10 CFU / g. The air inside the packaging container is replaced with nitrogen using a nitrogen filling device with a nitrogen flow rate of 5 L / min and an oxygen concentration of <0.5%. After sealing, it is stored in a brown glass bottle and protected from light.

[0058] Example 4 A gradient-targeted encapsulation process for oil-soluble active ingredients with high encapsulation efficiency includes the following steps: A. 1.0 g of a snake venom peptide (molecular weight, 496 Da; Chinese name: Dipeptide Diaminobutyroyl Benzylamide Diacetate; English name: Dipeptide Diaminobutyroyl Benzylamide Diacetate; Sequence: H-β-Ala-Pro-Dab-NH-Bzl·2AcOH; CAS number: 823202-99-9; Molecular formula: C 19 H 29 N5O3), 1.2 g octanoic acid and 0.06 g lipase Novozym 435 were mixed and reacted at 58℃ for 4 h. After the reaction was completed, the mixture was centrifuged at 4℃ and 8000×g for 15 min to gently remove the lipase. The supernatant was collected to obtain the hydrophobic modified active product. B. Preparation of RGD-modified liposome suspension, including: B1. Preparation of blank liposome suspension: 900 mg of lecithin and 100 mg of cholesterol were weighed as lipids and dissolved in 100 mL of a 2:1 mixture of chloroform and methanol. The mixture was stirred at 500 rpm for 30 min to ensure complete dissolution. Subsequently, the organic solvent was removed by rotary evaporation at 40 °C, 200 rpm, and -0.1 MPa vacuum to form a uniform lipid film. The film was then vacuum dried at -0.1 MPa and 25 °C for 24 h to completely remove any solvent residue. 10 mL of citrate buffer (containing 150 mM NaCl) at pH 4.0 was added to the lipid film, and the film was hydrated by shaking at 65 °C and 200 rpm for 30 min to allow it to fully expand. Finally, the film was subjected to ultrasonic treatment with a probe under the following conditions: 200 W power, 5 s working time followed by 5 s rest, repeated for 15 cycles to obtain a blank liposome suspension. B2. Active ingredient loading: The hydrophobic modified active ingredient prepared in step A was added to the above blank liposome suspension, wherein the mass ratio of the hydrophobic modified active ingredient to lipid was 1:8. The suspension was stirred at 42°C and 150 rpm for 20 min to obtain the active liposome suspension. B3, RGD modification: Add 5 mg of RGD peptide powder to the active liposome suspension obtained in step B2, wherein the amount of RGD peptide added is 0.5% of the lipid mass, and stir at 52℃ for 0.5 h; then perform ultrafiltration centrifugation, retaining a molecular weight cutoff of 100 kDa, 10,000×g×30 min, and discard the filtrate to remove unbound RGD peptide; dilute the retentate obtained after centrifugation with pH 4.0 citrate buffer (containing 150 mM NaCl) and restore it to the original volume to obtain the purified RGD modified liposome suspension; C. Based on the mass of the RGD-modified liposome suspension obtained in step B3, 12% isononyl isononanoate (ININ) was added at 35°C and stirred at 200 rpm for 3 minutes. Then, 3% caprylic / capric triglyceride (GTCC) was added and stirred at 100 rpm for 8 minutes. Finally, 0.8% cyclopentamethoxysiloxane (D5) was added as a stabilizer and stirred for 5 minutes. The mixture was then homogenized and cycled 3 times at 62°C and 800 bar to form a homogeneous encapsulation system. After each homogenization cycle, the mixture was cooled to below 40°C before proceeding to the next step. All percentages are mass percentages of the RGD-modified liposome suspension. D. The encapsulation system obtained in step C is filtered using a 0.22 μm microporous membrane. The total number of colonies is <10 CFU / g. The air inside the packaging container is replaced with nitrogen using a nitrogen filling device with a nitrogen flow rate of 5 L / min and an oxygen concentration of <0.5%. After sealing, it is stored in a brown glass bottle and protected from light.

