High-load high-stable submicron emulsion, preparation method and application thereof

Abstract

The application provides a high-load high-stability submicron emulsion and a preparation method and application thereof, and belongs to the field of medical, dental or cosmetic preparations. The emulsion comprises a hydrophobic hydrogen bond donor, a hydrophobic hydrogen bond acceptor, a non-ionic emulsifier, a charged amphiphilic polymer, a pH regulator and water, the pH is 5.00-8.50, the Z average particle size is 100-150 nm, and the particle size polydispersity index is less than or equal to 0.20. During preparation, a composite oil phase and a polymer pre-emulsion are formed, the non-ionic emulsifier is added after homogenization treatment, the pH is adjusted and defoaming is performed, and the submicron emulsion is obtained. The emulsion can be used for loading a poorly soluble cosmetic functional ingredient, and has high loading capacity, particle size uniformity and storage stability.

Description

Technical Field

[0001] This invention belongs to the field of formulations for medical, dental or cosmetic use, and particularly relates to a high-load, highly stable submicron emulsion, its preparation method and application. Background Technology

[0002] Cosmetics often contain vitamins, carotenoids, plant extracts, fragrances, oil-soluble antioxidants, and other fat-soluble active ingredients. Some of these ingredients have low solubility in water, and when directly added to aqueous solutions, serums, or gel systems, they can easily lead to uneven dispersion, crystallization, precipitation, turbidity, and a decrease in the content of active ingredients. Therefore, appropriate carrier systems are usually needed to improve their dispersibility, stability, and performance.

[0003] Commonly used methods in existing technologies include oil-phase dissolution, surfactant solubilization, emulsification dispersion, liposome encapsulation, cyclodextrin inclusion, solid lipid particles, polymer nanoparticles, and microencapsulation. Oil-phase dissolution is simple, but its limited oil-phase solubility restricts the amount of active ingredient added; when the concentration of the active ingredient increases, supersaturation, crystallization, or oil-water separation can easily occur. Surfactant solubilization can form micelles or mixed micelles, but usually requires high amounts of surfactant, which may lead to problems such as stickiness, increased irritation, and foaming. Furthermore, some solubilized systems are prone to instability during dilution, temperature changes, or long-term storage.

[0004] Emulsions are a widely used carrier form in cosmetics, improving the dispersion of oil-soluble ingredients. However, ordinary emulsions have relatively large droplet sizes, making them prone to aggregation, flocculation, stratification, and droplet breakage, and it is difficult to balance high active ingredient content with long-term stability. Nanoemulsions or submicron emulsions with smaller droplet sizes have larger interfacial areas and better appearance, but their preparation usually requires higher energy input or more emulsifiers. For poorly soluble and easily crystallizing active ingredients, reducing the droplet size may accelerate the migration of components between the oil and water phases, leading to Australse ripening, crystal precipitation, or loss of active ingredients.

[0005] Liposomes, solid lipid particles, and polymer nanoparticles can encapsulate or adsorb poorly soluble components, but their preparation processes may involve organic solvents, high temperatures, complex equipment, or numerous process steps. Some systems also suffer from problems such as unstable encapsulation efficiency, significant batch-to-batch variations, difficulty in controlling release behavior, and insufficient compatibility with conventional cosmetic matrices. Cyclodextrin inclusion and microencapsulation methods are limited by inclusion capacity, material compatibility, and release efficiency.

[0006] Furthermore, cosmetic production must also consider raw material safety, formulation compatibility, gentle processing, feasibility of scale-up production, and the scope of permitted use under regulations. Current technology still lacks a submicron-level delivery system that can maintain uniform particle size, long-term storage stability, gentle processing conditions, and suitability for cosmetic formulations while achieving high active ingredient loadings. Summary of the Invention

[0007] The first objective of this invention is to provide a high-loading, highly stable submicron emulsion comprising the following components by weight: Hydrophobic hydrogen bond donor, 2-8 parts; Hydrophobic hydrogen bond acceptor, 12-25 portions; Nonionic emulsifier, 1.5-4.0 parts; Charged amphiphilic polymer, 0.2-0.8 parts; pH adjuster, 0.05-0.30 parts; Water, 60-85 parts; The hydrophobic hydrogen bond donor has a hydroxyl value of 150-350 mg KOH / g and an HLB value of 3-7. The effective hydrogen bond acceptor density of the hydrophobic hydrogen bond acceptor is 2-6 mmol / g, and its solubility in water at 25°C is ≤1 mg / L. The nonionic emulsifier has an HLB value of 12-16, and when the oil core composed of the hydrophobic hydrogen bond donor and the hydrophobic hydrogen bond acceptor is used as the oil phase, its dynamic interfacial tension at 25°C for 30 seconds is ≤8 mN / m. The charged amphiphilic polymer is an amphiphilic polymer containing carboxyl groups and C8-C18 hydrophobic groups, with a weight-average molecular weight of 10-150 kDa and a molar content of C8-C18 hydrophobic groups of 0.5%-5.0%. The molar ratio of the effective hydrogen bond donor sites in the hydrophobic hydrogen bond donor to the effective hydrogen bond acceptor sites in the hydrophobic hydrogen bond acceptor is (0.5-2):1; The mass ratio of the nonionic emulsifier to the charged amphiphilic polymer is (2-8):1; The high-load submicron emulsion has a pH value of 5.00–8.50, an average particle size of 100–150 nm, and a particle size polydispersity index ≤0.20.

[0008] Preferably, the hydrophobic hydrogen bond donor contains at least one C16-C18 aliphatic hydrophobic segment with one carbon-carbon double bond, and its solubility in water at 25°C is ≤0.1 g / L; the hydrophobic hydrogen bond acceptor has a dynamic viscosity of 10-60 mPa·s at 25°C; and the mass ratio of the hydrophobic hydrogen bond donor to the hydrophobic hydrogen bond acceptor is 10:90-35:65.

[0009] The hydrophobic hydrogen bond donor is a polyol and a C16-C18 unsaturated fatty acid forming a lipophilic compound with a free hydroxyl group; the hydrophobic hydrogen bond acceptor is a neutral aliphatic ester oil that is liquid at 25°C, contains 1-3 ester carbonyl groups in its molecule, and does not contain free hydroxyl groups or dissociable carboxyl groups.

[0010] Preferably, the nonionic emulsifier contains at least one C8-C molecule. 14 Aliphatic hydrophobic segments.

[0011] The nonionic emulsifier contains an average of 1-2 C8-C atoms. 14 Polyol fatty acid esters with saturated fatty acid ester groups, 6-12 free hydroxyl groups and no dissociable ionic groups.

[0012] Preferably, the molar ratio of carboxyl groups to C8-C18 hydrophobic groups in the charged amphiphilic polymer is 3:1-10:1; the apparent pKa of the charged amphiphilic polymer is 3.0-4.5, and the apparent pKa is the half-neutralization point pH value measured by potentiometric titration at 25°C using 0.01 mol / L sodium chloride aqueous solution as the medium.

[0013] Preferably, the aqueous solution of the charged amphiphilic polymer with a mass concentration of 1.0% is prepared at 25°C and a shear rate of 10 s. -1 The apparent viscosity under the specified conditions is ≤100 mPa·s; the carboxyl content of the charged amphiphilic polymer is 0.3-2.0 mmol / g.

[0014] The charged amphiphilic polymer is an anionic amphiphilic polysaccharide derivative formed by covalently grafting C8-C18 aliphatic hydrophobic segments onto the polymer backbone using carboxylated polysaccharide as the polymer backbone.

