Multi-channel multi-target accurate delivery anti-allergy soothing nano-composite as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of cosmetics, and relates to a multichannel multi-target accurate delivery anti-allergy soothing nano-composite and a preparation method and application thereof, glycyrrhizic acid, bisabolol, 4-tert-butyl cyclohexanol and hydroxyphenyl propionamide benzoic acid are selected as anti-allergy soothing functional components. Comprising the following raw materials in percentage by mass: 0.1-5wt% of glycyrrhetinic acid; 0.1 to 10 weight percent of bisabolol; 0.001 wt% to 1 wt% of 4-tert-butyl cyclohexanol; 0.01 to 1 wt% of hydroxyphenyl propionamide benzoic acid; 10 to 50 wt% of an emulsifier; 1 to 20 wt% of a liquid lipid; 1 to 10 wt% of a co-emulsifier; 10 to 30 wt% of a polyol; and the balance of water. The sum of the mass percentages of the components is 100%. According to different passages of different active ingredients, the four active ingredients are simultaneously loaded in the same composition, so that multi-passage and multi-target accurate delivery can be realized, the skin can be timely and efficiently relieved from the source, the uncomfortable symptoms of the skin can be solved, and the immunity of the skin can be improved.

Description

Technical Field

[0001] This invention belongs to the field of cosmetics, specifically relating to a multi-pathway, multi-target precise delivery anti-allergic and soothing nanocomposite, its preparation method, and its application. Background Technology

[0002] Due to increased life and work pressures, as well as factors such as chemical irritants and unhealthy lifestyle habits, the number of people with skin allergies has increased dramatically, and skin sensitivity has become a social problem affecting human health. Sensitive skin has no clinical definition; it is a skin condition that exhibits an allergic reaction to certain stimuli. It affects all skin types: oily, dry, and normal skin, and can be permanent or occasional. The pathogenesis of sensitive skin is complex and diverse, mainly including the following possible factors: barrier function, neurological factors, and inflammatory responses. Clinical symptoms of sensitive skin generally manifest as itching, stinging, tingling, burning, and tightness; intolerance to any skincare products; dry skin, facial erythema and desquamation, and easy facial flushing; pale and dry skin; reactions to environmental factors, such as sensitivity to heat and rapid temperature changes; and frequent facial flushing. Based on the pathogenesis and clinical characteristics of sensitive skin, the following four active ingredients can effectively alleviate skin allergic reactions: 1) Glycyrrhizic acid has multiple activities such as antioxidant and anti-inflammatory properties, and can inhibit the activity of 11β-hydroxysteroid dehydrogenase (higher enzyme activity indicates skin disease), thus alleviating skin inflammatory reactions. , , All three have significant inhibitory effects and can enhance skin immunity; bisabolol can effectively regulate cytokines and inhibit inflammatory factors such as IL-1a, IL-6 & IL-8, thus regulating the inflammatory factors that cause redness at their source; 4-tert-butylcyclohexanol effectively inhibits the activity of TRPV1 capsaicin receptors, rapidly restoring calcium ion flow to normal, reducing burning and stinging sensations, promptly relieving skin discomfort, and increasing skin tolerance; hydroxyphenylpropionamide benzoic acid effectively inhibits histamine release that causes itching, promptly relieving skin itching and blocking the chain reaction of itching sensory neurons at its source. It can also effectively reduce skin damage induced by free radicals.

[0003] However, the application of the above four active ingredients is affected by many factors. In particular, glycyrrhizic acid is extremely difficult to dissolve, and it is basically difficult to find suitable solvents to disperse it well and apply it to the formulation; while 4-tert-butylcyclohexanol and hydroxyphenylpropionamide benzoic acid are mainly dispersed in pentanediol, with low content and high price; bisabolol is only oil-soluble, which limits the range of compounding.

[0004] Currently, due to restrictions on the ingredients and dosages in my country, most anti-allergy cosmetics suffer from drawbacks such as limited efficacy, slow onset of action, difficulty in skin penetration, poor anti-allergy effects, and a tendency to develop dependence on active ingredients. This invention, based on the pathogenesis and clinical characteristics of sensitive skin, loads four safe and highly effective anti-allergy active ingredients into the same nanocomposite. This enables precise delivery of the anti-allergy active ingredients to multiple pathways and targets in the dermal layer, providing long-lasting sustained-release action on multiple targets, synergistically enhancing the soothing and anti-allergy effects, promptly relieving skin discomfort, reducing redness and itching, improving fragile skin, and enhancing skin immunity.

