A whitening moisturizing composition and a method of preparing the same

Abstract

The present application relates to the field of cosmetic technology, and provides a whitening and moisturizing composition and a preparation method thereof, comprising (i) at least one whitening active ingredient; (ii) at least one moisturizing active ingredient; (iii) a multi-stage carrier system, wherein the multi-stage carrier system comprises a first carrier for encapsulating and releasing the whitening active ingredient, a second carrier for encapsulating and releasing the moisturizing active ingredient, and a third carrier for encapsulating and releasing the whitening active ingredient and / or the moisturizing active ingredient; wherein the first carrier, the second carrier and the third carrier release the encapsulated active ingredients at different time stages, respectively. The present application improves the stability and bioavailability of the active ingredients by constructing a multi-stage carrier system of "liposome+mesoporous silica+PLGA microspheres" to encapsulate and release the whitening ingredients and the moisturizing ingredients, controls the release rate to reduce irritation, realizes the spatiotemporal synergistic effect of whitening and moisturizing, and enhances the skin barrier repair and long-acting moisturizing ability.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of cosmetics, in particular to a whitening and moisturizing composition and a preparation method thereof. BACKGROUND

[0002] Currently, most commercially available whitening and moisturizing products use a "one-pot method" to add active ingredients to auxiliary materials by simple mixing. However, there are still some problems: 1) poor stability - such as vitamin C and arbutin which are easily oxidized or degraded; 2) uncontrolled release - active ingredients are released all at once, which is highly irritating and has low bioavailability; 3) insufficient synergy - whitening and moisturizing ingredients do not complement each other in time and space, and their effects are offset or weakened.

[0003] For example, CN111773142A discloses a composition containing multiple plant extracts such as silk algae, cherry blossoms, daisy, and okra, as well as niacinamide, which improves whitening and moisturizing power through "multiple plant synergy". However, its technology only stays at the level of "simple addition of ingredients", and does not achieve gradual release of active substances, nor does it solve the stability problem of some active components that are easily oxidized and degraded.

[0004] CN117797069A blends curcumin, protein melanin, willow strip extract, almond extract, and walnut branch extract, and introduces cellulose nanocrystals (CNC) as a suspension stabilizer to achieve antibacterial, whitening, and moisturizing in one. However, CNC only plays a "physical stabilization" role and does not encapsulate active substances, nor does it have a graded release design, making it difficult to meet the needs of sensitive skin for "gentle and long-lasting".

[0005] Industry reviews indicate that Japanese pH-responsive emulsions and German keratinocyte-like liquid crystal carriers can release ceramides and hyaluronic acid in a "30-minute fast + 8-hour slow" two-stage manner, increasing the water content of the stratum corneum by 45% in 28 days and reducing irritation by 60%. However, existing technologies are mostly "two-phase and two-membrane" structures, which only achieve "fast / slow" two-stage release and cannot simultaneously deliver more than three types of active substances (such as water-soluble, alcohol-soluble, and acid-sensitive) in a differentiated manner. The 8-hour slow-release moisturizing time is relatively short and cannot meet the daily life needs of a single skincare interval of 12 hours or more. In addition, the emulsion particle size is generally > 400 nm, and the penetration rate through the intercellular gap is still limited.

[0006] CN117731544B through the "inner oil phase-outer water phase" double layer wrapping, makes the apricot acid (outer phase) 2h release 50.9%, benzene ethyl m-dihydroxybenzene 377 (inner phase) only release 14.7% in the same period, preliminary verification "staged release" the value of lightening. But the system only involves "two heavy films" differential release of two active substances, has not yet been expanded to "three orders and above" carrier synergy, apricot acid 2h inner rapid release still brings greater irritation and challenge to the skin, not friendly to sensitive skin, also does not include moisturizing, barrier repair ingredients into the same delivery platform, it is difficult to overcome the pressure and damage to the skin caused by whitening products.

[0007] It can be seen that the prior art has not yet appeared the integration of multi-stage micro-nano carriers in the same whitening and moisturizing composition, lacks a staged release scheme that simultaneously considers the "fast whitening-continuous moisturizing-delayed repair" three time period requirements, and the "spatiotemporal synergy" platform for vitamin C derivatives, niacinamide, alpha-arbutin, hyaluronic acid, ceramide and other multi-property active substances is still blank.

[0008] Therefore, it is of significant technical advancement and market urgency to develop a whitening and moisturizing composition based on micro-nano structures that can implement "staged absorption-release" on different active ingredients and produce synergistic effects. SUMMARY

[0009] The present application aims to provide a whitening and moisturizing composition and a preparation method thereof, by constructing a "liposome+mesoporous silica+PLGA microsphere" multi-level carrier system, the whitening ingredients and moisturizing ingredients are packaged and released in stages, thereby improving the stability and bioavailability of active ingredients; controlling the release rate, reducing irritation; realizing the spatiotemporal synergy of whitening and moisturizing; enhancing the skin barrier repair and long-term moisturizing ability.

[0010] To achieve the above-mentioned purpose, the present application provides a whitening and moisturizing composition and a preparation method thereof.

[0011] A whitening and moisturizing composition, characterized in that it comprises:

[0012] (i) at least one whitening active ingredient;

[0013] (ii) at least one moisturizing active ingredient;

[0014] (iii) a multi-level carrier system, the multi-level carrier system comprising:

[0015] a first carrier for packaging and releasing the whitening active ingredient,

[0016] a second carrier for packaging and releasing the moisturizing active ingredient,

[0017] a third carrier for packaging and releasing the whitening active ingredient and / or the moisturizing active ingredient;

[0018] The first carrier, the second carrier and the third carrier release the active ingredients encapsulated therein at different time stages, respectively.

[0019] By adopting the technical scheme, the three carriers can encapsulate active ingredients of different properties separately, can avoid the combination or reaction between different active ingredients while avoiding the oxidative degradation of the active ingredients in the absence of oxygen and light, and can also meet the different storage requirements between different components, such as different pH and hydrophilic or hydrophobic properties, thereby improving the storage stability and prolonging the storage time; different components can be released at different rates at different times through different triggering mechanisms, which facilitates the separate regulation of the effectiveness and action time, release accumulation speed, etc. of each component in a complex system of multiple components according to the requirements, so that the different components achieve synergistic effect in time and space, thereby improving the whitening and moisturizing effect while being mild and non-irritating, repairing the barrier, and lasting in effect, and the invention is especially suitable for whitening and moisturizing of sensitive skin.

[0020] For example, the mild and non-irritating whitening component is released quickly to take effect, while the moisturizing component is subjected to a release process of “burst release + tailing”, to prevent the loss of the moisturizing component, achieve the effect of quickly reaching the moisturizing effect and prolonging the moisturizing time of the moisturizing component, and control the slow release of the irritating component, the process of increasing the concentration of which not only gives the skin time to adapt and build tolerance, but also allows the irritating component to be slowly replenished after consumption, so that the concentration is always maintained at a relatively low level, without the need to use a high concentration at one time, which not only achieves the whitening effect that is difficult to achieve with a low component concentration, but also overcomes the negative effects such as irritation caused by a high component concentration. Therefore, the invention not only maintains excellent whitening and moisturizing effects, but also reduces the irritation and damage to the skin, and prolongs the residence time and maintenance time of the active ingredients.

[0021] Further, the whitening active ingredient includes one or more of nicotinamide (NMN), arbutin (Arb), glabridin, rhodiola extract, resveratrol, kojic acid, mandelic acid, vitamin C and derivatives thereof.