[0015] As an optional implementation, the hydrophobic hydrogen bond donor can be selected from one or both of isostearic acid and octyldodecyl alcohol; the hydrophobic hydrogen bond acceptor can be selected from vegetable oils, including one or more of meadowfoam seed oil, camellia seed oil, argan oil, and sunflower seed oil; the nonionic emulsifier can be selected from one or more of inulin lauryl carbamate, polysaccharide-modified polymeric emulsifier, and alkyl glycoside emulsifier; the charged amphiphilic polymer or charged amphiphilic interfacial stabilizing component can be selected from one or more of subtilisin sodium lipopeptide, fermentation-derived glycolipids, and phospholipids. The above raw materials can be used alone or in combination, and the specific selection and dosage can be adjusted according to the target active ingredient, oil phase polarity, and required emulsion pH.

[0016] A second objective of this invention is to provide a method for preparing the aforementioned high-load submicron emulsion, comprising the following steps: S1. Mix the hydrophobic hydrogen bond donor and the hydrophobic hydrogen bond acceptor evenly to obtain a composite oil phase; S2. Disperse the charged amphiphilic polymer in the first part of water and fully hydrate it to obtain the polymer aqueous phase; S3. Under shear conditions, the composite oil phase is added to the polymer aqueous phase for emulsification, and stirring is continued to obtain a pre-emulsion; S4. The pre-emulsion is homogenized under high pressure to obtain a primary submicron emulsion; S5. Disperse the nonionic emulsifier in the second part of water to obtain an aqueous phase of emulsifier. After the high-pressure homogenization in step S4 is completed, add the aqueous phase of emulsifier to the primary submicron emulsion and mix evenly to obtain a submicron emulsion. S6. Adjust the pH value of the submicron emulsion to 5.00-8.50, and defoam to obtain the high-load submicron emulsion.

[0017] A third objective of this invention is to provide the application of the aforementioned high-load submicron emulsion in loading cosmetic active ingredients, wherein the cosmetic active ingredients are loaded in an oil core composed of hydrophobic hydrogen bond donors and hydrophobic hydrogen bond acceptors.

[0018] The dispersed phase of this emulsion consists of hydrophobic hydrogen bond donors and acceptors. Phase A contains residual hydroxyl groups and C16-C18 aliphatic hydrophobic segments, while Phase B contains hydrogen bond acceptor sites such as ester-type carbonyl groups. These two phases coordinate according to the molar ratio of effective hydrogen bond donor sites to acceptor sites, forming a homogeneous composite oil core through reversible hydrogen bonding and hydrophobic interactions. The residual hydroxyl groups in Phase A can interfere with the regular arrangement of oil phase molecules and the carried components, reducing the tendency for crystallization; Phase B has low water solubility and, as the main body of the oil core, can reduce the migration of oil phase components into the aqueous phase. This composite oil core belongs to a hydrogen-bonded, crystallization-inhibiting oil phase. Whether it constitutes a eutectic system should be determined based on measured phase diagrams, thermal analysis, and spectral data, and not solely on the liquid appearance.

[0019] During the preparation process, the charged amphiphilic polymer is first dispersed and hydrated in an aqueous phase. Under low pH conditions, some carboxyl groups in the polymer remain protonated, and the C8-C18 hydrophobic groups in the polymer can hydrophobically associate with the composite oil core and adsorb at the oil-water interface; the carboxylated hydrophilic segments extend into the aqueous phase, forming a preliminary interfacial protective layer. The molar ratio of carboxyl groups to hydrophobic groups in the polymer controls the interfacial anchoring ability and the aqueous phase extension ability, preventing the polymer from completely dissolving in the aqueous phase or undergoing excessive self-aggregation.

[0020] After the composite oil phase is added to the polymer aqueous phase, shear emulsification is performed to form a pre-emulsion. High-pressure homogenization breaks up the pre-emulsion droplets and generates a new oil-water interface, with the adsorbed amphiphilic polymer providing initial interfacial protection. After homogenization, a nonionic emulsifier is added. The nonionic emulsifier rapidly migrates to the new interface, reducing interfacial tension and filling interfacial defects in the polymer layer, thereby forming a composite interfacial layer composed of the polymer and the nonionic emulsifier.

[0021] The pH of the emulsion was then adjusted to 5.00–8.50 to increase the ionization of the polymer carboxyl groups. The ionized carboxyl groups induce electrostatic repulsion between adjacent droplets, while the hydrophilic segments form a hydration layer and create steric hindrance, reducing the probability of droplet approach and aggregation. Residual hydroxyl groups in A, the hydrophilic groups of the nonionic emulsifier, and the incompletely ionized carboxyl groups in the polymer can also form hydrogen bonds or polar interactions, maintaining a certain bonding strength at the interface. Thus, the system achieves high loading capacity and good droplet stability through the anti-crystallization effect of the composite oil core, the low water solubility of B, the interfacial anchoring and hydration steric hindrance of the polymer, and the rapid film-forming effect of the nonionic emulsifier.

[0022] The beneficial effects of this invention are manifested in at least the following aspects: (1) By combining the sites of A and B to form a crystallization-inhibiting composite oil core, the loading capacity of hydrophobic active ingredients is improved and the risk of crystallization is reduced.

[0023] (2) The preparation sequence of polymer pre-adsorption, homogenization droplet formation and nonionic emulsifier post-film replenishment is adopted to take into account both polymer interface anchoring and rapid coverage of the new interface.

[0024] (3) The synergistic effect of polymer charge repulsion, hydration steric hindrance and nonionic interfacial film enables the emulsion to obtain a Z average particle size of 100-150 nm and a particle size polydispersity index of ≤0.20.

[0025] (4) The low water-soluble oil core and the composite interface layer together reduce droplet aggregation, stratification and active ingredient migration, making it suitable for loading oil-soluble or water-insoluble cosmetic functional ingredients. Attached Figure Description

[0026] Figure 1 The 1H NMR spectra of the charged amphiphilic polymers P-1, P-2, and P-3 prepared in this invention are shown.

[0027] Figure 2 The appearance of Examples 1, 2, 5, and 11.

[0028] Figure 3 These are polarizing microscope images of Examples 1, 2, 5, and 11.

[0029] Figure 4 The appearance of Examples 2-H and 11 after loading in three states: initial, after 6 cycles of 4°C / 40°C temperature cycling, and after 90 days of light protection at 25°C.

[0030] Figure 5 The polarizing microscopes of Examples 2-H and 11 after loading were used in three states: initial, after 6 cycles of 4°C / 40°C temperature cycling, and after 90 days of light protection at 25°C. Detailed Implementation

[0031] The technical solutions in the embodiments of the present invention will be clearly and completely described below. 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 skilled in the art without creative effort are within the scope of protection of the present invention.

[0032] In the description of this invention, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the stated features. In the description of this invention, "a plurality of" means two or more, unless otherwise explicitly specified.

[0033] In the description of this invention, the term "for example" is used to mean "used as an example, illustration, or description." Any embodiment described as "for example" in this invention is not necessarily to be construed as being more preferred or advantageous than other embodiments. The following description is provided to enable any person skilled in the art to make and use the invention. Details are set forth in the following description for purposes of explanation. It should be understood that those skilled in the art will recognize that the invention can be made without using these specific details. In other instances, well-known structures and processes will not be described in detail to avoid obscuring the description of the invention with unnecessary detail. Therefore, the invention is not intended to be limited to the embodiments shown, but is consistent with the broadest scope of the principles and features disclosed herein.

[0034] Unless otherwise specified, the experimental methods used in the specific implementation methods are all conventional methods, and the materials and reagents used are all commercially available unless otherwise specified.