[0005] This multi-pathway, multi-target precise delivery anti-allergy and soothing nanocomplex has good transdermal absorption, long retention time, high safety, large drug loading capacity, and is easy to add to various cosmetic matrices. Summary of the Invention

[0006] The purpose of this invention is to provide a multi-pathway, multi-target precise delivery anti-allergy and soothing nanocomposite and its preparation method. This multi-pathway, multi-target precise delivery anti-allergy and soothing nanocomposite loads four anti-allergy active ingredients into the same nanocomposite. The anti-allergy active ingredients are precisely delivered to the dermal layer through multiple pathways and multiple targets, achieving sustained and controlled release. It has the effects of reducing redness and itching, soothing and relieving pain, and eliminating skin inflammation.

[0007] To achieve the purpose of this invention, the following technical solution is adopted: a multi-pathway, multi-target precise delivery anti-allergic and soothing nanocomposite, the formulation components and mass percentages of which are as follows: 0.1~5wt% glycyrrhetinic acid; 0.1~10wt% bisabolol; 0.001~1wt% of 4-tert-butylcyclohexanol; 0.01~3wt% of hydroxyphenylpropionamide benzoic acid; 10~50wt% emulsifier; 1~20wt% liquid lipids; 1~10wt% co-emulsifier; 10~30wt% polyols; The rest is water.

[0008] Unless otherwise specified, the present invention does not have any special requirements for the source of the specific raw materials used in the precise delivery of anti-allergy and soothing nanocomposites through multiple pathways and multiple targets; commercially available products known to those skilled in the art can be used.

[0009] In a preferred embodiment of the present invention, the polyol is selected from one or more of sorbitol, glycerol, dipropylene glycol, 1,2-pentanediol, 1,2-hexanediol, 1,3-propanediol, and propylene glycol.

[0010] In a preferred embodiment of the present invention, the liquid lipid is selected from one or more of propylene glycol monooctanoate, caprylic / capric triglyceride, isononyl isononanoate, isopropyl myristate, and isopropyl palmitate.

[0011] In a preferred embodiment of the present invention, the emulsifier is selected from one or more of polyglycerol-10 stearate, polyglycerol-10 diisostearate, polyglycerol-3 cocoate, polyglycerol-6 ricinoleate, polyoxyethylene hydrogenated castor oil, cetearyl alcohol polyether, cocoyl glucoside, polyethylene glycol laurate, lecithin, and polyglycerol-10 myristate.

[0012] In a preferred embodiment of the present invention, the co-emulsifier is selected from one or more of diethylene glycol monoethyl ether, PPG-26-butanol polyether-26, ethoxydiethylene glycol oleate, isosorbide dimethyl ether, cocoyl alcohol polyether-7, PPG-1-PEG-9 lauryl glycol ether, and octyl dodecyl alcohol.

[0013] This invention also includes a method for preparing the aforementioned multi-pathway, multi-target, precise delivery anti-allergic and soothing nanocomposite, comprising the following steps: S1: Add bisabolol, glycyrrhetinic acid, emulsifier, liquid lipid and co-emulsifier to oil phase container 1 at 30~60℃ and stir to mix. The stirring speed is 50-500r / min and the stirring time is 20-50min. After stirring evenly, phase A solution is obtained. S2: 4-tert-butylcyclohexanol, hydroxyphenylpropionamide benzoic acid and polyol are added to an emulsification tank at 20~50℃ and stirred at a speed of 100-800 r / min for 10-50 min until uniformly mixed to obtain phase B solution; S3: Slowly add the B-phase solution prepared in step S2 to the A-phase solution prepared in step S1. The mixing temperature is 30~60℃; the stirring speed is 50-500r / min; the stirring time is 30-60min; and the oil phase is obtained by stirring until homogeneous. S4: Add the remaining aqueous phase to the oil phase obtained in S3 and mix. Perform high-speed shear emulsification at a speed of 5000~10000rpm for 1~10min. Then, perform high-pressure microjets 2~10 times under a pressure of 0.1-0.8MPa and cool to room temperature to obtain the multi-channel multi-target precise delivery anti-allergy and soothing nanocomposite.