[0022] Further, the content of the whitening active ingredient ranges from 0.1 wt% to 10 wt%, preferably from 0.5 wt% to 5 wt%, relative to the total amount of the whitening and moisturizing composition. A content lower than the above range is difficult to ensure the effective concentration of the active ingredient, resulting in poor whitening and moisturizing effect of the skin care product; a content higher than the above range is likely to exceed the maximum safe amount of some whitening active ingredients, causing damage to the skin health.

[0023] Further, the moisturizing active ingredient includes one or more of sodium hyaluronate (HA), panthenol (B5), glycerol, amino acid mixture, and ectoin.

[0024] Further, the HA has a weight average molecular weight of Mw < 50 kDa, preferably 10 kDa ~ 30 kDa.

[0025] Further, the content of the moisturizing active ingredient ranges from 0.01 wt% to 10 wt%, preferably 0.5 wt% to 5 wt%, relative to the total amount of the whitening and moisturizing composition. Less than the above range is difficult to ensure the effective concentration of the active ingredient, and also difficult to amplify the moisturizing signal through the carrier, so that the skin care product has poor whitening and moisturizing effect; more than the above range is easy to cause sticky feeling and cost pressure due to high concentration of the moisturizing ingredient.

[0026] Further, the first carrier is a phospholipid-based vesicle carrier, which can be one or more of single-compartment liposome, multi-compartment liposome, flexible liposome, cationic liposome, anionic liposome, neutral liposome in terms of structure, and one or more of hydrogenated soybean phosphatidylcholine (HSPC), distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE), cholesterol in terms of membrane material.

[0027] The liposome as a carrier system can ensure the safety of the whitening active ingredient during storage and use. Its stable structure and good biocompatibility make the product more safe and reliable, reducing the safety risk caused by the instability or leakage of the whitening active ingredient; the liposome embedding can ensure the inactivation rate of the whitening active ingredient while increasing the transdermal absorption rate of the raw material.

[0028] In order to further improve the penetration and stability of the whitening active ingredient in the composition, hydrogenated soybean phosphatidylcholine is preferred, which can greatly improve the stability of the whitening active ingredient, the phase transition temperature and the molecular structure ensure the long-term effectiveness of the whitening composition product during the storage period, and also can perfectly control the appropriate release rate and release time under the corresponding conditions, thereby improving the whitening effect.

[0029] By adopting the above technical scheme, the first carrier can be released by one or more of shearing, temperature, ion, light, and pH, preferably by membrane fusion, transient pore or membrane rupture under the action of shear force generated by behaviors such as rubbing during use, which can quickly release and take effect during use, thereby improving the whitening effect.

[0030] Further, the first carrier is used to encapsulate mild and non-irritating whitening active ingredients, such as one or more of niacinamide, arbutin, glabridin, rhodiola extract, and resveratrol.

[0031] By adopting the above technical scheme, the whitening component can be stored in the dark and away from oxygen to improve storage stability, while the mild and non-irritating whitening component is quickly released and takes effect during use, thereby improving the whitening effect. Further, the particle size of the first carrier is 30-300 nm, preferably 50-150 nm.

[0032] Further, the first carrier releases the encapsulated active ingredient within 0-2 h, preferably within 0-1 h, and more preferably within 0-0.5 h.

[0033] Further, the content of the first carrier ranges from 0.5 wt% to 30 wt%, preferably from 5 wt% to 20 wt%, and more preferably from 8 wt% to 15 wt%, relative to the total amount of the whitening and moisturizing composition. If the content of the first carrier is lower than the above range, it is difficult to form a sufficient shear trigger point and interact with the second carrier and the third carrier to construct a structurally stable responsive release system, thereby reducing the stability and trigger responsiveness of the system. If the content of the first carrier is higher than the above range, the excess phospholipid can cause greasiness and oxidation risk.

[0034] Further, the second carrier is an ordered-pore inorganic carrier, such as mesoporous silica (MSN), mesoporous carbon, mesoporous metal oxide, etc. The mesoporous silica is one or more of SBA-15, MCM-41, HMS, FDU, KIT-6, and bi-pore MSN. The bi-pore MSN can achieve a release process combining "burst release" and "tail release" through two different structures and sizes of pores to prevent the loss of moisturizing ingredients and achieve rapid moisturizing effect and prolonged moisturizing time of the moisturizing ingredients.

[0035] By adopting the above technical scheme, the second carrier can be triggered to release by one or more conditions such as ionic strength, humidity, temperature, enzyme, light, and magnetism, preferably by the change in ionic strength on the surface of the skin, and can be naturally released after use without applying other measures, thereby meeting the demand for controlling the release time and release rate of the active ingredients.

[0036] Further, the second carrier is used to encapsulate moisturizing active ingredients, such as one or more of sodium hyaluronate, panthenol, glycerol, amino acid mixture, and ectoine.

[0037] By adopting the above technical scheme, the release rate and release time of the moisturizing component can be controlled, the loss of the moisturizing component can be prevented, the moisturizing effect can be quickly achieved, and the moisturizing time of the moisturizing component can be prolonged. Further, the particle size of the second carrier is 20-200 nm, preferably 50-100 nm; the pore size of the second carrier is 2-20 nm, preferably 5-15 nm; the specific surface area of the second carrier is 200-1200 m² / g, preferably 300-500 m² / g; further, the core pore of the double-pore MSN is 1-5 nm, and the shell pore is 6-15 nm, preferably the core pore is 2-4 nm, and the shell pore is 8-10 nm.

[0038] Further, the second carrier releases the encapsulated active ingredient for 0-24 h, preferably 0.5-18 h, and more preferably 0.5-12 h.

[0039] Further, the content of the second carrier ranges from 0.2 wt% to 20 wt%, preferably from 1 wt% to 10 wt%, and more preferably from 3 wt% to 7 wt%, relative to the total amount of the whitening and moisturizing composition. If the content of the second carrier is lower than the above range, the second carrier is difficult to interact with the first carrier and the third carrier to construct a stable responsive release system, and the system triggering and release stability are reduced. If the content of the second carrier is higher than the above range, the excess inorganic particles can easily cause a sandy feel and centrifugal sedimentation.

[0040] Further, the third carrier is a degradable polyester microsphere, and the degradable polyester is one or more of polylactic acid (PLA), polyglycolic acid (PGA) microsphere, polylactic acid-glycolic acid copolymer (PLGA), polycaprolactone (PCL), polylactic acid-ε-caprolactone copolymer (PLCL), and polyethylene glycol-polyglutamic acid-polylactic acid copolymer (PGA-PEG-PLGA).

[0041] By adopting the above technical scheme, the third carrier can be triggered to release by one or more conditions such as esterase, temperature, pH, mechanical crushing, and osmotic pressure, and preferably triggered to release by esterase. The third carrier can be naturally released by the natural accumulation of the esterase concentration on the skin surface after use without applying other measures, thereby meeting the functions of controlling the slow release of the active ingredient, maintaining the concentration balance of the active ingredient, and giving the skin an adaptation time.

[0042] Further, in the PLGA, the molar ratio of polylactic acid (LA) to glycolic acid (GA) is LA:GA=100:0-25:75, and preferably LA:GA=60:40-40:60.

[0043] Further, the weight average molecular weight of the third carrier is 5 kDa-100 kDa, and preferably 20 kDa-40 kDa; and the particle size of the third carrier is 1 µm-200 µm, and preferably 10 µm-30 µm.

[0044] Further, the third carrier releases the encapsulated active ingredient for 1-24 h, preferably 2-18 h, more preferably 2-12 h.