[0035] In this invention, unless otherwise specified, "%" represents a percentage by mass; the raw materials and reagents used are all commercially available products.

[0036] Unless otherwise specified, the following raw material specifications are all test values ​​of the actual batches used.

[0037] 1. Hydrophobic hydrogen bond donor A-1: Glyceryl monooleate, CAS No. 25496-72-4, monooleate content 92.4%, hydroxyl value 315mgKOH / g, HLB value 3.4, solubility in water at 25℃ 0.08g / L; A-2: Polyglycerol-3 oleate, with an average degree of polymerization of 3.0, a hydroxyl value of 342 mgKOH / g, an HLB value of 6.8, and a water solubility of 0.09 g / L at 25°C; A-3: Diglyceride, diester content 91.6%, hydroxyl value 158 mg KOH / g, HLB value 2.7, solubility in water at 25℃ 0.03 g / L.

[0038] 2. Hydrophobic hydrogen bond acceptor B-1: Medium-chain triglycerides, mainly composed of caprylic acid triglycerides and capric acid triglycerides, with caprylic acid component content of 61.2% and capric acid component content of 37.8%, effective hydrogen bond acceptor density of 5.7 mmol / g, solubility in water at 25℃ of 0.4 mg / L, and dynamic viscosity at 25℃ of 27.5 mPa·s; B-2: Propylene glycol dioctanoate, purity 98.6%, effective hydrogen bond acceptor density 5.4 mmol / g, water solubility at 25℃ 0.7 mg / L, dynamic viscosity at 25℃ 18.6 mPa·s; B-3: Squalane, purity 98.3%, effective hydrogen bond acceptor density 0 mmol / g, solubility in water at 25℃ 0.02 mg / L, dynamic viscosity at 25℃ 31.8 mPa·s.

[0039] B-4: Isoceryl palmitate, liquid at 25°C, with an effective hydrogen bond acceptor density of 2.03 mmol / g, a water solubility of 0.08 mg / L, and a dynamic viscosity of 34.2 mPa·s at 25°C. It does not contain free hydroxyl groups or dissociable carboxyl groups.

[0040] 3. Nonionic emulsifiers The nonionic emulsifier contains saturated aliphatic hydrophobic segments and no dissociable ionic groups. Its 30-second dynamic interfacial tension was measured using a composite oil phase composed of hydrophobic hydrogen bond donors and acceptors.

[0041] N-1: Polyglycerol-6 laurate, with an average of 1.1 laurate groups and 6.3 free hydroxyl groups, HLB value of 12.3, and a 30-second dynamic interfacial tension of 7.7 mN / m measured with B-1 as the oil phase; N-2: Polyglycerol-10 decanoate, with an average of 1.8 decanoate groups and 11.6 free hydroxyl groups, HLB value of 15.7, and a 30-second dynamic interfacial tension of 5.3 mN / m measured with B-1 as the oil phase; N-3: Polysorbate 80, HLB value 15.0, hydrophobic segments contain an average of 18 carbon atoms, and the dynamic interfacial tension measured over 30 seconds using B-1 as the oil phase is 6.4 mN / m.

[0042] 4. Other raw materials The pH adjuster used was citric acid with a purity of 99.5% and sodium hydroxide with a purity of 99.0%; the water used was deionized water with a conductivity of 0.8 μS / cm. The above raw materials were kept consistent in all examples and comparative examples.

[0043] 5. Electrophilic polymers The charged amphiphilic polymer was prepared by the following method: (1) Preparation of carboxylated dextran intermediates Weigh out 10.00 g each of dextran with weight average molecular weight of 12 kDa, 142 kDa and 172 kDa respectively, place them in three reaction vessels, add 200 mL of deionized water, and stir at 25 °C until completely dissolved.

[0044] Weigh out the following succinic anhydrides: P-1 is used at a dose of 488mg; P-2 is used in a dose of 1.21g; P-3 is used at 592mg.

[0045] Succinic anhydride was dissolved in 20 mL of acetone and slowly added to the corresponding dextran solution under stirring. The pH of the reaction system was maintained at 8.5 using a 2 mol / L sodium hydroxide aqueous solution. After the addition was complete, the reaction was continued at 25 °C for 6 h.

[0046] After the reaction was complete, the pH of the system was adjusted to 7.0 using hydrochloric acid aqueous solution to obtain a carboxylated dextran solution. The resulting solutions were then placed into dialysis bags with the corresponding molecular weight cutoffs. P-1 uses a 3.5kDa dialysis bag; P-2 and P-3 use 10kDa dialysis bags.

[0047] Dialysis was performed with deionized water for 72 hours, with the dialysis water being changed every 12 hours. After dialysis, the resulting solution was freeze-dried to obtain carboxylated dextran intermediates D-1, D-2, and D-3, respectively.

[0048] The degrees of carboxylation of D-1, D-2 and D-3 were determined by proton nuclear magnetic resonance spectroscopy and conductivity titration to be 0.066, 0.163 and 0.080, respectively.

[0049] (2) Grafting reaction of dodecylamine Take 10.00 g each of D-1, D-2 and D-3, add 200 mL of 0.1 mol / L 2-(N-morpholino)ethanesulfonic acid buffer solution with pH 5.5, and stir to dissolve at 25 °C.

[0050] Weigh out dodecylamine hydrochloride separately: P-1 is used at a dose of 96 mg; P-2 is used at a dose of 657mg; P-3 is used at 889mg.

[0051] Dodecylamine hydrochloride was dissolved in a mixed solvent of ethanol and deionized water, wherein the volume ratio of ethanol to deionized water was 1:1.

[0052] Weigh out 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide separately: P-1 was administered at 100 mg and 60 mg respectively; P-2 was administered at 680 mg and 408 mg respectively; P-3 was administered at doses of 922 mg and 552 mg, respectively.

[0053] The above-mentioned carbodiimide salt and N-hydroxysuccinimide were added to the corresponding carboxylated dextran solutions and pre-activated at 25°C and pH 5.5 for 30 min. Subsequently, dodecylamine hydrochloride solution was added, and the pH of the system was maintained at 5.5 using 0.5 mol / L sodium hydroxide aqueous solution, and the reaction was continued for 6 h.

[0054] After 6 hours of reaction, the pH of the system was adjusted to 7.0, and the reaction was continued at 25°C for 12 hours to deactivate unreacted activated carboxyl groups. After the reaction was completed, dialysis was performed under the above dialysis conditions to remove unreacted dodecylamine hydrochloride, carbodiimide byproducts, N-hydroxysuccinimide, and inorganic salts.

[0055] After dialysis, the polymer solution was filtered through a 0.22 μm filter membrane and then freeze-dried to obtain charged amphiphilic polymers P-1, P-2 and P-3, respectively.

[0056] 3. Determination of polymer structural parameters The weight-average molecular weight was determined by gel permeation chromatography. The molar content of dodecyl grafting was calculated by the integral area ratio of the dodecyl terminal methyl peak to the dextran anolyte peak in the proton NMR spectrum. The carboxyl content was determined by conductivity titration.

[0057] The parameters of the obtained polymer are as follows: P-1: Weight average molecular weight is 13 kDa, molar content of dodecyl hydrophobic groups is 0.7%, and molar ratio of carboxyl groups to hydrophobic groups is 9.4:1; P-2: Weight average molecular weight is 145 kDa, molar content of dodecyl hydrophobic groups is 4.8%, and molar ratio of carboxyl groups to hydrophobic groups is 3.4:1; P-3: Weight average molecular weight is 175 kDa, the molar content of dodecyl hydrophobic groups is 6.5%, and the molar ratio of carboxyl groups to hydrophobic groups is 1.2:1.