[0059] Example 5 A gradient-targeted encapsulation process for oil-soluble active ingredients with high encapsulation efficiency includes the following steps: A. Mix 1.8 g of mussel adhesive protein (in this example, the mussel adhesive protein is Mfp-1 subtype, with a molecular weight of 17 kDa, protein content ≥95%, and DOPA content ≥3%), 1.45 g of lauric acid, and 0.09 g of lipase Novozym 435, and react at 58℃ for 6.5 h. After the reaction, centrifuge at 4℃ and 8000×g for 15 min to gently remove the lipase, and collect the supernatant to obtain the hydrophobic modified active product. B. Preparation of RGD-modified liposome suspension, including: B1. Preparation of blank liposome suspension: 800 mg of lecithin and 200 mg of cholesterol were weighed as lipids and dissolved in 100 mL of a chloroform and methanol mixture (2:1 volume ratio). The mixture was stirred at 500 rpm for 30 min to ensure complete dissolution. Subsequently, the organic solvent was removed by rotary evaporation at 40 °C, 200 rpm, and -0.1 MPa vacuum to form a uniform lipid film. The film was then vacuum dried at -0.1 MPa and 25 °C for 24 h to completely remove any solvent residue. 10 mL of citrate buffer (containing 150 mM NaCl) at pH 4.0 was added to the lipid film, and the film was hydrated by shaking at 65 °C and 200 rpm for 30 min to allow it to fully expand. Finally, the film was subjected to ultrasonic treatment with a probe under the following conditions: 200 W power, 5 s working time followed by 5 s rest, repeated 20 times to obtain a blank liposome suspension. B2. Active ingredient loading: The hydrophobic modified active ingredient prepared in step A was slowly added dropwise to the above blank liposome suspension, wherein the mass ratio of the hydrophobic modified active ingredient to lipid was 1:12. After stirring at 39°C and 150 rpm for 45 min, a gentle probe ultrasonic treatment was performed. The ultrasonic conditions were: power 150 W, working for 5 s and resting for 5 s, repeated for 15 cycles to obtain the active liposome suspension. B3, RGD modification: 4 mg of RGD peptide powder was added to the active liposome suspension obtained in step B2, wherein the amount of RGD peptide added was 0.4% of the lipid mass, and the mixture was stirred at 53°C for 1.2 h. Subsequently, ultrafiltration centrifugation was performed, with a molecular weight cutoff of 100 kDa, at 10,000 × g × 30 min, and the filtrate was discarded to remove unbound RGD peptides. The retentate obtained after centrifugation was diluted with pH 4.0 citrate buffer (containing 150 mM NaCl) and restored to its original volume to obtain the purified RGD modified liposome suspension. C. Based on the mass of the RGD-modified liposome suspension obtained in step B3, at 35°C, first add 21% isononyl isononanoate (ININ) and stir at 150 rpm for 5 minutes. Then add 9% caprylic / capric triglyceride (GTCC) and continue stirring at 150 rpm for 5 minutes. Finally, add 1.2% polydimethylsiloxane (PDMS) as a stabilizer and stir for 3 minutes. Then, homogenize and cycle twice at 52°C and 550 bar pressure to form a homogeneous encapsulation system. After each homogenization cycle, cool to below 40°C before proceeding to the next step. The polydimethylsiloxane is a trimethylsiloxy-terminated linear polydimethylsiloxane with a molecular weight of 35,000 Da and a kinematic viscosity of 350 cSt. All percentages are mass percentages of the RGD-modified liposome suspension. D. The encapsulation system obtained in step C is filtered using a 0.22 μm microporous membrane. The total number of colonies is <10 CFU / g. The air inside the packaging container is replaced with nitrogen using a nitrogen filling device with a nitrogen flow rate of 5 L / min and an oxygen concentration of <0.5%. After sealing, it is stored in a brown glass bottle and protected from light.