[0045] Further, the third carrier is used to encapsulate a stimulating whitening active ingredient and / or the moisturizing active ingredient, such as one or more of kojic acid, mandelic acid, vitamin C and derivatives thereof, vitamin B5.

[0046] By adopting the above technical solution, the stimulating ingredient can be slowly released while avoiding light and oxygen, and the process of increasing the concentration of the stimulating ingredient not only provides time for the skin to adapt and build tolerance, but also allows the stimulating ingredient to be slowly replenished after consumption, so that the stimulating ingredient is always maintained at a real-time concentration that is relatively low but has a high whitening and moisturizing efficiency. This solution not only achieves the whitening and moisturizing effect that is difficult to achieve with a low concentration of ingredients, but also overcomes the negative effects such as irritation caused by a high concentration of ingredients.

[0047] Further, the content of the third carrier ranges from 0.2wt% to 20wt%, preferably from 1wt% to 10wt%, and more preferably from 3wt% to 7wt%, relative to the total amount of the whitening and moisturizing composition. A third carrier with a content lower than the above range has poor slow-release controllability and is difficult to interact with the first carrier and the second carrier to form a stable structure responsive release system, which reduces the stability of the system triggering and release. A microsphere with a content higher than the above range is prone to cause a dense film feeling and esterolysis residue.

[0048] Further, the first carrier is a liposome (Lip), the second carrier is mesoporous silica, and the third carrier is a PLGA microsphere.

[0049] In the system where the "liposome-mesoporous silica-PLGA microsphere" three-step micro-nano carriers coexist, the three particles do not simply physically mix, but exist in a synergistic form of "structural mutual embedding, functional complementation, and release mutual adjustment" through three mechanisms of spatial hierarchical distribution, surface charge / hydrogen bond / hydrophobic complementation, and degradation time difference. Specifically, it can be divided into the following points:

[0050] 1. Spatial existence form - hierarchical dispersion of "large ball wrapping small ball"

[0051] In the composition, a hybrid aggregate is formed with "PLGA as the large core, MSN as the satellite, and Lip as the shell", and the particle size distribution shows three peaks, but the absolute value of the Zeta potential is <30mV, and the electrostatic repulsion prevents sedimentation, forming a reversible network.

[0052] 2. Interaction force - four kinds of weak forces synergistically stabilize

[0053] The hydrogen bonding between PLGA and the silicon hydroxyl groups of MSN prevents the aggregation of MSNs and improves the stability of the colloid; the electrostatic interaction between the anions of PLGA and the positive charges on the surface of the liposomes enables the liposomes to "stick" to the surface of the microspheres, forming a semi-coating structure; the hydrophobic force between the ester chains of PLGA and the phosphatidyl chains of the liposomes can enhance the interface anchoring and reduce free liposomes; and the van der Waals forces between the three carriers can provide short-range attraction, maintaining a loose aggregate without sedimentation.

[0054] Through the interaction between the three carriers, both irreversible aggregation is prevented and "dynamic clusters" are allowed to continue to exchange, effectively increasing the stability of the composition, while also forming a "water-locking network" on the skin surface, effectively reducing water loss.

[0055] 3. Synergy and timing of degradation / release

[0056] Under the action of the shear force of the liposomes being applied or rubbed and the skin temperature, the liposomes rapidly release the non-irritating whitening active ingredients through membrane fusion, transient pores or membrane rupture within 0-0.5 h; after the liposomes are broken, the local osmotic pressure increases, the water channels open, and the mesoporous silica is triggered by the ionic strength of sweat to release the moisturizing active ingredients within 0.5-12 h, rapidly and continuously replenishing water to effectively prevent the evaporation of the moisturizing ingredients; the PLGA microspheres can slowly release the irritating whitening active ingredients under the natural accumulation of esterases on the skin surface and the action of temperature within 2-12 h, on the one hand giving the skin time to adapt, and on the other hand reducing the real-time accumulation concentration of the irritating whitening active ingredients, both of which reduce the irritation and damage to the skin while extending the whitening duration. The three carriers are designed according to the "fast-medium-tail" time window to avoid the one-time burst release of the ingredients, achieve the synergy of 0.5 h onset, 2-6 h peak, and 12 h continuous release, and ensure continuous whitening, moisturizing and skin care within the entire time interval between the two times of washing the face in daily life, which not only improves the whitening effect but also prolongs the continuous action time of the whitening and moisturizing ingredients, and is mild and non-irritating, suitable for sensitive skin.

[0057] Therefore, the three carriers form reversible dynamic clusters rather than simple blending through the triple mechanism of "spatial hierarchy-weak force interaction-degradation time difference"; the structure not only ensures the independence of their respective release time and release rate, but also adjusts each other through "water channels-microenvironment-charge shielding", ultimately realizing the unity of graded release and synergistic effect.

[0058] Further, the whitening and moisturizing composition further comprises an auxiliary material, and the auxiliary material includes one or more of emulsifiers, moisturizers, gellan gum, thickening agents, pH adjusters, skin feel adjusters, preservatives, fragrances, and water.

[0059] As a preferred technical scheme, the whitening and moisturizing composition comprises the following components (mass percentage): ethyl ascorbic acid (VCE) 0.2-1%, nicotinamide 0.5-3%, alpha-arbutin 0.2-1%, sodium hyaluronate 0.1-0.5%, panthenol 0.2-1%, liposome (Lip) 5-15%, double-hole MSN 3-7%, and PLGA microspheres 3-7%.

[0060] It should be noted that in the above technical scheme, nicotinamide can block the transport of melanin; alpha-arbutin can competitively inhibit tyrosinase, thereby inhibiting melanin production; VCE can inhibit melanin production and improve the DPPH clearance rate; sodium hyaluronate HA can deeply moisturize, has anti-inflammatory effect, inhibits hyaluronidase, and indirectly inhibits melanin production; panthenol can moisturize, reduce the thermal stability of tyrosinase, and synergistically enhance the skin barrier with HA. The present application starts from several stages of melanin production, not only inhibits tyrosinase, hyaluronidase, and improves the DPPH clearance rate to reduce the production of melanin from three aspects, but also blocks the transport process of melanin to prevent the accumulation of generated melanin. At the same time, panthenol and HA synergistically moisturize, have anti-inflammatory effect, effectively enhance the skin barrier, reduce inflammation and the melanin caused by inflammation, and block melanin layer by layer. Several active ingredients have a synergistic effect, realize the inhibition of melanin in all directions and all pathways, and have excellent whitening and moisturizing effect.

[0061] By adopting the technical scheme, the nicotinamide and the alpha-arbutin are mild and non-irritating whitening active ingredients at the above dosages, the liposome is adopted for loading, which can avoid oxidation and deterioration of the alpha-arbutin under the action of light or destruction of the structure of the alpha-arbutin by the VCE, and can release the nicotinamide and the alpha-arbutin instantaneously within 0-0.5 hours under the action of the shearing force of smearing or rubbing and the skin temperature in use, so as to quickly block the melanin transport and the tyrosinase activity, and quickly establish the first barrier of "transfer-synthesis double blocking"; the moisturizing components such as panthenol and HA are loaded by the double-hole MSN, the double-hole structure of the MSN enables the MSN to realize two-stage release at different speeds under the trigger of the skin surface sweat ion intensity, first, the panthenol and the HA are released at a faster speed by the small nuclear pore within 0.5-2 hours, and about 30-40% of the panthenol and the HA are released, so as to quickly meet the needs of water replenishment and anti-inflammation in the early stage, then, the remaining 40-50% of the panthenol and the HA are slowly released by the large shell pore within 2-12 hours, so as to supplement the loss of the moisturizing active ingredients at any time, form a "moisturizing reservoir", make the water content curve appear a platform period, realize 12-hour continuous water replenishment and inhibition of hyaluronidase, reduce melanin production, and synergistically enhance the skin barrier, and form the second barrier of "anti-inflammatory-moisturizing-enzyme inhibition"; the VCE is a stimulating active ingredient, the PLGA microsphere loading can avoid the irritation of the VCE to the skin, the VCE can be slowly released by the skin surface esterase under the action of the natural accumulation and the temperature within 2-12 hours, so that the VCE is always maintained at a low real-time concentration but a high whitening efficiency, the skin is not damaged while the VCE continuously reduces dopaquinone and weakly acid inhibits the enzyme, and the whitening time is prolonged, meanwhile, the weak acid condition formed by the degradation product can also inhibit the enzyme activity and melanin production, and realize the third barrier of "end reduction + long-term inhibition of melanin and antioxidant". The three carriers play their respective roles, the time-target-mechanism three-dimensional alignment, and the synergistic effect can hit a combination of whitening and moisturizing in all directions and all pathways, and the effective and healthy whitening and moisturizing can be realized without damaging the cells and the body.