[0058] Nuclear magnetic resonance hydrogen spectrum as follows Figure 1As shown.

[0059] Example 1: Preparation of a Highly Loaded Submicron Emulsion 1. Formula Composition The formula for this embodiment, calculated by parts by weight, is as follows: 6.10 parts of glyceryl monooleate, 12.00 parts of medium-chain triglycerides, 1.50 parts of polyglycerol-6-laurate, 0.20 parts of carboxylated dextran-dodecylamide grafted derivative P-1, 0.05 parts of sodium hydroxide, and 60.00 parts of deionized water.

[0060] Sodium hydroxide is prepared in advance as a 1.0% sodium hydroxide aqueous solution, and the deionized water used in the preparation is included in the above 60.00 parts of deionized water.

[0061] 2. Preparation steps S1. Preparation of composite oil phase Weigh 6.10 parts of glycerol monooleate and 12.00 parts of medium-chain triglycerides, and add them sequentially to a clean, dry mixing container. First, stir at 300 r / min for 5 min to initially disperse the glycerol monooleate in the medium-chain triglycerides; then increase the stirring speed to 600 r / min and continue stirring for 20 min until the mixture appears uniform and there are no visible undispersed substances on the inner wall and bottom of the container, thus obtaining the composite oil phase.

[0062] S2, Preparation of the polymer aqueous phase Weigh 30.00 parts from 60.00 parts of deionized water and add them to the aqueous phase container. Under stirring conditions of 500 r / min, slowly sprinkle 0.20 parts of carboxylated dextran-dodecylamide grafted derivative P-1 into the water, controlling the feeding time to 5 min to avoid polymer agglomeration.

[0063] After the addition of the material is completed, the stirring speed is increased to 1000 r / min and stirring is continued for 30 min to fully wet and disperse P-1; then the stirring speed is reduced to 400 r / min and hydration is continued for 2 h.

[0064] Under continuous stirring, a 1.0% (w / w) sodium hydroxide aqueous solution was added dropwise to adjust the pH of the polymer aqueous phase to 4.80. This step consumed 0.018 parts of sodium hydroxide. After adjustment, stirring was continued for 15 minutes to ensure the pH of the system was uniform, thus obtaining the polymer aqueous phase.

[0065] S3. Preparation of preemulsion The polymer aqueous phase was placed under a rotor-stator high-speed shear emulsifier and pre-sheared at 6000 r / min for 2 min.

[0066] While maintaining the shearing state, add the composite oil phase obtained in step S1 to the polymer aqueous phase at a uniform rate, controlling the feeding time to be 6 min. During the feeding process, gradually increase the shearing rate to 10000 r / min. After the composite oil phase is added, continue shearing at 10000 r / min for 10 min.

[0067] After shearing, the resulting emulsion was transferred to a mechanical stirring device and stirred at 600 r / min for 30 min to ensure that P-1 was in full contact with the emulsion droplets, thus obtaining a pre-emulsion.

[0068] S4, High-pressure homogenization The pre-emulsion was added to the feed tank of a high-pressure homogenizer and circulated at low speed for 2 minutes to purge air from the pipeline. It was then homogenized three times consecutively at 80 MPa. After each homogenization, the emulsion was collected in a clean container and then added back to the homogenizer for the next homogenization.

[0069] During homogenization, circulating cooling water is used to control the material temperature to ≤35℃. After the third homogenization, the resulting emulsion is cooled to 25℃ to obtain a homogenized emulsion.

[0070] S5. Add nonionic emulsifier Weigh 25.05 parts from the remaining deionized water and add it to another container. Add 1.50 parts of polyglycerol-6 laurate while stirring at 500 r / min. After the addition is complete, increase the stirring speed to 800 r / min and continue stirring for 20 min to obtain a homogeneous emulsion aqueous phase.

[0071] The homogeneous emulsion obtained in step S4 was placed in a mechanical stirrer and stirred at 800 r / min. The aqueous phase of the emulsifier was then uniformly added to the homogeneous emulsion over 10 min. After the addition was complete, the stirring speed was increased to 1000 r / min, and stirring was continued for 30 min to obtain a submicron emulsion.

[0072] S6, pH adjustment and defoaming Under stirring at 500 r / min, the remaining 1.0% (w / w) sodium hydroxide aqueous solution was added dropwise to the submicron emulsion obtained in step S5 to adjust the pH of the emulsion to 6.20. This step consumed 0.032 parts of sodium hydroxide, and the total amount of sodium hydroxide used in the two pH adjustment steps was 0.05 parts.

[0073] After adjustment, continue stirring for 15 minutes, let stand for 10 minutes, and then retest the pH value. After confirming that the pH value is 6.20, place the emulsion in a vacuum degassing device and degas for 5 minutes under a vacuum of -0.06 MPa to obtain a high-load submicron emulsion.

[0074] 3. Characterization Tests The resulting emulsion was sealed and allowed to stand at 25°C for 24 h before being characterized.

[0075] (1) Appearance and dispersion state The resulting emulsion has a uniform milky white appearance, is fluid, and no visible oil droplets, flocculents, sediments, or stratification were observed.

[0076] (2) pH value At 25°C, the pH electrode, calibrated with a standard buffer solution, was directly inserted into the emulsion for measurement. The measurement was performed in parallel three times, and the resulting pH value of the emulsion was 6.20.

[0077] (3) Z-mean particle size and particle size polydispersity index The emulsion was diluted 100 times with deionized water and measured using a dynamic light scattering instrument at 25°C. Each sample was measured in triplicate, with at least 10 valid data points obtained from each measurement, and the average value was taken. The Z-mean particle size of the obtained emulsion was 128.6 nm, and the polydispersity index was 0.16.

[0078] (4) Zeta potential The emulsion was diluted 100 times with deionized water and measured using electrophoretic light scattering at 25°C, with three parallel measurements. The resulting emulsion had a Zeta potential of -25.8 mV.

[0079] (5) Polarized light microscopy A drop of the emulsion was placed on a glass slide, covered with a coverslip, and observed under a polarizing microscope in five random fields of view. No obvious birefringent crystals or large particles were observed in any field of view.

[0080] (6) Centrifugal stability Take 10 mL of the emulsion and place it in a centrifuge tube. Centrifuge at 25℃ and a relative centrifugal force of 4000×g for 30 min. After centrifugation, no obvious layering, precipitation, or oil phase separation was observed in the emulsion.

[0081] Example 2: Preparation of a High-Loaded Submicron Emulsion The difference between this embodiment and Example 1 is that the dosage of each component is increased to prepare a blank submicron emulsion without cosmetic active ingredients. Except for the dosage, the raw materials and their specifications are the same as in Example 1.

[0082] 1. Formula Composition The formula for this embodiment, calculated by parts by weight, is as follows: 8.00 parts of glyceryl monooleate, 15.50 parts of medium-chain triglycerides, 4.00 parts of polyglycerol-6-laurate, 0.80 parts of carboxylated dextran-dodecylamide grafted derivative P-1, 0.30 parts of sodium hydroxide, and 85.00 parts of deionized water.

[0083] The sodium hydroxide was prepared in advance as a 1.0% sodium hydroxide aqueous solution, and the deionized water used was included in the above 85.00 parts of deionized water.

[0084] 2. Preparation steps S1. Preparation of composite oil phase Weigh 8.00 parts of glyceryl monooleate and 15.50 parts of medium-chain triglycerides and add them to a clean, dry mixing container.