[0014] Compared with the prior art, the present invention has the following beneficial effects: (1) This invention can effectively solve the problem of poor solubility of glycyrrhetinic acid, bisabolol, 4-tert-butylcyclohexanol and hydroxyphenylpropionamide benzoic acid, and encapsulate the active ingredients. The entire nanocomposite system has excellent stability. The water solubility problem of the active ingredients of the prepared multi-pathway multi-target precise delivery anti-allergy and soothing nanocomposite is solved. Therefore, it can be matched with a variety of matrices and has excellent compatibility, solving the problem of application of active ingredients in different formulations. (2) The present invention rationally combines glycyrrhetinic acid, bisabolol, 4-tert-butylcyclohexanol and hydroxyphenylpropionamide benzoic acid into the same nanocomposition to achieve precise delivery of active ingredients through multiple pathways and multiple targets, and long-lasting sustained release, so as to maximize the effects of soothing and reducing redness, relieving pain and itching, and anti-allergy repair. The combination of active ingredients through different pathways has a synergistic effect. (3) The method for preparing anti-allergic and soothing nanocomposites through multi-pathway and multi-target precise delivery provided by the present invention is simple to operate, low in cost, and easy to industrially produce. Attached Figure Description

[0015] The following is a further explanation with reference to the accompanying drawings.

[0016] Figure 1 Line graph of cumulative permeability of nanocomposite at different times in transdermal absorption experiment; Figure 2 Bar graph of cumulative skin retention of nanocomposite in transdermal absorption experiment; Figure 3 A graph showing the average rate of change in skin redness value in subjects during a skin irritation repair experiment. Detailed Implementation

[0017] To make the objectives, technical solutions, and beneficial effects of this invention clearer, the invention is described with reference to the following specific embodiments, but the invention is by no means limited to these examples.

[0018] Example 1: This embodiment provides a multi-pathway, multi-target precise delivery method for anti-allergic and soothing nanocomposites, including the following steps: S1 At 30°C, 10wt% bisabolol, 0.1wt% glycyrrhetinic acid, 15wt% polyglycerol-10 stearate, 5wt% caprylic / capric triglyceride, and 8wt% ethoxydiethylene glycol oleate were added sequentially to oil phase container 1 and stirred at 450r / min for 50min until completely dissolved to obtain phase A solution. S2 was prepared by adding 0.05 wt%, 4-tert-butylcyclohexanol, 1.5 wt% hydroxyphenylpropionamide benzoic acid and 15 wt% dipropylene glycol sequentially to an emulsification tank at 30 °C and stirring at 700 r / min for 40 min to obtain a homogeneous B-phase solution. S3. The B-phase solution prepared in step S2 is slowly added to the A-phase solution prepared in step S1, and the mixing temperature is controlled at 50°C; the mixture is stirred at 500 r / min for 30 min to form a uniform oil phase.

[0019] S4. The remaining aqueous phase is added to the oil phase prepared in S3 and mixed. The mixture is then sheared at 8000 rpm for 8 min. After that, it is subjected to high-pressure microjets five times under a pressure of 0.8 MPa and then naturally cooled to room temperature to obtain the multi-pathway, multi-target precise delivery anti-allergy and soothing nanocomposite described in Example 1.

[0020] The particle size and zeta potential of the above nanoemulsion were measured under standard laboratory conditions. The data is the average of three measurements, showing a particle size of 89.5 nm and a zeta potential of -33.2 mV.

[0021] Example 2: This embodiment provides a multi-pathway, multi-target precise delivery method for anti-allergic and soothing nanocomposites, including the following steps: S1 is prepared by adding 8wt% bisabolol, 2wt% glycyrrhetinic acid, 20wt% polyglycerol-3 cocoate, 8wt% propylene glycol monooctanoate, and 6wt% PPG-26-butanol polyether-26 sequentially to the oil phase container 1 at 35℃ and stirring at 500r / min for 45min until completely dissolved to obtain phase A solution.

[0022] S2 was prepared by adding 0.001 wt% of 4-tert-butylcyclohexanol, 0.5 wt% of hydroxyphenylpropionamide benzoic acid, and 18 wt% of 1,2-pentanediol sequentially to an emulsification tank under a 25°C water bath and stirring at 600 r / min for 35 min to obtain a homogeneous B-phase solution. S3. The B-phase solution prepared in step S2 is slowly added to the A-phase solution prepared in step S1, and the mixing temperature is 45℃; the mixture is stirred at 450r / min for 35min to form a homogeneous oil phase. S4. Add the remaining aqueous phase to the oil phase prepared in S3 and mix. Then, perform high-speed shear emulsification at 9000 rpm for 6 min. Next, perform high-pressure microjets at 0.6 MPa for 6 times and cool to room temperature to obtain the multi-pathway multi-target precise delivery anti-allergy and soothing nanocomposite described in Example 2.

[0023] The particle size potential of the above nanoemulsion was measured, and the particle size was 78.4 nm and the zeta potential was -31.7 mV.