[0062] The three carriers form reversible dynamic clusters through various interaction forces in the spatial dimension, which can ensure different release programs of the three carriers, and can also adjust each other through "water channel-microenvironment-charge shielding", so as to increase the stability of the system and prolong the storage time.

[0063] The second aspect of the present application provides a preparation method of a whitening and moisturizing composition, including the following steps:

[0064] S1, forming a first carrier and loading whitening active ingredients;

[0065] S2, forming a second carrier and loading moisturizing active ingredients;

[0066] S3, forming a third carrier and loading whitening active ingredients and / or moisturizing active ingredients;

[0067] S4, mixing the first carrier, the second carrier and the third carrier after the encapsulation with excipients to obtain a synergistic composition releasing the encapsulated active ingredients at different time stages.

[0068] As a preferred technical solution, the first carrier in step S1 is HSPC liposome, and the step S1 specifically comprises:

[0069] S11, dissolving HSPC, cholesterol and DOTAP in anhydrous ethanol, pouring into a container, heating and stirring in a water bath until transparent, and then rotary evaporation drying;

[0070] S12, preheating the solution containing whitening active ingredients, pouring into the above-mentioned container at one time, hydrating, and ultrasonic.

[0071] Further, the heating temperature of the water bath heating in step S11 is 40-80℃, preferably 50-60℃; and the stirring speed is 50-200rpm, preferably 80-140rpm.

[0072] Further, the hydrating temperature in step S12 is 40-80℃, preferably 50-60℃; the ultrasonic power is 30-60kHz, preferably 40-50kHz; and the ultrasonic time is 5-40min, preferably 10-20min.

[0073] As a preferred technical solution, the second carrier in step S2 is a double-pore MSN, and the step S2 specifically comprises:

[0074] S21, preparation of core liquid and shell liquid: mixing template agent A with alkali solution to obtain A core liquid, and mixing template agent B with acid solution to obtain B shell liquid;

[0075] S22, low-temperature nucleation: quickly adding a part of tetraethyl orthosilicate (TEOS) to the A core liquid under water bath stirring, centrifuging and washing after reaction to obtain primary core particles;

[0076] S23, temperature rising and shell growing: dispersing the primary core particles in the B shell liquid, heating, and adding the remaining part of TEOS drop by drop, continuing to react until obvious Tyndall effect appears in the solution, centrifuging and washing to obtain primary core-shell silica;

[0077] S24, template removal: drying and calcining the primary core-shell silica, and obtaining double-pore MSN after cooling;

[0078] S25, amino modification: dispersing the double-pore MSN in an organic solvent, quickly adding amino silane after heating and stirring activation, continuing to stir, high-speed centrifuging, washing, vacuum drying to obtain amino-modified double-pore MSN;

[0079] S26, preparation of moisturizing active solution: adding the moisturizing active ingredient into PBS buffer solution, stirring to dissolve, obtaining PBS solution of the moisturizing active ingredient;

[0080] S27, vacuum impregnation: adding the PBS solution into the amino-modified dual-pore MSN, making the liquid surface completely cover the particles, vacuumizing at room temperature, then recovering normal pressure to carry out the vacuumizing and releasing cycle, making the liquid fully enter the pores; repeating the vacuumizing and releasing cycle for 3-5 times, centrifuging, washing, obtaining the MSN wet particles loaded with the moisturizing active ingredient;

[0081] S28, ion plug: slowly adding sodium sulfate solution into the chitosan solution under stirring, forming chitosan-sulfate complex colloid; adding the MSN wet particles loaded with the moisturizing active ingredient into the above colloid, oscillating, making the complex deposit on the shell pore mouth of the MSN wet particles; centrifuging, washing, obtaining the plug-MSN wet particles loaded with the moisturizing active ingredient;

[0082] S29, hydrophobic tail modification: dispersing the plug-MSN wet particles loaded with the moisturizing active ingredient in organic solvent, adding OTES, carrying out reflux reaction, then centrifuging and washing, vacuum drying, obtaining the hydrophobic tail modification-MSN wet particles loaded with the moisturizing active ingredient.

[0083] It should be noted that, when the Na + ≥40mM, the increase of local ion intensity will compress the double electric layer on the surface of the MSN, so that the absolute value of Zeta potential is reduced; the mechanism of S28 ion plug is that the channel is closed at low ion intensity, and the Na + ≥40mM, the ion intensity triggered MSN releases the moisturizing active ingredient; and the OTES on the hydrophobic tail modification can make the contact angle of the MSN shell pore surface rise directly, so that the hydration rate is greatly reduced, thereby prolonging the time of the MSN tail release of the moisturizing active ingredient. When there is no sweat (Na + The ion intensity <10mM, the channel of the MSN is closed, and it basically does not release, that is, the release rate is low when the composition is not used, and the storage stability is good.

[0084] Further, the dual-pore MSN is a dual-pore MSN with 2-4nm nuclear pores and 8-10nm shell pores.

[0085] Further, the template agent A in step S21 is cetyltrimethylammonium bromide (CTAB), and the template agent B is polyether, preferably P123.

[0086] Further, the water bath temperature in step S22 is 15-30℃, preferably 20-25℃; and the reaction time is 1-4h, preferably 2-3h.

[0087] Further, the temperature in step S23 is 35-60°C, preferably 40-50°C.

[0088] Further, the drying temperature in step S24 is 40-80°C, preferably 50-60°C; the drying time is 2-12h, preferably 4-8h; the calcination temperature is 400-700°C, preferably 500-600°C; the calcination time is 2-6h, preferably 3-5h.

[0089] Further, the heating temperature in step S25 is 80-120°C, preferably 100-120°C; the heating time is 0.5-3h, preferably 1-2h; the drying temperature is 40-80°C, preferably 50-60°C; the drying time is 2-24h, preferably 4-12h; the amino silane comprises one or more of KH550, KH602, and KH792.

[0090] Further, the pH of the PBS buffer in step S26 is 5.5-6.5.

[0091] Further, the weight average molecular weight of the chitosan in step S28 is 1kDa≤Mw≤50kDa, preferably 5kDa≤Mw≤10kDa.

[0092] Further, the reflux temperature in step S29 is 40-80°C, preferably 50-70°C; the reflux time is 1-4h, preferably 2-3h; the drying temperature is 40-80°C, preferably 50-70°C; the drying time is 2-24h, preferably 4-12h.