[0085] First, stir at 300 r / min for 5 min to uniformly disperse glycerol monooleate in medium-chain triglycerides; then increase the stirring speed to 600 r / min and continue stirring for 25 min. After stirring, observe the state of the mixture to confirm that the system is a uniform transparent or uniform oily liquid, and that there are no obvious deposits on the bottom and inner wall of the container, thus obtaining a composite oil phase.

[0086] S2, Preparation of the polymer aqueous phase 42.50 parts of water were taken from 85.00 parts of deionized water as the aqueous phase for polymer preparation, including the water required to prepare the sodium hydroxide aqueous solution.

[0087] Under stirring at 500 r / min, 0.80 parts of carboxylated dextran-dodecylamide grafted derivative P-1 were slowly added to the above water over a time of 8 min. Avoid pouring the mixture all at once during addition to reduce polymer agglomeration.

[0088] After the material is added, the stirring speed is increased to 1000 r / min and stirred for 40 min to fully wet and disperse P-1; then the stirring speed is reduced to 400 r / min and hydration continues for 2 h.

[0089] 0.30 parts of sodium hydroxide were prepared into a 1.0% (w / w) sodium hydroxide aqueous solution, which was then slowly added dropwise to the polymer dispersion under stirring at 400 r / min. The pH value of the system was continuously measured during the addition, and the pH of the polymer aqueous phase was adjusted to 4.80. After the addition was complete, stirring was continued for 20 min to ensure the pH of the system was homogeneous, thus obtaining the polymer aqueous phase.

[0090] S3. Preparation of preemulsion The polymer aqueous phase was transferred to a rotor-stator high-speed shear emulsifier and pre-sheared at 6000 r / min for 3 min.

[0091] Under constant shear conditions, the composite oil phase obtained in step S1 was slowly added to the polymer aqueous phase, with the feeding time controlled at 8 min. During the feeding process, the shear rate was gradually increased to 10000 r / min.

[0092] After all the composite oil phase was added, the mixture was sheared at 10,000 r / min for 12 min to break up the oil phase and form uniform coarse droplets. Then the shear rate was reduced to 600 r / min and stirring was continued for 30 min to ensure that P-1 was fully contacted and dispersed in the formed droplet system, thus obtaining a pre-emulsion.

[0093] S4, High-pressure homogenization Add the obtained pre-emulsion to the feed tank of the high-pressure homogenizer and circulate it at low speed for 2 minutes to fill the feed pipe and remove air bubbles.

[0094] The emulsion was then subjected to high-pressure homogenization at 80 MPa, for a total of three homogenizations. After each homogenization, the emulsion was collected and returned to the homogenizer for the next homogenization. During the homogenization process, circulating cooling water was used to cool the material, keeping the material temperature ≤35℃.

[0095] After the third homogenization, the emulsion was cooled to 25°C to obtain a homogenized emulsion.

[0096] S5. Preparation and addition of the aqueous phase of the emulsifier Take 42.50 parts from the remaining deionized water, add them to a clean container, and add 4.00 parts of polyglycerol-6 laurate while stirring at 500 r / min.

[0097] After the material is added, increase the stirring speed to 800 r / min and continue stirring for 25 min to uniformly disperse polyglycerol-6 laurate and obtain the emulsifier aqueous phase.

[0098] The homogeneous emulsion obtained in step S4 is placed in a mechanical stirrer and stirred at 800 r / min. The aqueous phase of the emulsifier is continuously added to the homogeneous emulsion over 12 min, with the addition rate controlled to be uniform to avoid excessively high local emulsifier concentrations.

[0099] After all the emulsifier in the aqueous phase was added, the stirring speed was increased to 1000 r / min, and stirring was continued for 30 min to obtain a submicron emulsion.

[0100] S6, pH adjustment and defoaming The stirring speed of the submicron emulsion obtained in step S5 was reduced to 500 r / min, and the remaining sodium hydroxide aqueous solution was added dropwise under continuous stirring to adjust the pH of the system to 6.45.

[0101] After the addition is complete, continue stirring for 20 minutes, let stand for 10 minutes, and then measure the pH value again. When the pH value stabilizes at 6.45, transfer the emulsion to a vacuum degassing device and degas for 8 minutes under a vacuum of -0.06 MPa.

[0102] After degassing, the pressure was restored to normal to obtain the high-load submicron emulsion of Example 2.

[0103] 3. Characterization Tests The resulting emulsion was characterized after standing at 25°C for 24 h.

[0104] (1) Appearance The resulting emulsion has a uniform milky white appearance, good fluidity, and no visible oil droplets, flocculents, sediments, or stratification were observed.

[0105] (2) pH value The pH of the emulsion was measured at 25°C using a calibrated pH meter and was 6.45.

[0106] (3) Z-mean particle size and particle size polydispersity index The obtained emulsion was diluted 100 times with deionized water and measured using dynamic light scattering at 25°C. The measurements were performed in triplicate. The Z-mean particle size of the obtained emulsion was 136.8 nm, and the polydispersity index (PDI) was 0.18.

[0107] (4) Zeta potential The emulsion was diluted 100 times with deionized water and measured by electrophoretic light scattering at 25°C. The measurement was performed in triplicate, and the zeta potential of the emulsion was -29.6 mV.

[0108] (5) Polarized light microscopy A small amount of emulsion was placed on a glass slide, covered with a coverslip, and observed in five random fields of view under a polarizing microscope. No obvious birefringent crystals or large solid particles were observed in any field of view.

[0109] (6) Centrifugal stability Take 10 mL of the emulsion and place it in a centrifuge tube. Centrifuge at 25℃ and a relative centrifugal force of 4000×g for 30 min. After centrifugation, no obvious layering, precipitation, or oil phase separation was observed in the emulsion.

[0110] Example 3 The difference between this embodiment and Embodiment 1 is that the formula composition is as follows: 8.00 parts of polyglycerol-3 oleate, 12.00 parts of isocetyl palmitate, 1.50 parts of polyglycerol-6 laurate, 0.20 parts of P-1, 0.05 parts of pH adjuster, and 60.00 parts of deionized water.

[0111] Except for the raw materials and dosages mentioned above, the preparation steps and process conditions are the same as in Example 1.

[0112] After preparation, the emulsion was allowed to stand at 25℃ for 24 h. The resulting emulsion had a uniform milky white appearance with no visible oil droplets, flocculents, precipitates, or stratification. The pH value was 6.18, the average particle size was 121.7 nm, the PDI was 0.14, and the Zeta potential was -26.4 mV. No birefringent crystals were observed under a polarizing microscope. After centrifugation at 25℃ and 4000×g for 30 min, no stratification, precipitation, or oil phase separation occurred.

[0113] Example 4 The difference between this embodiment and Example 1 is that the amount of P-1 is adjusted from 0.20 parts to 0.75 parts, while the other components and their amounts remain unchanged. That is, polyglycerol-6 laurate is 1.50 parts and P-1 is 0.75 parts, with a mass ratio of 2:1.

[0114] When preparing the polymer aqueous phase, 0.75 parts of P-1 were slowly added to 30.00 parts of deionized water, stirred and dispersed for 40 min, and then hydrated for 2 h. The remaining preparation steps and process conditions were the same as in Example 1.

[0115] After preparation, the emulsion was allowed to stand at 25℃ for 24 h. The resulting emulsion had a uniform milky white appearance with no visible oil droplets, flocculents, precipitates, or stratification. The pH value was 6.21, the average particle size was 142.5 nm, the PDI was 0.19, and the Zeta potential was -33.2 mV. No birefringent crystals were observed under a polarizing microscope. After centrifugation at 25℃ and 4000×g for 30 min, no stratification, precipitation, or oil phase separation occurred.