[0024] Example 3: This embodiment provides a multi-pathway, multi-target precise delivery method for anti-allergic and soothing nanocomposites, including the following steps: S1 is prepared by adding 5wt% bisabolol, 3wt% glycyrrhetinic acid, 18wt% polyglycerol-10 myristate, 6wt% isononyl isononanoate, and 5wt% diethylene glycol monoethyl ether to oil phase 1 at 40℃. The mixture is stirred at 400r / min for 40min until it is completely dissolved to obtain phase A solution.

[0025] S2 was prepared by adding 0.01 wt% 4-tert-butylcyclohexanol, 2 wt% hydroxyphenylpropionamide benzoic acid, and 20 wt% glycerol sequentially to an emulsification tank under a 30°C water bath and stirring at 650 r / min for 30 min to obtain a homogeneous phase B solution. S3. The B-phase solution prepared in step S2 is slowly added to the A-phase solution prepared in step S1, and the mixing temperature is 55℃; the mixture is stirred at 480r / min for 40min to form a homogeneous oil phase. S4. The remaining aqueous phase is added to the oil phase prepared in S3 and mixed. The mixture is then emulsified at a high speed of 7500 rpm for 9 min. After that, it is subjected to high-pressure microfluidic treatment 4 times at a pressure of 0.7 MPa and cooled to room temperature to obtain the multi-pathway multi-target precise delivery anti-allergy and soothing nanocomposite described in Example 3.

[0026] The particle size potential of the above nanoemulsion was measured, and the particle size was 37.6 nm, with a zeta potential of -34.5 mV.

[0027] Example 4: This embodiment provides a multi-pathway, multi-target precise delivery method for anti-allergic and soothing nanocomposites, including the following steps: S1 is prepared by adding 1 wt% bisabolol, 4 wt% glycyrrhetinic acid, 125 wt% lecithin, 10 wt% isopropyl myristate, and 7 wt% isosorbide dimethyl ether to the oil phase container 1 at 45°C and stirring at 480 r / min for 35 min until completely dissolved to obtain phase A solution.

[0028] S2 was prepared by adding 0.1 wt% 4-tert-butylcyclohexanol, 0.01 wt% hydroxyphenylpropionamide benzoic acid, and 22 wt% 1,3-propanediol sequentially to an emulsification tank under a 35°C water bath and stirring at 720 r / min for 25 min to obtain a homogeneous B-phase solution. S3. The B-phase solution prepared in step S2 is slowly added to the A-phase solution prepared in step S1, and the mixing temperature is 50°C; the mixture is stirred at 500 r / min for 45 min to form a homogeneous oil phase. S4. Add the remaining aqueous phase to the oil phase prepared in S3 and mix. Then, perform high-speed shear emulsification at 10,000 rpm for 5 min. Next, perform high-pressure microjets at 0.5 MPa for 7 times and cool to room temperature to obtain the multi-pathway, multi-target precise delivery anti-allergy and soothing nanocomposite described in Example 4.

[0029] The particle size of the above nanoemulsion was measured to be 56.3 nm, and the zeta potential was -30.9 mV.

[0030] Example 5: This embodiment provides a multi-pathway, multi-target precise delivery method for anti-allergic and soothing nanocomposites, including the following steps: S1 is prepared by adding 0.5 wt% bisabolol, 1 wt% glycyrrhetinic acid, 22 wt% polyoxyethylene hydrogenated castor oil, 9 wt% isopropyl palmitate, and 4 wt% octyldodecyl alcohol sequentially to oil phase tank 1 at 50°C, and stirring at 480 r / min for 35 min until completely dissolved to obtain phase A solution.

[0031] S2 was prepared by adding 0.5 wt% 4-tert-butylcyclohexanol, 1 wt% hydroxyphenylpropionamide benzoic acid, and 25 wt% 1,2-hexanediol sequentially to an emulsification tank under a 20°C water bath and stirring at 750 r / min for 20 min to obtain a homogeneous B-phase solution. S3. The B-phase solution prepared in step S2 is slowly added to the A-phase solution prepared in step S1, and the mixing temperature is 45℃; the mixture is stirred at 460r / min for 50min to form a homogeneous oil phase. S4. Add the remaining aqueous phase to the oil phase prepared in S3 and mix. Then, perform high-speed shear emulsification at 8500 rpm for 7 min. Next, perform high-pressure microjets at 0.6 MPa for 6 times and cool to room temperature to obtain the multi-pathway multi-target precise delivery anti-allergy and soothing nanocomposite described in Example 5.

[0032] The particle size of the above nanoemulsion was measured to be 68.7 nm, and the zeta potential was -32.4 mV.