[0093] As a preferred technical solution, the third carrier in step S3 is a PLGA microsphere, and the step S3 specifically comprises:

[0094] S31, dissolving the PLGA copolymer in an organic solvent, stirring to obtain a transparent viscous oil phase (o), and adding a pore-forming agent, a whitening active ingredient, and / or a moisturizing active ingredient into water, stirring to dissolve, to obtain an inner water phase (w1);

[0095] S32, slowly pouring the inner water phase into the oil phase, immediately emulsifying with a high-speed dispersion homogenizer to form a white viscous primary emulsion (w1 / o), and then transferring to an ice bath;

[0096] S33, adding purified water to polyvinyl alcohol, stirring to dissolve at room temperature to obtain an outer water phase (w2); pre-cooling the outer water phase, and then starting mechanical stirring, slowly dripping the primary emulsion in the ice bath into the outer water phase, and immediately increasing the stirring speed after the dripping is completed, to form a white emulsion of double emulsion (w1 / o / w2);

[0097] S34. Transfer the two emulsions to room temperature and stir magnetically with the stirring outlet open to evaporate the organic solvent; after evaporation, wash with deionized water, centrifuge after each wash, collect the white precipitate, and obtain a wet cake of microspheres.

[0098] S35. Disperse the microsphere wet cake in mannitol solution and freeze-dry under vacuum.

[0099] It should be noted that as esterases accumulate on the skin surface over time, their activity reaches 5–15 U / mg. 角质 During this process, the surface of PLGA microspheres is enzymatically cleaved, and the molecular weight gradually decreases, causing the glass transition temperature (Tg) of PLGA to drop from above 45°C to below 37°C. Under the influence of skin surface temperature, the glass transition temperature occurs, synergistically accelerating the release of active substances. When the composition is not used during the storage period, there are no esterases, and the degradation rate is slow. At the same time, PLGA is located at the innermost part of the tertiary carrier system, and is surrounded and filled by the first and second carriers through interactions such as hydrogen bonds, electrostatic interactions, hydrophobic interactions, and van der Waals forces, which further reduces the degradation rate of PLGA and enables long-term stable storage.

[0100] Further, the organic solvent mentioned in step S31 is a mixed solvent of dichloromethane and ethyl acetate, wherein the volume ratio of dichloromethane to ethyl acetate in the mixed solvent is 1:(0.5-2).

[0101] Furthermore, in step S32, the water phase is slowly poured into the oil phase at a water-to-oil volume ratio of 1:(5-10), the high-speed homogenizer rotates at 8000 rpm to 15000 rpm, and the duration is 1 min to 5 min.

[0102] It should be noted that the ice bath mentioned in step S32 can prevent the active ingredients from being degraded by heat, while reducing the evaporation rate of organic solvents and avoiding premature solidification.

[0103] Furthermore, the mechanical stirring speed in step S33 is 300 rpm to 500 rpm; the stirring speed is increased to 3000 rpm to 5000 rpm.

[0104] Furthermore, in step S34, the magnetic stirring speed is 200 rpm to 300 rpm; the open stirring time is 2 h to 6 h; the centrifugation speed is 3000 rpm to 4000 rpm; and the centrifugation time is 5 min to 15 min.

[0105] Further, the mass-to-volume ratio of the wet cake to the mannitol solution in step S35 is 1:(2-5).

[0106] As a preferred technical solution, step S4 specifically includes:

[0107] S41, after the first carrier is loaded, the water bath is stirred to form a gentle vortex, and the loaded third carrier is added in portions, and the stirring is continued;

[0108] S42, turn off the heating, maintain stirring, add the loaded second carrier in portions, each interval is 5min-10min;

[0109] S43, keep stirring, slowly pour the swollen and cooled gellan gum pre-gel into the barrel, continue to stir to form a reversible gel network, and obtain a concentrated hybrid slurry;

[0110] S44, under stirring, add the base to the concentrated hybrid slurry, start the cooling cycle, reduce the temperature of the liquid to 25℃, adjust the pH to 6.0, filter, and obtain the whitening and moisturizing composition.

[0111] Further, the water bath temperature in step S41 is 30℃-35℃, the stirring speed is 50rpm-150rpm, and the continuous stirring time is 20min-60min; the number of times of adding in portions is 3-5 times.

[0112] Further, the number of times of adding in portions in step S42 is 3-5 times.

[0113] Further, the gellan gum pre-gel in step S43 is 0.2% low acyl gellan gum containing 0.1% CaCl2.

[0114] The third aspect of the present application also provides an application of the whitening and moisturizing composition in the field of personal care and medical treatment.

[0115] Further, the personal care includes whitening and moisturizing products for each part of the face, body, scalp, lips, etc.; and the whitening and moisturizing products include one or more of emulsion, gel, cream, freeze-dried powder, mask, ampoule.

[0116] Further, the application mode of the whitening and moisturizing composition in the medical field includes application in the fields of wound repair dressings, medical postoperative repair patches, laser / microneedle partners, etc.

[0117] Compared with the prior art, the present application has the following advantages and beneficial effects:

[0118] 1. The three carriers of the present application form a reversible dynamic cluster rather than a simple blend through the three mechanisms of "spatial hierarchy-weak force interaction-degradation time difference"; this structure not only ensures independent release program of each carrier, but also adjusts each other through "water channel-microenvironment-charge shielding", and finally realizes the unity of graded release and synergistic effect; the three carriers reduce precipitation and degradation through spatial position relationship and interaction force, and improve the storage stability;

[0119] 2. Through the complex collocation of active ingredients and carriers, time and space grading release is realized, mutual interference between components is avoided, component stability and skin penetration rate are improved, and on the basis of all-round and all-path whitening, moisturizing and anti-inflammatory can also be achieved, realizing the synergistic effect of whitening and moisturizing;

[0120] 3. Through the synergistic effect of the three carrier systems, the irritability of the active ingredients is reduced, the skin is not irritated or damaged, and it is suitable for sensitive skin;

[0121] 4. Through the use of double-hole MSN, the mutual cooperation between large holes and small holes realizes the organic combination of rapid onset and tailing release of moisturizing components, which not only rapidly increases the content of moisturizing components to obtain instant moisturizing effect, but also prolongs the moisturizing time. BRIEF DESCRIPTION OF DRAWINGS

[0122] The drawings described herein are used to provide further understanding of the embodiments of the present application, constitute a part of the present application, and do not constitute a limitation on the embodiments of the present application. In the drawings:

[0123] Figure 1 The hydration rate change curve of the present application embodiment 1 and comparative examples 4, 6-9. DETAILED DESCRIPTION

[0124] In order to make the purpose, technical scheme and advantages of the present application more clear and obvious, the present application is further described in detail below, the illustrative embodiments of the present application and their descriptions are only used to explain the present application, and do not constitute a limitation on the present application, the following described embodiments are a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor belong to the scope of protection of the present application.

[0125] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application pertains. Although preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In the event of conflict between any incorporated document and the content of this specification, the content of this specification shall prevail.

[0126] Many modifications and variations of the specific embodiments of the present application described in the specification can be made without departing from the scope or spirit of the present application, which will be apparent to those skilled in the art. Other embodiments obtained from the specification of the present application will be apparent to those skilled in the art. The specification and examples of the present application are only illustrative.

[0127] As used herein, the terms "comprising", "including", "containing", "have" and "including" are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0128] In the present text, all features defined by a numerical range or a percentage range, such as numerical values, amounts, contents and concentrations, are only for the sake of brevity and convenience. Accordingly, the description of a numerical range or a percentage range shall be considered to have encompassed and specifically disclosed all possible sub-ranges and individual numerical values within the range, including integers and fractions.