[0116] Example 5 The difference between this embodiment and Example 1 is that polyglycerol-3 oleate is used instead of glycerol monooleate, propylene glycol dioctanoate is used instead of medium-chain triglycerides, polyglycerol-10 decanoate is used instead of polyglycerol-6 laurate, and P-2 is used instead of P-1.

[0117] The formulation of this embodiment is as follows: 6.10 parts of polyglycerol-3 oleate, 12.00 parts of propylene glycol dioctyl ester, 1.50 parts of polyglycerol-10 decanoate, 0.20 parts of P-2, 0.05 parts of pH adjuster, and 60.00 parts of deionized water.

[0118] After preparation, the emulsion was allowed to stand at 25℃ for 24 h. The resulting emulsion had a uniform milky white appearance with no visible oil droplets, flocculents, precipitates, or stratification. The pH value was 6.19, the average particle size was 118.4 nm, the PDI was 0.13, and the Zeta potential was -31.7 mV. No birefringent crystals were observed under a polarizing microscope. After centrifugation at 25℃ and 4000×g for 30 min, no stratification, precipitation, or oil phase precipitation occurred.

[0119] Example 6 This embodiment is a comprehensive oversized raw material comparison. The difference from Example 1 is that glyceryl dioleate is used instead of glyceryl monooleate, squalane is used instead of medium-chain triglycerides, polysorbate 80 is used instead of polyglycerol-6 laurate, and P-3 is used instead of P-1.

[0120] The formulation of this embodiment is as follows: Diglyceride 6.10 parts, squalane 12.00 parts, polysorbate 80 1.50 parts, P-3 0.20 parts, pH adjuster 0.05 parts and deionized water 60.00 parts.

[0121] Except for the above-mentioned raw material substitutions, the preparation steps and process conditions are the same as in Example 1.

[0122] After preparation, the emulsion was allowed to stand at 25℃ for 24 h. The resulting emulsion was milky white with a small amount of flocculent material and a slight oil ring at the bottom. The pH value was 6.18, the average particle size was 268.5 nm, the PDI was 0.34, and the Zeta potential was -12.1 mV. A small amount of particulate birefringent material was visible under a polarizing microscope. After centrifugation at 25℃ and 4000×g for 30 min, a distinct floating oil layer and bottom sediment appeared.

[0123] Example 7 This example is used to investigate the effect of the size of the hydrophobic hydrogen bond donor. The only difference from Example 1 is that 6.10 parts of diglyceride ester is used instead of 6.10 parts of monoglyceride ester; the other components, amounts, and preparation steps are the same as in Example 1.

[0124] After preparation, the emulsion was allowed to stand at 25℃ for 24 h. The resulting emulsion was milky white with a small amount of flocculent matter. The pH value was 6.20. The average particle size was 211.4 nm, the PDI was 0.29, and the Zeta potential was -22.8 mV. A small amount of birefringent particles were visible under a polarizing microscope. After centrifugation at 25℃ and 4000×g for 30 min, a slight emulsion layer appeared.

[0125] Example 8 This example is used to investigate the effect of hydrophobic hydrogen bond acceptor structure. The only difference from Example 1 is that 12.00 parts of squalane are used instead of 12.00 parts of medium-chain triglycerides; the other components, amounts, and preparation steps are the same as in Example 1.

[0126] Since squalane does not have effective hydrogen bond acceptor sites, the system cannot form the prescribed donor / acceptor site ratio.

[0127] After preparation, the emulsion was allowed to stand at 25℃ for 24 h. The resulting emulsion was milky white with a slight oil ring. The pH value was 6.21. The average particle size was 236.8 nm, the PDI was 0.31, and the Zeta potential was -21.5 mV. Dispersed particulate birefringent material was visible under a polarizing microscope. After centrifugation at 25℃ and 4000×g for 30 min, obvious emulsification and a small amount of free oil appeared.

[0128] Example 9 This example is used to investigate the effect of nonionic emulsifier structure. The only difference from Example 1 is that 1.50 parts of polysorbate 80 are used instead of 1.50 parts of polyglycerol-6 laurate; the other components, amounts, and preparation steps are the same as in Example 1.

[0129] After preparation, the emulsion was allowed to stand at 25℃ for 24 h. The resulting emulsion was milky white and had a basically uniform appearance. The pH value was 6.20, the average particle size was 157.6 nm, the PDI was 0.24, the Zeta potential was -22.4 mV, and no obvious birefringent crystals were observed under a polarizing microscope. After centrifugation at 25℃ and 4000×g for 30 min, a slight emulsion layer appeared, and no obvious free oil was observed.

[0130] Example 10 This example is used to investigate the effect of the specifications of charged amphiphilic polymers. The only difference from Example 1 is that 0.20 parts of P-3 are used instead of 0.20 parts of P-1, while the other components, amounts, and preparation steps are the same as in Example 1.

[0131] After preparation, the emulsion was allowed to stand at 25℃ for 24 h. The resulting emulsion was milky white with a small amount of flocculent matter; the pH value was 6.19; the average particle size was 174.5 nm, the PDI was 0.26, and the Zeta potential was -17.8 mV. No obvious birefringent crystals were observed under a polarizing microscope, but a small amount of aggregated particles were visible. After centrifugation at 25℃ and 4000×g for 30 min, a distinct emulsion layer appeared.

[0132] Example 11 This example is used to investigate the effect of charged amphiphilic polymers. The only difference from Example 1 is that P-1 is not added; the remaining components, amounts, and preparation steps are the same as in Example 1. In step S2, no polymer is added; only the pH of the corresponding aqueous phase is adjusted to 4.80 before being used to prepare the preemulsion.

[0133] After preparation, the emulsion was allowed to stand at 25℃ for 24 h. The resulting emulsion showed droplet flocculation and slight stratification; the pH value was 6.20; the average particle size was 325.7 nm, the PDI was 0.41, the Zeta potential was -6.8 mV; irregular aggregated particles were visible under a polarizing microscope; after centrifugation at 25℃ and 4000×g for 30 min, obvious oil-water stratification occurred.

[0134] Example 12 This example is used to investigate the effect of the order of addition of nonionic emulsifiers. The formulation composition is the same as in Example 1, except that: the aqueous phase of polyglycerol-6 laurate is added to the pre-emulsion before high-pressure homogenization, mixed evenly, and then homogenized three times at 80 MPa; after homogenization, no more nonionic emulsifiers are added, and the pH is directly adjusted and defoamed.

[0135] After preparation, the emulsion was allowed to stand at 25℃ for 24 h. The resulting emulsion was milky white and basically uniform in appearance, but a small amount of flocculent matter was visible. The pH value was 6.20; the average particle size was 146.9 nm and the PDI was 0.22; the Zeta potential was -14.6 mV; no obvious birefringent crystals were observed under a polarizing microscope; a slight emulsion layer appeared after centrifugation at 25℃ and 4000×g for 30 min.

[0136] Example 13 The raw materials and quantities used in this embodiment, by weight, are as follows: 3.00 parts isostearic acid, 3.10 parts octyldodecyl alcohol, 6.00 parts meadowfoam seed oil, 6.00 parts camellia seed oil, 1.50 parts inulin lauryl carbamate, 0.20 parts sodium subtilis lipopeptide, 0.10 parts sodium hydroxide, and 60.00 parts deionized water. The sodium hydroxide is prepared into a 1.0% aqueous solution, and the water used in the preparation is included in the total amount of deionized water.