[0033] Example 6: This embodiment provides a multi-pathway, multi-target precise delivery method for anti-allergic and soothing nanocomposites, including the following steps: S1 is prepared by adding 0.1 wt% bisabolol, 5 wt% glycyrrhetinic acid, 30 wt% cetearyl alcohol polyether, 12 wt% caprylic / capric triglyceride, and 9 wt% cocoyl alcohol polyether-7 sequentially to oil phase container 1 at 60°C, and stirring at 550 r / min for 25 min until completely dissolved to obtain phase A solution.

[0034] S2 was prepared by adding 1 wt% 4-tert-butylcyclohexanol, 3 wt% hydroxyphenylpropionamide benzoic acid, and 28 wt% propylene glycol sequentially to an emulsification tank under a 40°C water bath and stirring at 800 r / min for 15 min to obtain a homogeneous B-phase solution. S3. The B-phase solution prepared in step S2 is slowly added to the A-phase solution prepared in step S1, and the mixing temperature is 60℃; the mixture is stirred at 520r / min for 35min to form a homogeneous oil phase. S4. Add the remaining aqueous phase to the oil phase prepared in S3 and mix. Then, perform high-speed shear emulsification at 9500 rpm for 6 min. Next, perform high-pressure microjets at 0.4 MPa for 8 times and cool to room temperature to obtain the multi-pathway multi-target precise delivery anti-allergy and soothing nanocomposite described in Example 5.

[0035] The particle size of the above nanoemulsion was measured to be 79.2 nm, and the zeta potential was -30.8 mV.

[0036] Comparative Example 1: Compared to Example 1, the four active ingredients in Example 1 were directly dissolved in 10 wt% pentanediol, with the remainder being water, and no lipids, emulsifiers, or microfluidic treatment were used.

[0037] Comparative Example 2: Compared to Example 1, only high-speed shear emulsification at 8000 rpm for 8 min was used, eliminating the 0.8 MPa microfluidic treatment.

[0038] Comparative Example 3: Compared with Example 5, glycyrrhetinic acid was removed from the formulation of Example 5, while the rest of the process remained unchanged.

[0039] Comparative Example 4: Compared with Example 5, bisabolol was removed from the formulation of Example 5, while the rest of the process remained unchanged.

[0040] Comparative Example 5: Compared to Example 5, 4-tert-butylcyclohexanol was removed from the formulation of Example 5, while the rest of the process remained unchanged.

[0041] Comparative Example 6: Compared to Example 5, hydroxyphenylpropionamide benzoic acid was removed from the formulation of Example 5, while the rest of the process remained unchanged.

[0042] Performance testing (I) Stability testing of multi-pathway, multi-target precise delivery anti-allergic and soothing nanocomposites The multi-pathway, multi-target precise delivery anti-allergy and soothing nanocomposite samples prepared in Examples 1-6 and Comparative Examples 1-2 were placed in sterile, sealed containers and stored at room temperature (25℃±2℃), 4℃, and 45℃ for 90 days. The appearance of the samples was observed at the initial state and after 4 weeks, with a focus on detecting the presence of precipitates, oil-water separation, or sedimentation. Simultaneously, after dilution, particle size changes were detected using a dynamic light scattering particle size analyzer (Malvern Zetasizer Nano ZS90), and the Zeta potential was measured by electrophoretic light scattering to comprehensively assess the physical stability of the nanocomposite system.

[0043]

[0044] Table 1 Stability test results of the embodiments The experimental results are shown in Table 1. After 90 days of observation at three temperatures, the multi-pathway, multi-target precise delivery anti-allergy and soothing nanocomposites prepared in Examples 1-6 did not exhibit any precipitates, oil-water separation, or sedimentation. Furthermore, after 90 days of storage at room temperature, 4℃, and 45℃, the particle size change was within 5%, and the Zeta potential remained within the range of -29mV to -35mV, without significant aggregation or separation. Comparative Example 1 (without nano-encapsulation): A distinct oil ring appeared on the shoulder of the bottle on the 3rd day of storage, and a large amount of crystal precipitation was observed at the bottom on the 7th day, indicating "unstable". Comparative Example 2 (without high-pressure microjets): Slight emulsification occurred on the 10th day of storage at room temperature, and the particle size change rate was 20.5% on the 90th day, with a Zeta potential of -17.9mV, indicating "unstable". The multi-pathway, multi-target precise delivery anti-allergy and soothing nanocomposites prepared in Examples 1-6 of this invention still maintain uniform appearance, particle size drift <5%, and Zeta potential <-29mV after standing at 25℃, 4℃, and 45℃ for 90 days. Their physical stability is significantly better than that of the comparative examples, and they can be safely used for long-term storage of cosmetic products.