[0060] Comparative Example 1 Compared to Example 1, the only difference is that the collagen was not hydrophobically modified; all other steps are the same as in Example 1. Specifically: A. Take collagen (provided by Shandong Saiya Biotechnology Co., Ltd., brand name Jiaobeichu Col III) for later use; B. Preparation of RGD-modified liposome suspension, including: B1. Preparation of blank liposome suspension 800 mg of lecithin and 200 mg of cholesterol were weighed as lipids and dissolved in 100 mL of a chloroform and methanol mixture (2:1 volume ratio). The mixture was stirred at 500 rpm for 30 min to ensure complete dissolution. Subsequently, the organic solvent was removed by rotary evaporation at 40 °C, 200 rpm, and -0.1 MPa vacuum to form a uniform lipid film. The film was then vacuum dried at -0.1 MPa and 25 °C for 24 h to completely remove any solvent residue. 10 mL of citrate buffer (containing 150 mM NaCl) at pH 4.0 was added to the lipid film, and the film was hydrated by shaking at 65 °C and 200 rpm for 30 min to allow it to fully swell. Finally, the film was subjected to ultrasonic treatment with a probe under the following conditions: 200 W power, 5 s working time followed by a 5 s rest, repeated 20 times to obtain a blank liposome suspension. B2, Active ingredient loading Add 200 mg of collagen prepared in step A to a blank liposome suspension, wherein the mass ratio of collagen to lipid is 1:5, stir at 40℃ and 150 rpm for 30 min; then sonicate with a probe under the following conditions: 200W, 5s pulse / 5s interval, 20 cycles to obtain an active liposome suspension. B3, RGD modification Add 3 mg of RGD peptide powder to the active liposome suspension obtained in step B2, wherein the amount of RGD peptide added is 0.3% of the lipid mass, and stir at 55℃ for 1 h; then perform ultrafiltration centrifugation, retaining a molecular weight cutoff of 100 kDa, 10,000×g×30 min, and discard the filtrate to remove unbound RGD peptide; dilute the retentate obtained after centrifugation with pH 4.0 citrate buffer (containing 150 mM NaCl) and restore it to the original volume to obtain the purified RGD modified liposome suspension; C. Using the mass of the RGD-modified liposome suspension obtained in step B3 as a baseline, at 35°C, first add 28% isononyl isononanoate (ININ, polarity > 3), and stir at 150 rpm for 5 minutes. Then add 12% caprylic / capric triglyceride (GTCC, polarity < 2.5), and continue stirring at 150 rpm for 5 minutes. Finally, add 1.0% polydimethylsiloxane (PDMS) as a stabilizer, stir for 3 minutes, and then homogenize twice at 50°C and 600 bar pressure to form a homogeneous encapsulation system. After each homogenization cycle, cool to below 40°C before proceeding to the next step. The polydimethylsiloxane is a trimethylsiloxy-terminated linear polydimethylsiloxane with a molecular weight of 60,000 Da and a kinematic viscosity of 1000 cSt. D. The encapsulation system obtained in step C is filtered through a 0.22 μm microporous membrane, with a total bacterial count <10 CFU / g. The air inside the packaging container is then replaced with nitrogen using a nitrogen filling device at a flow rate of 5 L / min, ensuring an oxygen concentration <0.5%. After sealing, the container is stored in a brown glass bottle, protected from light.