[0129] In the present text, unless specifically stated otherwise, parts are parts by mass.

[0130] In order to better illustrate the effects of the technical solutions in the present embodiments, the following specific examples are provided for illustration.

[0131] Example 1 A method for preparing a whitening and moisturizing composition, comprising the following steps:

[0132] S1, forming a first carrier and entrapping a whitening active ingredient

[0133] S11, dissolve HSPC 18 parts, cholesterol 3 parts, DOTAP 1 part in 200 parts of anhydrous ethanol, and after stirring to transparency at 50°C water bath, pour into a round-bottom flask, and after rotary evaporation into a uniform white film at 50°C, 100 rpm, continue to vacuum for 10 min to remove ethanol;

[0134] S12, preheat 300 parts of a pH 6.0 PBS solution containing 3 parts of nicotinamide and 1 part of a- arbutin to 50°C, pour into the round-bottom flask at one time, hydrate at 50°C, 100 rpm for 30 min to obtain a milky white crude liposome entrapping system; After intermittent ultrasonic treatment at 42 kHz and 25°C for 15 min, pass through a 0.22 μm filter membrane to obtain NMN / Arb@Lip with a particle size of about 92 nm;

[0135] Tested, the encapsulation efficiency of nicotinamide is about 72%, the drug loading is about 13.5%, the encapsulation efficiency of a- arbutin is about 76 w / w % and the drug loading is about 4.8 w / w %.

[0136] S2, forming a second carrier and entrapping a moisturizing active ingredient

[0137] The two-step co-condensation is carried out by adopting the idea of "preparing 2-4 nm core pores by using cetyltrimethylammonium bromide micelles as a template" and "preparing 8-10 nm shell pores by using P123 large cells as a template", first nucleating at low temperature, then lengthening the shell at high temperature, and finally removing the template by step-by-step calcination to obtain dual-pore MSN master batches with 2-4 nm core pores / 8-10 nm shell pores, and then carrying out plug and tail modification after loading active ingredients to adjust the release time and release rate of the active ingredients in the shell pores, so as to realize the combination of rapid water replenishment and long-acting moisturizing in cooperation with the core pores.

[0138] S21, preparation of core liquid and shell liquid:

[0139] CTAB 0.15 parts, 2M NaOH solution 0.5 parts and 50 parts of deionized water are fully mixed to obtain A core liquid;

[0140] P123 0.2 parts, 2M HCl 0.5 parts and 50 parts of deionized water are fully mixed to obtain B shell liquid;

[0141] S22, low-temperature nucleation

[0142] A core liquid 50 parts is placed in a 25℃ water bath and stirred, and TEOS 1.0 parts is added at one time, and the solution is gradually changed from transparent to milky white after 2h of 25℃ reaction; after centrifugation, the solid precipitate is collected, and washed with water for 2 times to obtain primary core particles;

[0143] S23, lengthening the shell at high temperature

[0144] The wet primary core particles are redispersed in B shell liquid 50 parts, and the temperature is raised to 40℃, and TEOS 2.0 parts is added dropwise, and the solution appears obvious Tyndall effect after 12h of 40℃ continuous reaction; after centrifugation, the solid precipitate is collected, and washed with water for 2 times and ethanol for 1 time to obtain primary core-shell silica;

[0145] S24, template removal

[0146] The primary core-shell silica is dried at 60℃ for 6h to obtain a white powder, which is heated to 550℃ at a rate of 2℃ / min and calcined at 550℃ for 4h, and then naturally cooled to obtain dual-pore MSN master batches, and the BET specific surface area thereof is about 680m² / g and the pore volume is 0.82cm³ / g.

[0147] S25, amino modification

[0148] 5 parts of the dual-pore MSN master batches prepared in step S24 are dispersed in 60 parts of anhydrous toluene, and stirred at 110℃ for 1h for activation, then γ-aminopropyltriethoxysilane 1.5 parts is quickly added, and the stirring is continued at 110℃ for 24h, and then the white colloid is collected by high-speed centrifugation, and washed with toluene and anhydrous ethanol for 2 times respectively, and dried at 60℃ under vacuum to obtain amino-modified dual-pore MSN, which is ready for use.

[0149] S26, preparing a moisturizing active solution

[0150] Another clean container was taken, 300 parts of purified water was added, and the pH was adjusted to 6.0 with sodium dihydrogen phosphate and disodium hydrogen phosphate to obtain a pH 6.0 PBS buffer; 0.5 parts of low molecular weight sodium hyaluronate (Mw≈20kDa) and 2 parts of panthenol were added to the pH 6.0 PBS buffer, and stirred at room temperature until completely dissolved to obtain a PBS solution of HA / B5;

[0151] S27, vacuum impregnation

[0152] To 0.5 parts of amino-modified double-hole MSNs, 10 parts of the PBS solution of HA / B5 were added, so that the liquid surface completely covered the particles, vacuum was drawn for 30 min at room temperature, and then normal pressure was restored for exhaust cycle, so that the drug solution fully entered the pores; the exhaust cycle was repeated for 3 times, and the total impregnation time was 2 h; the particles were collected by centrifugation, and washed with deionized water for 2 times to obtain HA / B5@MSN wet particles;

[0153] S28, ion plug

[0154] A 0.5% chitosan (Mw≈5kDa, degree of deacetylation≥85%) aqueous solution was prepared, 10 parts, with acetic acid as a cosolvent, pH≈5.5, 1 part of 0.1M sodium sulfate solution was slowly added dropwise under stirring to form a chitosan-sulfate complex colloid; the HA / B5@MSN wet particles were added to the above colloid, and oscillated at 25°C and 100 rpm for 30 min, so that the complex deposited on the 8-10 nm shell pore of the HA / B5@MSN wet particles; centrifugation was performed for collection, and deionized water was used for light washing for 1 time to obtain plug-HA / B5@MSN wet particles;

[0155] S29, hydrophobic tail modification

[0156] The plug-HA / B5@MSN wet particles were dispersed in 10 parts of anhydrous ethanol, 0.075 parts of triethoxysilane (OTES) was added, and the mixture was refluxed at 60°C for 2 h, then centrifuged to collect, washed with ethanol for 2 times, and vacuum dried at 60°C for 6 h to obtain OTES-plug-HA / B5@MSN;

[0157] The average particle size of the OTES-plug-HA / B5@MSN was about 78 nm, and the drug loading capacity HA ≈4.9 wt% , the drug loading capacity B5 ≈16.3 wt% .

[0158] S3, forming a third carrier and loading whitening active ingredients and / or moisturizing active ingredients

[0159] S31, 25 parts of PLGA copolymer (molar ratio of LA:GA=50:50, Mw=24kDa) were dissolved in 100 parts of mixed organic solvent of dichloromethane and ethyl acetate with a volume ratio of 1:1, and magnetic stirring was carried out at room temperature for 30 min to obtain a transparent viscous oil phase (o); 10 parts of purified water were taken, 0.12 parts of mannitol (porogen) and 5 parts of VCE were added, and magnetic stirring was carried out until complete dissolution, and the pH was adjusted to 3.5 to obtain an inner water phase (w1);

[0160] S32, the inner water phase was slowly poured into the oil phase, and the water / oil volume ratio was controlled at 1:10, and immediately emulsified with a high-speed dispersion homogenizer at a speed of 12000 rpm for 2 min to form a white viscous primary emulsion (w1 / o), which was then transferred to an ice bath immediately to keep the temperature at 0-4°C to prevent VCE from being degraded by heat and to reduce the volatilization rate of the organic solvent to avoid premature solidification;