[0045] (II) Hyaluronidase Inhibition Test Hyaluronidase is involved in allergic reactions and is strongly correlated with inflammation and allergies. Many anti-allergy drugs work by inhibiting hyaluronidase activity. Therefore, testing the inhibition rate of hyaluronidase activity is used as an anti-allergy standard. Specific grading criteria are shown in Table 2.

[0046]

[0047] Table 2. Anti-allergy grading standards Test samples: The anti-allergic and soothing nanocomposites prepared in Examples 1-6 and Comparative Examples 1-6 were diluted 20 times with culture medium.

[0048] Reagent preparation: Hyaluronidase solution: Dissolve lyophilized hyaluronidase powder in pH 6.0 phosphate buffer to prepare a 2 U / mL working solution; Sodium hyaluronate substrate solution: Dissolve 0.03% sodium hyaluronate in pH 6.0 phosphate buffer; Acetylacetone colorimetric solution: Dissolve 2 mL of acetylacetone in 100 mL of 0.5 mol / L sodium carbonate solution. The acetylacetone solution should be prepared fresh before use; Ehrlich reagent: Dissolve 1 g of p-dimethylaminobenzaldehyde in 100 mL of concentrated hydrochloric acid-anhydrous ethanol (1:1, v / v) and store at 0–4℃ protected from light.

[0049] Take 0.1 mL of 0.25 mmol / L calcium chloride solution and 0.5 mL of hyaluronidase solution and incubate at 37℃ for 20 min; add 0.5 mL of test sample and continue incubation at 37℃ for 20 min; add 0.5 mL of sodium hyaluronate solution and incubate at 37℃ for 30 min, then let stand at room temperature for 5 min; add 0.1 mL of 0.4 mol / L sodium hydroxide solution and 0.5 mL of acetylacetone solution, heat in a boiling water bath for 15 min, and immediately cool with ice water for 5 min; add 1.0 mL of Ehrlich reagent and dilute with 3.0 mL of anhydrous ethanol, let stand for 20 min for color development, and measure the absorbance value (A value) at 530 nm using a spectrophotometer, and calculate the hyaluronidase inhibition rate (%). Hyaluronidase inhibition rate = [( ; In the formula, A is the absorbance value of the control solution (using phosphate buffer solution instead of the test sample solution), B is the absorbance value of the blank control solution (using phosphate buffer solution instead of the test sample solution and enzyme solution), C is the absorbance value of the test sample solution, and D is the absorbance value of the blank sample solution (using phosphate buffer solution instead of hyaluronic acid solution). The hyaluronidase inhibition rates of Examples 1-6 and Comparative Examples 1 and 6 are shown in Table 3.

[0050] Table 3 Hyaluronidase Inhibition Rate The test results are shown in Table 2. The nanocomposites prepared in Examples 1-6 of this invention can significantly inhibit hyaluronidase activity (>70%), while the inhibition rates of Comparative Examples 1 and 2 are less than 50%, indicating that the poor encapsulation process leads to exposure of active ingredients and low bioavailability. After Comparative Examples 3-6 were found to lack any of the four essential active ingredients from the examples, the inhibition rate decreased by 15-20%, indicating that glycyrrhetinic acid, bisabolol, 4-tert-butylcyclohexanol, and hydroxyphenylpropionamide benzoic acid are all key components in the synergistic inhibition of the enzyme, and none can be omitted.

[0051] (III) Franz diffusion cell transdermal retention experiment To evaluate the transdermal penetration and basal layer retention performance of the multi-pathway, multi-target precise delivery of the anti-allergic and soothing nanocomposite of this invention, fresh pig ear skin was used as an in vitro model, with a thickness controlled at approximately 0.8-1.0 mm. After removing the underlying fat layer, the skin was soaked in PBS buffer (pH 7.4) for 30 minutes to maintain moisture. The experiment used a Franz diffusion cell (effective diffusion area approximately 1.77 cm², recipient chamber capacity 6-10 mL). The recipient solution was PBS buffer (containing 20% ​​ethanol) at 37 ± 0.5 °C, and the temperature was maintained stable using a constant-temperature circulating water bath. Simultaneously, a magnetic stirrer was used to maintain a constant stirring state of 300 rpm. The treated pig skin, with the keratinized layer facing upwards, was laid flat between the donor and recipient chambers and fixed with clamps. Then, 0.5 mL of the nanocomposite prepared in Examples 3, 4, and 5 was added to the donor chamber, while an equal amount of nanocomposite was added to Comparative Examples 5 and 6. At 1, 2, 4, 8, 12, and 24 hours, 0.5 mL samples were taken from the recipient chamber, and an equal volume of fresh PBS buffer was added to maintain a constant liquid level. The active ingredient content of the collected recipient fluid was detected using high-performance liquid chromatography (HPLC, Agilent 1260). The cumulative permeability of the nanocomposite prepared in different time-dependent examples was calculated, and transdermal curves were plotted as shown below. Figure 1 As shown.