[0061] Comparative Example 2 Compared with Example 1, the only difference is that RGD peptide modification was not used; all other steps are the same as in Example 1. The specific steps are as follows: A. Collagen (16.6 kDa, provided by Shandong Saiya Biotechnology Co., Ltd., brand name Col III), decanoic acid, and lipase Novozym 435 were mixed and reacted at 60℃ for 6 hours. After the reaction, the mixture was centrifuged at 4℃ and 8000×g for 15 minutes to gently remove the lipase Novozym 435. The supernatant was collected to obtain the hydrophobically modified active product. The amount of lipase Novozym 435 added was 5% of the collagen protein mass. The mass ratio of collagen to decanoic acid was 1:0.54. B. Preparation of active liposome suspension, including: B1. Preparation of blank liposome suspension 800 mg of lecithin and 200 mg of cholesterol were weighed as lipids and dissolved in 100 mL of a chloroform and methanol mixture (2:1 volume ratio). The mixture was stirred at 500 rpm for 30 min to ensure complete dissolution. Subsequently, the organic solvent was removed by rotary evaporation at 40 °C, 200 rpm, and -0.1 MPa vacuum to form a uniform lipid film. The film was then vacuum dried at -0.1 MPa and 25 °C for 24 h to completely remove any solvent residue. 10 mL of citrate buffer (containing 150 mM NaCl) at pH 4.0 was added to the lipid film, and the film was hydrated by shaking at 65 °C and 200 rpm for 30 min to allow it to fully expand. Finally, the film was subjected to ultrasonic treatment with a probe under the following conditions: 200 W power, 5 s working time followed by 5 s rest, repeated 20 times to obtain a blank liposome suspension. B2, Active ingredient loading Add 200 mg of the hydrophobic modified active ingredient prepared in step A to a blank liposome suspension, wherein the mass ratio of the hydrophobic modified active ingredient to lipid is 1:5. Stir at 40℃ and 150 rpm for 30 min; then sonicate with a probe under the following conditions: 200W, 5s pulse / 5s interval, 20 cycles to obtain an active liposome suspension. C. Based on the mass of the active liposome suspension obtained in step B2, at 35°C, first add 28% isononyl isononanoate (ININ, polarity > 3), and stir at 150 rpm for 5 minutes. Then add 12% caprylic / capric triglyceride (GTCC, polarity < 2.5), and continue stirring at 150 rpm for 5 minutes. Finally, add 1.0% polydimethylsiloxane (PDMS) as a stabilizer, stir for 3 minutes, and then homogenize twice at 50°C and 600 bar pressure to form a homogeneous encapsulation system. After each homogenization cycle, cool to below 40°C before proceeding to the next step. The polydimethylsiloxane is a trimethylsiloxy-terminated linear polydimethylsiloxane with a molecular weight of 60,000 Da and a kinematic viscosity of 1000 cSt. D. The encapsulation system obtained in step C is filtered using a 0.22 μm microporous membrane. The total number of colonies is <10 CFU / g. The air inside the packaging container is replaced with nitrogen using a nitrogen filling device with a nitrogen flow rate of 5 L / min and an oxygen concentration of <0.5%. After sealing, it is stored in a brown glass bottle and protected from light.

[0062] Comparative Example 3 Compared to Example 1, the only difference is that the mixture of oily matrix was added directly, not in sequence; all other steps are the same as in Example 1. The specific steps are as follows: A. Collagen (16.6 kDa, provided by Shandong Saiya Biotechnology Co., Ltd., brand name Col III), decanoic acid, and lipase Novozym 435 were mixed and reacted at 60℃ for 6 hours. After the reaction, the mixture was centrifuged at 4℃ and 8000×g for 15 minutes to gently remove the lipase Novozym 435. The supernatant was collected to obtain the hydrophobically modified active product. The amount of lipase Novozym 435 added was 5% of the collagen protein mass. The mass ratio of collagen to decanoic acid was 1:0.54. B. Preparation of RGD-modified liposome suspension, including: B1. Preparation of blank liposome suspension 800 mg of lecithin and 200 mg of cholesterol were weighed as lipids and dissolved in 100 mL of a chloroform and methanol mixture (2:1 volume ratio). The mixture was stirred at 500 rpm for 30 min to ensure complete dissolution. Subsequently, the organic solvent was removed by rotary evaporation at 40 °C, 200 rpm, and -0.1 MPa vacuum to form a uniform lipid film. The film was then vacuum dried at -0.1 MPa and 25 °C for 24 h to completely remove any solvent residue. 10 mL of citrate buffer (containing 150 mM NaCl) at pH 4.0 was added to the lipid film, and the film was hydrated by shaking at 65 °C and 200 rpm for 30 min to allow it to fully expand. Finally, the film was subjected to ultrasonic treatment with a probe under the following conditions: 200 W power, 5 s working time followed by 5 s rest, repeated 20 times to obtain a blank liposome suspension. B2, Active ingredient loading Add 200 mg of the hydrophobic modified active ingredient prepared in step A to a blank liposome suspension, wherein the mass ratio of the hydrophobic modified active ingredient to lipid is 1:5. Stir at 40℃ and 150 rpm for 30 min; then sonicate with a probe under the following conditions: 200W, 5s pulse / 5s interval, 20 cycles to obtain an active liposome suspension. B3, RGD modification Add 3 mg of RGD peptide powder to the active liposome suspension obtained in step B2, wherein the amount of RGD peptide added is 0.3% of the lipid mass, and stir at 55℃ for 1 h; then perform ultrafiltration centrifugation (molecular weight cutoff 100 kDa, 10,000×g×30 min), discard the filtrate to remove unbound RGD peptide; dilute the retentate obtained after centrifugation with pH 4.0 citrate buffer (containing 150 mM NaCl) and restore it to the original volume to obtain the purified RGD modified liposome suspension; C. Based on the mass of the RGD-modified liposome suspension obtained in step B3, a mixture of 28% isononyl isononanoate, 12% caprylic / capric triglyceride, and 1.0% polydimethylsiloxane was added at 35°C. The mixture was stirred at 150 rpm for 5 minutes, and then homogenized twice at 50°C and 600 bar to form a homogeneous encapsulation system. After each homogenization cycle, the mixture was cooled to below 40°C before proceeding to the next step. The polydimethylsiloxane was a trimethylsiloxy-terminated linear polydimethylsiloxane with a molecular weight of 60,000 Da and a kinematic viscosity of 1000 cSt. D. The encapsulation system obtained in step C is filtered using a 0.22 μm microporous membrane. The total number of colonies is <10 CFU / g. The air inside the packaging container is replaced with nitrogen using a nitrogen filling device with a nitrogen flow rate of 5 L / min and an oxygen concentration of <0.5%. After sealing, it is stored in a brown glass bottle and protected from light.