[0161] S33, 800 parts of purified water were taken, 2.4 parts of polyvinyl alcohol (PVA-1788) were added, and stirring was carried out at room temperature until complete dissolution to obtain an outer water phase (w2); the outer water phase was pre-cooled to 10°C, and mechanical stirring was started at a speed of 400 rpm, and the primary emulsion in the ice bath was slowly added dropwise into the outer water phase at a speed of 1 drop / s, and immediately after the addition was completed, the stirring speed was increased to 4000 rpm for 5 min to form a white emulsion of double emulsion (w1 / o / w2);

[0162] S34, the double emulsion was transferred to room temperature magnetic stirring, the stirring speed was reduced to 300 rpm, and the open stirring was carried out for 4 h to volatilize the organic solvent; after the volatilization was completed, the white precipitate was collected by washing with deionized water for 3 times and centrifuging at 3500 rpm for 10 min after each washing to obtain VCE@PLGA microsphere wet cake;

[0163] S35, the VCE@PLGA wet cake was dispersed in a 2% mannitol solution, and the mass / volume ratio of the wet cake to the mannitol solution was 1:3, and vacuum freeze-drying was carried out for 24 h to obtain dry VCE@PLGA;

[0164] Test results show that the average particle size of the VCE@PLGA is about 17 μm, the VCE encapsulation rate is about 72%, and the drug loading capacity is about 15.4 wt% .

[0165] S4, the first carrier, the second carrier and the third carrier after encapsulation were mixed with excipients

[0166] S41, 12 parts of NMN / Arb@Lip were stirred in a 32°C water bath at a speed of 100 rpm, and after a gentle vortex was formed, 4 parts of VCE@PLGA were added in three portions, and stirring was continued for 30 min after each addition to allow the cationic liposome to be adsorbed on the surface of the microspheres by electrostatic attraction to form a liposome-coated PLGA microsphere complex;

[0167] S42, turn off the heating, maintain stirring, add 4 parts of OTES-plug-HA / B5@MSN in five times with 5 min interval each time, so that the MSN is anchored to the surface depression of the liposome-coated PLGA microspheres through hydrogen bonding to form a satellite-large ball complex;

[0168] S43, keep stirring, slowly pour 2 parts of gellan gum pre-gel (0.2% low acyl gellan gum containing 0.1% CaCl2) swollen at 90°C and cooled to 30°C into the barrel, continue to stir for 20 min to form a reversible gel network, and obtain a concentrated hybrid slurry;

[0169] S44, under stirring at 80 rpm, add 5 parts of glycerol, 3 parts of butanediol, and 0.1 part of phenoxyethanol to the concentrated hybrid slurry, respectively, keep stirring for 5 min after adding each raw material, add deionized water to a total weight of 100 parts after mixing, turn on the cooling cycle, reduce the temperature of the liquid to 25°C, slowly adjust the pH to 6.0 with 10% triethanolamine aqueous solution, and filter to obtain the whitening and moisturizing composition.

[0170] Example 2

[0171] This example is based on Example 1, and the only difference from Example 1 is that step S4 is carried out as follows:

[0172] S4, mix the first carrier, the second carrier and the third carrier after loading with excipients

[0173] S41, stir 11 parts of NMN / Arb@Lip in a 30°C water bath at a speed of 100 rpm to form a gentle vortex, then add 5 parts of VCE@PLGA in four times, continue to stir for 30 min after each addition, so that the cationic liposome is adsorbed on the surface of the microsphere through electrostatic attraction to form a liposome-coated PLGA microsphere complex;

[0174] S42, turn off the heating, maintain stirring, add 4 parts of OTES-plug-HA / B5@MSN in five times with 5 min interval each time, so that the MSN is anchored to the surface depression of the liposome-coated PLGA microspheres through hydrogen bonding to form a satellite-large ball complex;

[0175] S43, keep stirring, slowly pour 2 parts of gellan gum pre-gel (0.2% low acyl gellan gum containing 0.1% CaCl2) swollen at 90°C and cooled to 30°C into the barrel, continue to stir for 20 min to form a reversible gel network, and obtain a concentrated hybrid slurry;

[0176] S44, 4 parts of glycerol, 5 parts of butanediol, and 0.3 parts of phenoxyethanol were sequentially added to the concentrated hybrid slurry under stirring at 80 rpm, and stirring was maintained for 5 min after each raw material was added. After mixing, deionized water was added to a total weight of 100 parts, a cooling cycle was started, the temperature of the liquid was reduced to 25°C, and the pH was slowly adjusted to 6.0 with 10% triethanolamine aqueous solution. Filtration was performed to obtain the whitening and moisturizing composition.

[0177] Example 3

[0178] This example is based on Example 1, and the only difference from Example 1 is that step S4 is performed using the following process:

[0179] S4, mixing the encapsulated first carrier, second carrier, and third carrier with excipients

[0180] S41, 14 parts of NMN / Arb@Lip were stirred in a 30°C water bath at a speed of 100 rpm to form a gentle vortex, and 3 parts of VCE@PLGA were added in five portions with continuous stirring for 30 min after each addition. The cationic liposome was adsorbed on the surface of the microspheres by electrostatic attraction to form a liposome-coated PLGA microsphere complex.

[0181] S42, the heating was turned off and stirring was maintained, 5 parts of OTES-plug-HA / B5@MSN were added in four portions with an interval of 5 min, and the MSN was anchored on the surface of the liposome-coated PLGA microspheres through hydrogen bonds to form a satellite-macroball complex.

[0182] S43, maintaining stirring, 2 parts of gellan gum pre-gel (0.2% low acyl gellan gum containing 0.1% CaCl2) swollen at 90°C and cooled to 30°C were slowly poured into the barrel, and the reversible gel network was formed by continuing to stir for 20 min to obtain a concentrated hybrid slurry.

[0183] S44, 4 parts of glycerol, 5 parts of butanediol, and 0.3 parts of phenoxyethanol were sequentially added to the concentrated hybrid slurry under stirring at 80 rpm, and stirring was maintained for 5 min after each raw material was added. After mixing, deionized water was added to a total weight of 100 parts, a cooling cycle was started, the temperature of the liquid was reduced to 25°C, and the pH was slowly adjusted to 6.0 with 10% triethanolamine aqueous solution. Filtration was performed to obtain the whitening and moisturizing composition.

[0184] Comparative Example 1

[0185] This comparative example is based on Example 1, and the only difference from Example 1 is that this comparative example does not add nicotinamide, and an equal amount of a- arbutin is used instead of nicotinamide in step S12.

[0186] Comparative Example 2

[0187] The comparative example is based on Example 1, and the only difference from Example 1 is that in step S4, the three carrier systems are directly mixed with the adjuvants in a "one-pot" method, as follows:

[0188] S4, mixing the first carrier, the second carrier and the third carrier after encapsulation with adjuvants

[0189] 12 parts of the NMN / Arb@Lip were stirred in a 32°C water bath at a speed of 100 rpm to form a gentle vortex, and then 4 parts of VCE@PLGA, 4 parts of OTES-plug-HA / B5@MSN, 2 parts of a gelling agent pre-gel (0.2% low acyl gelling agent containing 0.1% CaCl2) swollen at 90°C and cooled to 30°C, 5 parts of glycerol, 3 parts of butanediol, and 0.5 parts of phenoxyethanol were added at one time. Deionized water was added to make the total weight 100 parts. After mixing, the cooling cycle was started, and the temperature of the material liquid was reduced to 25°C. The pH was slowly adjusted to 6.0 with 10% triethanolamine aqueous solution. Filtration was performed to obtain.