[0052] Calculate the cumulative transmittance Q per unit diffusion area using Formula II. t : Q t = In the formula, Ct is the concentration of the active ingredient in the receptor fluid at time t, V is the total volume of the receptor chamber, Ci is the concentration of each sampling solution, Vs is the volume of a single sampling, and A is the effective diffusion area.

[0053] Calculate the cumulative permeability Q0 according to Formula III: P t = ; In the formula, Q0 is the initial total amount of active ingredient in the donor chamber.

[0054] After the 24-hour diffusion experiment, the skin was removed, the surface residue was washed with PBS, and the sample was frozen and sectioned (20 μm thick). The stratum corneum, epidermis, and dermis were separated, and the active ingredients were extracted using acetonitrile ultrasonication. The retention amount in each layer was determined again by HPLC. The cumulative retention amount in the skin was obtained as follows: Figure 2 As shown.

[0055] Calculate the cumulative retention R per unit area using formula V: R= ; In the formula, Qr represents the amount of active ingredient in the extract of each skin layer.

[0056] By comparing the performance of the ordinary emulsion group and the nanocomposite group using cumulative permeation curves and retention rate data, the transdermal delivery capability and long-term retention characteristics of the nanocomposite of the present invention can be comprehensively evaluated.

[0057] Franz diffusion cell transdermal retention experiment results: Depend on Figure 1 As can be seen, the cumulative permeability over 24 hours in Examples 3–5 was greater than 30%, significantly higher than all comparative examples (<13%), indicating that the nanocomposite prepared by this patented method has a significant function in promoting transdermal transport. Compared with the examples, the absence of any active ingredient in Comparative Examples 3–6 resulted in a decrease in permeability of approximately 20%, indicating that all four active ingredient components are indispensable and that the multi-pathway synergistic effect is significant. Figure 2 The results showed that the active ingredient was most significantly enriched in the stratum corneum in terms of cumulative retention per unit area, with Example 3 reaching as high as 21.3%, and Examples 4 and 5 reaching 19.5% and 22.0%, respectively. The cumulative retention rates in the stratum corneum, dermis, and epidermis were 40.8%, 37.1%, and 42.2%, respectively, while the corresponding values ​​in Comparative Examples 3–6 were less than 10%. This confirms that the nanocomposite prepared in the embodiments of the present invention not only penetrates efficiently but also forms a continuous release reservoir in the stratum corneum and basal layer, providing long-lasting support for its soothing and anti-allergic effects.

[0058] (iv) Human capsaicin sting test (clinical efficacy) To verify the anti-allergic, soothing, analgesic, and antipruritic effects of the multi-pathway, multi-target, and precise delivery of the anti-allergic and soothing nanocomposite of the present invention under clinical conditions, 30 healthy volunteers aged 18-45 years were selected, with their specific gender composition randomly determined.

[0059] The experiment was conducted under constant temperature (22±2℃) and constant humidity (50%-60%) conditions. Two symmetrical areas (2cm×2cm each) were marked on the inner forearm of each subject. One side was coated with the nanocomposite prepared in Examples 4-6, and the other side was the area from Comparative Examples 3-6. Thirty minutes after application, 0.05mL of 0.01% capsaicin ethanol solution was added to both test areas and gently massaged for 5 seconds to induce a local tingling response at nerve endings. The tingling intensity score (VAS scale, 0 for no tingling, 10 for severe tingling) was recorded at 0, 1, 3, 5, 10, and 15 minutes. Two professional evaluators independently scored the subjects, and the average score was used as the result, as shown in Table 4. Simultaneously, skin temperature changes were recorded using a skin surface temperature monitor, and local erythema changes were observed using high-resolution imaging (Visia skin analysis system). The average rate of change in skin erythema is shown in the figure below. Figure 3 As shown.

[0060] Table 4. Minute-by-minute stinging score Results of human capsaicin sting test: Table 4 shows that the nanocomposites prepared in Examples 4-6 have anti-allergic and soothing effects. Within 15 minutes of stimulation, volunteers reduced the stinging intensity to 0.1 points, with a skin redness value reduction of nearly 30%–35%, while the redness value change rate in Comparative Examples 3–6 was only 2%–12%, with a flat curve and no significant soothing effect. These results clearly demonstrate that the nanocomposites of this invention, through multi-pathway synergistic action, can significantly inhibit capsaicin-induced vasodilation and erythema reactions in a very short time. Comparative Examples 3-6, lacking one of the active ingredients glycyrrhetinic acid, bisabolol, 4-tert-butylcyclohexanol, or hydroxyphenylpropionamide benzoic acid respectively, only produced weak relief. The results confirm that the nanocomposites of this invention possess significant clinical-grade anti-allergic, soothing, analgesic, and antipruritic effects.