[0137] The preparation method is as follows: isostearic acid, octyldodecyl alcohol, meadowfoam seed oil and camellia seed oil are mixed and stirred at 300 r / min for 5 min, and then stirred at 600 r / min for 20 min to obtain a composite oil phase; sodium subtilis lipopeptide is added to 30.00 parts of deionized water and stirred at 500 r / min for 10 min, and then stirred at 1000 r / min for 30 min to obtain an aqueous phase; the composite oil phase is added to the aqueous phase under shearing conditions of 10000 r / min and shearing is continued for 10 min to obtain a pre-emulsion; the pre-emulsion is homogenized three times at 80 MPa and cooled to 25°C; inulin lauryl carbamate is dispersed in the remaining deionized water and added to the homogenized emulsion under stirring at 800 r / min and stirring is continued for 30 min; sodium hydroxide aqueous solution is added dropwise to adjust the pH of the final emulsion to 5.00, and defoaming is performed according to the method of Example 1.

[0138] Example 14 The raw materials and quantities used in this embodiment, by mass, are as follows: 6.10 parts octyl dodecanol, 6.00 parts argan oil, 6.00 parts sunflower seed oil, 1.50 parts polysaccharide-modified polymeric emulsifier (hydrophobic modified hydroxyethyl cellulose), 0.20 parts fermentation-derived glycolipids (sophorolipids), 0.15 parts sodium hydroxide, and 60.00 parts deionized water. The sodium hydroxide is prepared into a 1.0% aqueous solution, and the water used in the preparation is included in the total amount of deionized water.

[0139] The preparation method is as follows: Octyldodecyl alcohol, argan oil and sunflower seed oil are mixed and stirred at 300 r / min for 5 min, then stirred at 600 r / min for 20 min to obtain a composite oil phase; Sophorolipids are added to 30.00 parts of deionized water and stirred at 500 r / min for 10 min, then stirred at 1000 r / min for 30 min to obtain an aqueous phase; The composite oil phase is added to the aqueous phase under shearing conditions of 10000 r / min and shearing is continued for 10 min to obtain a pre-emulsion; The pre-emulsion is homogenized three times at 80 MPa and cooled to 25°C; The polysaccharide-modified polymeric emulsifier is dispersed in the remaining deionized water and added to the homogenized emulsion under stirring at 800 r / min and stirring is continued for 30 min; Sodium hydroxide aqueous solution is added dropwise to adjust the pH of the final emulsion to 6.80, and defoaming is performed according to the method of Example 1.

[0140] Example 15 The raw materials and quantities used in this embodiment, by weight, are as follows: 6.10 parts octyl dodecanol, 3.00 parts meadowfoam seed oil, 3.00 parts camellia seed oil, 3.00 parts argan oil, 3.00 parts sunflower seed oil, 1.50 parts alkyl glycoside emulsifier (cetearyl glucoside), 0.20 parts phospholipid (hydrogenated lecithin), 0.25 parts sodium hydroxide, and 60.00 parts deionized water. The sodium hydroxide is prepared into a 1.0% aqueous solution, and the water used in the preparation is included in the total amount of deionized water.

[0141] The preparation method is as follows: Octyldodecyl alcohol, meadowfoam seed oil, camellia seed oil, argan oil, and sunflower seed oil are mixed and stirred at 300 r / min for 5 min, then stirred at 600 r / min for 20 min to obtain a composite oil phase; hydrogenated lecithin is added to 30.00 parts of deionized water and stirred at 500 r / min for 10 min, then stirred at 1000 r / min for 30 min to obtain an aqueous phase; the composite oil phase is added to the aqueous phase under shearing conditions of 10000 r / min and shearing is continued for 10 min to obtain a pre-emulsion; the pre-emulsion is homogenized three times at 80 MPa and cooled to 25°C; cetearyl glucoside is dispersed in the remaining deionized water and added to the homogenized emulsion under stirring at 800 r / min and stirring is continued for 30 min; sodium hydroxide aqueous solution is added dropwise to adjust the pH of the final emulsion to 8.50, and defoaming is performed according to the method of Example 1.

[0142] The appearance of Examples 1, 2, 5, and 11 is as follows: Figure 2 As shown. Polarizing microscope images of Examples 1, 2, 5, and 11 are shown below. Figure 3 As shown.

[0143] Coenzyme Q10 loading performance test The following tests used Coenzyme Q10 as the cosmetic active ingredient to evaluate the loading performance of the submicron emulsions obtained in Examples 1-12, and further verified the high loading capacity of Example 2.

[0144] I. Preparation of Loaded Samples The coenzyme Q10 used had a purity of 98.6% and was used under light-protected conditions. Examples 1-12 prepared normal-loaded samples, with the amount of coenzyme Q10 added calculated as 15% of the total mass of hydrophobic hydrogen bond donor A and hydrophobic hydrogen bond acceptor B. Example 2 also prepared a high-loaded sample 2-H, increasing the coenzyme Q10 oil core loading rate to 30%. The molar ratio of sites A to B, and the mass ratio of nonionic emulsifier to charged amphiphilic polymer, were not considered in the coenzyme Q10 calculation.

[0145] The oil core loading rate L is calculated using the following formula: L = mQ / (mA + mB) × 100%, Where mQ is the mass of coenzyme Q10, mA is the mass of hydrophobic hydrogen bond donor A, and mB is the mass of hydrophobic hydrogen bond acceptor B. See Table 1 for details.

[0146] Table 1 ; In step S1 of each embodiment, A and B are first mixed evenly, and then the appropriate mass of coenzyme Q10 is added. The mixture is stirred at 600 r / min for 15 min under light-protected conditions, followed by stirring at 800 r / min for 30 min, until no visible solid particles remain in the oil phase. The coenzyme Q10-containing composite oil phase is then used to prepare an emulsion according to steps S2-S6 of the corresponding embodiment.

[0147] II. Coenzyme Q10 content determination Take 0.500 g of the prepared loaded emulsion, add 10 mL of a mixed extract of ethanol and isopropanol (ethanol to isopropanol volume ratio 1:1), vortex mix for 2 min, sonicate for 10 min, and then centrifuge at 10000 r / min for 10 min. Take the supernatant, filter it through a 0.22 μm filter membrane, and perform high performance liquid chromatography analysis.

[0148] The high-performance liquid chromatography (HPLC) conditions were as follows: C18 reversed-phase column; mobile phase: acetonitrile and isopropanol, v / v ratio 75:25; flow rate: 1.0 mL / min; column temperature: 30℃; detection wavelength: 275 nm; injection volume: 10 μL. The actual content was calculated based on the coenzyme Q10 standard curve, and the recovery rate R = (mactual / mtheoretical) × 100%.

[0149] III. Determination of Oil-Core Binding Ratio A size exclusion separation method validated for coenzyme Q10 recovery was used to separate the emulsion droplet phase from the continuous aqueous phase. Both phases were collected separately, and coenzyme Q10 was extracted and its content determined by high-performance liquid chromatography (HPLC). The oil-core binding ratio B = m_emulsion droplet phase / (m_emulsion droplet phase + m_continuous phase) × 100%.

[0150] IV. Stability Testing Each sample underwent a 4℃ / 40℃ temperature cycling test: 24 h at 4℃ followed by 24 h at 40℃ constituted one cycle, with a total of 6 cycles performed. The samples were also stored at 25℃ in the dark for 90 days, with samples taken on days 0, 30, 60, and 90. Appearance, Z-mean particle size, PDI, Zeta potential, and coenzyme Q10 retention were measured before and after the tests, and polarized light microscopy was performed for observation. The results are shown in Table 2.