[0063] Comparative Example 4 Traditional liposome encapsulation process A. Preparation of blank liposomes: The blank liposome suspension was obtained exactly as described in step B1 of Example 1. B. Encapsulates hydrophilic collagen: Recombinant type III humanized collagen that has not undergone any hydrophobic modification and is naturally hydrophilic (same batch as in Example 1) was directly added to the above blank liposome suspension; the mass ratio of collagen to lipid was set to 1:5 (consistent with the final lipid ratio in Example 1); the mixture was stirred at 40°C for 1 hour and then subjected to probe sonication (under the same conditions as in Example 1).

[0064] Without subsequent steps such as RGD peptide modification and oil phase dispersion, the performance of the obtained liposome suspension was directly tested to purely compare the effect of the encapsulation technology itself.

[0065] Test case The average particle size, encapsulation efficiency, activity retention rate, loading, transdermal absorption, and physical stability of the products prepared in the examples and comparative examples were determined. The RGD peptide binding rate of the RGD modified liposome suspensions of the examples, comparative examples 1 and 3 were determined. The determination items and methods are shown in Table 1, and the determination results are shown in Table 2.

[0066] Table 1

[0067] The specific methods for determining the transdermal absorption rate in the table above are as follows: Transdermal absorption rate determination: Franz diffusion cell (pigskin model), referring to General Chapter 0931 "Determination of Transdermal Patch Release Rate" in Chinese Pharmacopoeia, Part IV (2020 Edition) and OECD TG428: Guidelines for In Vitro Skin Permeability Testing.

[0068] The specific method is as follows: 1. Pigskin processing: Take fresh pig ear skin (thickness 0.8±0.1mm), remove hair and peel off subcutaneous fat, wash with PBS, and store at -20℃ for later use.

[0069] 2. Experimental setup: Effective diffusion area of ​​the diffusion cell: 1.8 cm²; Receptor solution: pH 7.4 PBS (containing 0.01% NaN3 for antibacterial effect); Temperature: 32±2℃ (simulating human skin surface temperature); Sampling time point: 24 hours.

[0070] 3. Transdermal dose calculation: The collagen concentration in the recipient fluid was determined by HPLC, and the cumulative transdermal transdermal volume (Qn) was calculated using the following formula:

[0071] in: A The effective diffusion area is the skin area. C n For the first n Concentration of active ingredient in the recipient fluid at the time of the second sampling; V The total volume of the receptor pool is 5 mL. C i For the first i Concentration of active ingredient in the recipient fluid at the time of the second sampling; V i The volume of each sample taken is 0.5 mL. Table 2

[0072] GC-MS analysis of solvent residue showed that the residue levels in Examples 1-5 were all less than 0.1%, which meets the ECOCERT cosmetic standards.