[0061] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A multi-pathway, multi-target precise delivery anti-allergic and soothing nanocomposite, characterized in that, The raw materials include the following components by mass fraction: 0.1-5 wt% glycyrrhetinic acid; 0.1-10 wt% bisabolol; 0.001-1 wt% 4-tert-butylcyclohexanol; 0.01-3 wt% hydroxyphenylpropionamide benzoic acid; 10-50 wt% emulsifier; 1-20 wt% liquid lipid; 1-10 wt% co-emulsifier; 10-30 wt% polyol; and the remainder is water.

2. The multi-pathway, multi-target precise delivery anti-allergic and soothing nanocomposite according to claim 1, characterized in that: The emulsifier is selected from one or more of polyglycerol-10 stearate, polyglycerol-10 diisostearate, polyglycerol-3 cocoate, polyglycerol-6 ricinoleate, polyoxyethylene hydrogenated castor oil, cetearyl alcohol polyether, cocoyl glucoside, polyethylene glycol laurate, lecithin, and polyglycerol-10 myristate.

3. The multi-pathway, multi-target precise delivery anti-allergic and soothing nanocomposite according to claim 1, characterized in that: The liquid lipid is selected from one or more of the following: cocoa seed butter, squalene and soybean oil, caprylic / capric triglyceride, isononyl isononanoate, isopropyl myristate, isopropyl palmitate, isoamyl laurate, dimethyl silicone oil, propylene glycol monocaprylate, and triacetin.

4. The multi-pathway, multi-target precise delivery anti-allergic and soothing nanocomposite according to claim 1, characterized in that: The co-emulsifier is selected from one or more of diethylene glycol monoethyl ether, PPG-26-butanol polyether-26, ethoxydiethylene glycol oleate, isosorbide dimethyl ether, cocoyl alcohol polyether-7, PPG-1-PEG-9 lauryl glycol ether, and octyl dodecyl alcohol.

5. The multi-pathway, multi-target precise delivery anti-allergic and soothing nanocomposite according to claim 1, characterized in that: The polyol is selected from one or more of sorbitol, glycerol, 1,3-propanediol, propylene glycol, 1,2-butanediol, butylene glycol, 1,2-pentanediol, 1,2-hexanediol, dipropylene glycol, and polyethylene glycol-400.

6. The method for preparing the complex according to any one of claims 1-5, characterized in that, Includes the following steps: S1: Add bisabolol, glycyrrhetinic acid, emulsifier, liquid lipid and co-emulsifier to the oil phase premix tank and mix, stirring evenly to obtain phase A solution; S2: 4-tert-butylcyclohexanol, hydroxyphenylpropionamide benzoic acid and polyol are added to an emulsification tank in sequence and mixed and stirred until homogeneous to obtain phase B solution; S3: Slowly add the B-phase solution obtained in step S2 to the A-phase solution obtained in step S1, stir evenly, and prepare the oil phase; S4: Add the remaining aqueous phase to the oil phase prepared in S3 and mix. Perform high-speed shear emulsification, process with high-pressure microfluidic jet, and cool to room temperature to obtain the multi-pathway, multi-target precise delivery anti-allergy and soothing nanocomposite.

7. The preparation method according to claim 6, characterized in that: In step S1, the mixing temperature is 30~60℃; the stirring speed during mixing is 50-500 r / min, and the stirring time is 20-50 min. In step S2, the mixing temperature is 20~50℃; the stirring speed during mixing is 100-800 r / min, and the stirring time is 10-50 min. In step S3, the mixing temperature is 30~60℃; the stirring speed during mixing is 50-500 r / min, and the stirring time is 30-60 min. In step S4, the rotation speed of the shear emulsification treatment is 5000~10000 rpm, and the time is 1~10 min. The high-pressure microjet treatment conditions are: 2-10 treatments under a pressure of 0.1-0.8 MPa.

8. The multi-pathway, multi-target precise delivery anti-allergy and soothing nanocomposite as described in claims 1-5, and the application of the multi-pathway, multi-target precise delivery anti-allergy and soothing nanocomposite in the fields of soothing and anti-inflammatory, analgesic and antipruritic, and anti-allergy repair cosmetics.

Images