[0151] V. Normal Load Test Results Table 2 ; As shown in Table 2, Examples 1-5 maintained a particle size of around 100-150 nm and a PDI ≤ 0.20 at a 15% oil core loading rate, and no obvious crystals were observed under a polarizing microscope. Examples 6-12 showed varying degrees of decrease in particle size, PDI, content recovery rate, or oil core binding ratio, accompanied by flocculation, emulsification, or bright crystal spots.

[0152] VI. High Load Test Results of Example 2 Table 3 ; Sample 2-H maintained a uniform milky white appearance when the coenzyme Q10 oil core loading rate reached 30%, with an average particle size of 148.6 nm and a PDI of 0.20. No obvious oil phase precipitation or coenzyme Q10 crystals were observed.

[0153] VII. Temperature Cycling Test Results Table 4 ; VIII. Results of 90-day storage test Table 5 ; The above results indicate that, under the same normal coenzyme Q10 loading, Examples 1-5 exhibit higher coenzyme Q10 content recovery and oil-core binding ratio, and maintain smaller particle size and lower PDI after temperature cycling and long-term storage. In Example 2, even after the oil-core loading rate was increased to 30%, no significant crystal or oil phase precipitation occurred, indicating that this formulation has a high carrying capacity for poorly soluble active ingredients. In contrast, Examples 6-12 showed varying degrees of decrease in particle size, PDI, content retention, oil-core binding ratio, and appearance stability.

[0154] The appearance of Examples 2-H and 11 after loading in three states: initial, after 6 cycles of 4°C / 40°C temperature cycling, and after 90 days of light protection at 25°C. Figure 4 As shown.

[0155] Polarizing microscope images of Examples 2-H and 11 after loading in three states: initial, after 6 cycles of 4°C / 40°C temperature cycling, and after 90 days of light protection at 25°C. Figure 5 As shown.

[0156] The above detailed description is a specific description of one of the feasible embodiments of the present invention. This embodiment is not intended to limit the patent scope of the present invention. All equivalent implementations or modifications that do not depart from the present invention should be included within the scope of the technical solution of the present invention.

Claims

1. A high-loading submicron emulsion, characterized in that, The following components are included in parts by mass: Hydrophobic hydrogen bond donor, 2-8 parts; Hydrophobic hydrogen bond acceptor, 12-25 portions; Nonionic emulsifier, 1.5-4.0 parts; Charged amphiphilic polymer, 0.2-0.8 parts; pH adjuster, 0.05-0.30 parts; Water, 60-85 parts; The hydrophobic hydrogen bond donor has a hydroxyl value of 150-350 mg KOH / g and an HLB value of 3-7. The effective hydrogen bond acceptor density of the hydrophobic hydrogen bond acceptor is 2-6 mmol / g, and its solubility in water at 25°C is ≤1 mg / L. The nonionic emulsifier has an HLB value of 12-16, and when the oil core composed of the hydrophobic hydrogen bond donor and the hydrophobic hydrogen bond acceptor is used as the oil phase, its dynamic interfacial tension at 25°C for 30 seconds is ≤8 mN / m. The charged amphiphilic polymer is an amphiphilic polymer containing carboxyl groups and C8-C18 hydrophobic groups, with a weight-average molecular weight of 10-150 kDa and a molar content of C8-C18 hydrophobic groups of 0.5%-5.0%. The molar ratio of the effective hydrogen bond donor sites in the hydrophobic hydrogen bond donor to the effective hydrogen bond acceptor sites in the hydrophobic hydrogen bond acceptor is (0.5-2):1; The mass ratio of the nonionic emulsifier to the charged amphiphilic polymer is (2-8):1; The high-load submicron emulsion has a pH value of 5.00–8.50, an average particle size of 100–150 nm, and a particle size polydispersity index ≤0.

20.

2. The high-load submicron emulsion according to claim 1, characterized in that, The hydrophobic hydrogen bond donor contains at least one C16-C18 aliphatic hydrophobic segment with one carbon-carbon double bond, and its solubility in water at 25°C is ≤0.1 g / L; the hydrophobic hydrogen bond acceptor has a dynamic viscosity of 10-60 mPa·s at 25°C; and the mass ratio of the hydrophobic hydrogen bond donor to the hydrophobic hydrogen bond acceptor is 10:90-35:

65.

3. The high-load submicron emulsion according to claim 2, characterized in that, The hydrophobic hydrogen bond donor is a polyol and a C16-C18 unsaturated fatty acid forming a lipophilic compound with a free hydroxyl group; the hydrophobic hydrogen bond acceptor is a neutral aliphatic ester oil that is liquid at 25°C, contains 1-3 ester carbonyl groups in its molecule, and does not contain free hydroxyl groups or dissociable carboxyl groups.

4. The high-load submicron emulsion according to claim 1, characterized in that, The nonionic emulsifier contains at least one C8-C molecule. 14 Aliphatic hydrophobic segments.

5. The high-load submicron emulsion according to claim 4, characterized in that, The nonionic emulsifier contains an average of 1-2 C8-C atoms. 14 Polyol fatty acid esters with saturated fatty acid ester groups, 6-12 free hydroxyl groups and no dissociable ionic groups.

6. The high-load submicron emulsion according to claim 1, characterized in that, The molar ratio of carboxyl groups to C8-C18 hydrophobic groups in the charged amphiphilic polymer is 3:1-10:1; the apparent pKa of the charged amphiphilic polymer is 3.0-4.5, and the apparent pKa is the half-neutralization point pH value measured by potentiometric titration at 25°C using 0.01 mol / L sodium chloride aqueous solution as the medium.

7. The high-load submicron emulsion according to claim 6, characterized in that, The 1.0% (w / w) aqueous solution of the charged amphiphilic polymer was subjected to a shear rate of 10 s⁻¹ at 25 °C. -1 The apparent viscosity under the specified conditions is ≤100 mPa·s; the carboxyl content of the charged amphiphilic polymer is 0.3-2.0 mmol / g.

8. The high-load submicron emulsion according to claim 6, characterized in that, The charged amphiphilic polymer is an anionic amphiphilic polysaccharide derivative formed by covalently grafting C8-C18 aliphatic hydrophobic segments onto the polymer backbone using carboxylated polysaccharide as the polymer backbone.

9. A method for preparing a high-load submicron emulsion, characterized in that, Includes the following steps: S1. Mix the hydrophobic hydrogen bond donor and the hydrophobic hydrogen bond acceptor evenly to obtain a composite oil phase; S2. Disperse the charged amphiphilic polymer in the first part of water and fully hydrate it to obtain the polymer aqueous phase; S3. Under shear conditions, the composite oil phase is added to the polymer aqueous phase for emulsification, and stirring is continued to obtain a pre-emulsion; S4. The pre-emulsion is homogenized under high pressure to obtain a primary submicron emulsion; S5. Disperse the nonionic emulsifier in the second part of water to obtain an aqueous phase of emulsifier. After the high-pressure homogenization in step S4 is completed, add the aqueous phase of emulsifier to the primary submicron emulsion and mix evenly to obtain a submicron emulsion. S6. Adjust the pH value of the submicron emulsion to 5.00-8.50, and defoam to obtain the high-load submicron emulsion.

10. The application of the high-load submicron emulsion according to any one of claims 1-8 in loading cosmetic functional ingredients, characterized in that, The cosmetic active ingredients are loaded in an oil core composed of hydrophobic hydrogen bond donors and hydrophobic hydrogen bond acceptors.

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