[0073] Application examples The product from Example 1 was added to actual formulations such as essential oils, lotions, and creams, and its compatibility and stability were observed.

[0074] The results show that the product of Example 1 of the present invention can be directly used as a raw material for cosmetics and used in the manufacture of cosmetics without affecting the properties of the original skin care essence oil system.

[0075] The RGD peptide used in this invention is a chemically synthesized oligopeptide whose sequence is widely found in human extracellular matrix proteins, exhibiting good biocompatibility. In the process of this invention, its dosage is extremely low, at 0.2-0.5% of the total lipid mass, and unbound free peptides are effectively removed through ultrafiltration and centrifugation, ensuring the safety of the final product. This ingredient has been used as a signal peptide in cosmetics for many years and is safe and reliable.

[0076] The above are merely preferred embodiments of the present invention and are 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 within the protection scope of the present invention.

Claims

1. A high encapsulation efficiency oil-soluble active gradient targeting encapsulation process characterized by, It comprises the following steps: A. mixing the active substance, fatty acid and lipase Novozym 435, reacting at 55-60℃ for 4-7h to obtain a hydrophobic modified active substance; wherein the active substance is SOD, mussel mucin, collagen, acetyl hexapeptide-8 or a snake venom-like peptide; B. preparing an RGD modified liposome suspension, comprising: B1. preparing blank liposomes using lipids to obtain a blank liposome suspension; B2. adding the hydrophobic modified active substance to the blank liposome suspension and stirring to obtain an active liposome suspension; B3. adding RGD peptide at 0.2-0.5% of the mass of the lipids to the active liposome suspension, stirring, and ultrafiltration centrifugation to obtain an RGD modified liposome suspension; C. adding an oily base I with a polarity value > 3 to the RGD modified liposome suspension first, stirring for the first time, then adding an oily base II with a polarity value < 2.5, stirring for the second time, finally adding a stabilizer, stirring for the third time, and then homogenizing; wherein the addition amounts of the oily base I, the oily base II and the stabilizer are 12-28%, 3-12% and 0.8-1.5% of the RGD modified liposome suspension, respectively.

2. A high encapsulation oil-soluble active gradient targeting encapsulation process according to claim 1, wherein, The fatty acid is decanoic acid, octanoic acid or lauric acid.

3. A high encapsulation oil-soluble active gradient targeting encapsulation process according to claim 1, wherein, The addition amount of the lipase Novozym 435 is 4-6% of the mass of the active substance; the mass ratio of the active substance to the fatty acid is 1:0.3-1.

2.

4. The high encapsulation oil-soluble active gradient targeting encapsulation process of claim 1, wherein, The mass ratio of the hydrophobic modified active substance to the lipids is 1:5-1:

15.

5. A high encapsulation oil-soluble active gradient targeting encapsulation process according to claim 1, wherein, The molecular weight of the active substance is 368 Da-35 kDa.

6. A high encapsulation oil-soluble active gradient targeting encapsulation process according to claim 1, wherein, The lipids comprise lecithin and cholesterol at a mass ratio of 3-9:

1.

7. A high encapsulation oil-soluble active gradient targeting encapsulation process according to claim 1, wherein, The preparation method of the blank liposomes comprises: dissolving lecithin and cholesterol in a solvent, stirring, removing the solvent to prepare a lipid film; adding a buffer solution with a pH of 3.8-4.2 to the lipid film, oscillating to make it swell, and then treating with a probe ultrasonic to obtain blank liposomes.

8. A high encapsulation oil-soluble active gradient targeting encapsulation process according to claim 6, wherein, The homogenization in step C comprises: homogenizing 2-3 times at 50-62℃ and 500-800 bar pressure.

9. The high encapsulation oil-soluble active gradient targeting encapsulation process of claim 1, wherein, The oily base with a polarity value > 3 is isononyl isononanoate or isopropyl isostearate, and the oily base with a polarity value < 2.5 is caprylic / capric triglyceride or cocoyl octanoate / caprate.

10. The high encapsulation oil-soluble active gradient targeting encapsulation process of claim 1, wherein, The stabilizer is dimethicone or cyclopentadimethylsiloxane.

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