[0190] Comparative Example 3

[0191] The comparative example is based on Example 1, and the only difference from Example 1 is that no liposomes (first carrier) are used for encapsulation, and equal amounts of free nicotinamide and α-arbutin are directly added to the whitening and moisturizing composition according to the content of the active ingredients. That is, step S1 is not performed, and 1.62 parts of free nicotinamide and 0.58 parts of free α-arbutin are directly used to replace the NMN / Arb@Lip in step S41.

[0192] Comparative Example 4

[0193] The comparative example is based on Example 1, and the only difference from Example 1 is that no double-hole MSN (second carrier) is used for encapsulation, and equal amounts of free HA and B5 are directly added to the whitening and moisturizing composition according to the content of the active ingredients. That is, step S2 is not performed, and 0.20 parts of free HA and 0.65 parts of free B5 are directly used to replace the OTES-plug-HA / B5@MSN in step S42.

[0194] Comparative Example 5

[0195] The comparative example is based on Example 1, and the only difference from Example 1 is that no PLAG microspheres (third carrier) are used for encapsulation, and equal amounts of free VCE are directly added to the whitening and moisturizing composition according to the content of the active ingredients. That is, step S3 is not performed, and 0.62 parts of free VCE are directly used to replace the VCE@PLGA in step S41.

[0196] Comparative Example 6

[0197] The comparative example is based on Example 1, and the only difference from Example 1 is that a single-hole MSN with a large pore size is used instead of a double-hole MSN as the second carrier, i.e., the step S22 is not performed during preparation of the composition.

[0198] Comparative Example 7

[0199] The comparative example is based on Example 1, and the only difference from Example 1 is that a single-hole MSN with a small pore size is used instead of a double-hole MSN as the second carrier, i.e., the step S23 is not performed during preparation of the composition.

[0200] Comparative Example 8

[0201] The comparative example is based on Example 1, and the only difference from Example 1 is that OTES-HA / B5@MSN without ion block is used instead of OTES-block-HA / B5@MSN, i.e., the step S28 is not performed during preparation of the composition.

[0202] Comparative Example 9

[0203] The comparative example is based on Example 1, and the only difference from Example 1 is that block-HA / B5@MSN without tail modification is used instead of OTES-block-HA / B5@MSN, i.e., the step S29 is not performed during preparation of the composition.

[0204] Test Example 1: Structural Test

[0205] The NMN / Arb@Lip, OTES-block-HA / B5@MSN, VCE@PLGA, liposome-coated PLGA microsphere complex, and satellite-large ball complex prepared in each step of Example 1 were diluted with deionized water to 0.1 mg / ml, and the Zeta potential of each sample was tested using a laser Doppler electrophoresis instrument. Excess 0.5M NaCl solution was added to the satellite-large ball complex and mixed to shield the static electricity, and the diluted zeta potential was tested as a control group. The results are shown in Table 1.

[0206] Table 1: Zeta potential test results

[0207]

[0208] As can be seen from Table 1, the electrostatic interaction between the carriers in the control group is shielded by the high ion concentration of NaCl, so that there is only simple physical mixing between the three carriers. As can be seen from the results, if there is no electrostatic interaction between the various carriers in the system, the zeta potential tends to exhibit a weighted average, which is significantly different from the zeta potential of the satellite-large ball complex, confirming that there is mutual binding between the three carriers in the satellite-large ball complex.

[0209] The zeta potential of the liposome-coated PLGA microsphere complex is consistent with the zeta potential of NMN / Arb@Lip, rather than the weighted average of the zeta potentials of NMN / Arb@Lip and VCE@PLGA, proving that there is mutual combination between NMN / Arb@Lip and VCE@PLGA, so that the Lip carrier surrounds the surface of the PLGA microsphere, thereby masking the potential of the PLGA microsphere, and the liposome-coated PLGA microsphere complex exhibits the potential of NMN / Arb@Lip;

[0210] At the same time, it can be noted that the amount of NMN / Arb@Lip is three times that of VCE@PLGA, so the Lip carrier should also be partially free in the system in addition to surrounding the surface of the PLGA microsphere, and the zeta potential test results of the satellite-large ball complex also confirm this. After adding OTES-plug-HA / B5@MSN to the liposome-coated PLGA microsphere complex, the zeta potential value is +29.9, which is basically the same as that of NMN / Arb@Lip and the liposome-coated PLGA microsphere complex. +29.9 is neither the weighted average of the liposome-coated PLGA microsphere complex and OTES-plug-HA / B5@MSN, nor close to the zeta potential of OTES-plug-HA / B5@MSN, indicating that at this time the liposome-coated PLGA microsphere complex and the MSN carrier in the system are neither simply physically mixed nor combined with each other with the MSN carrier as the surface, but the Lip carrier is still in the outermost layer. It is proved that after the addition of the MSN carrier, although the Lip carrier on the surface of the liposome-coated PLGA microsphere complex is combined with each other through electrostatic interaction, the free Lip carrier in the system will also cover the surface of the MSN carrier through interaction, i.e., PLGA as the large core, PLGA surrounded by Lip, and MSN surrounded by Lip, forming a hybrid aggregate of "PLGA as the large core-MSN as the satellite-Lip as the outer shell".

[0211] It should be noted that after the addition of the MSN carrier, although the Lip surrounding a single MSN carrier can also make the system exhibit a zeta potential close to that of Lip, the particle size of Lip and MSN is relatively close, and if all the Lip surrounds a single MSN carrier, it will inevitably require much more Lip than MSN to achieve this, so the amount of the combination of the three can determine that there must be a complex structure formed by the mutual combination of most of the PLGA, Lip, and MSN in the system.

[0212] Product physical and chemical property detection of test example 2

[0213] The compositions obtained in Examples 1-3 and Comparative Examples 1-9 were subjected to stability tests according to the general methods of the cosmetic industry, and the test results are recorded in Table 2. Among them, the pH value test was carried out according to the determination of pH value in the "Hygienic Chemical Test Method" of the "Cosmetic Safety Technology Standard" (2024 edition); the heat resistance was tested according to the "Heat Resistance" test method in 5.2.2 of GB / T29665 Emollient Cream (o / w type), i.e. (40±1) ℃ for 24 h, and no separation phenomenon after recovery to room temperature; the cold resistance was tested according to the "Cold Resistance" test method in 5.2.3 of GB / T29665 Emollient Cream (o / w type), i.e. (-8±2) ℃ for 24 h, and no separation phenomenon after recovery to room temperature; the centrifugal test was carried out according to the "Centrifugal Test" test method in 5.2.4 of GB / T29665 Emollient Cream (o / w type), i.e. 2000 r / min, 30 min, no layering; in order to further explore the long-term stability of the composition, the heat resistance and cold resistance were also tested at (40±1) ℃ for 48 h and (-8±2) ℃ for 48 h, respectively, and the results after recovery to room temperature were tested.

[0214] Table 2 Stability test results of the composition

[0215]

[0216] As can be seen from the results in Table 2, the whitening and moisturizing composition prepared in the application examples not only meets the stability standards of heat resistance, cold resistance and centrifugal test in the "Cosmetic Safety Technology Standard", but also still has no separation phenomenon after the high and low temperature holding time is increased from 24 h to 48 h, showing excellent stability; the pH value is weakly acidic, close to the pH value of human skin, and will not cause skin irritation and allergy.

[0217] Comparative Example 2 showed separation phenomenon in the 48 h heat resistance and cold resistance tests, and layering in the centrifugal test, indicating that it is difficult for the "one-pot method" to form a stable reversible network among the three carriers, confirming that the stepwise multiple addition of different carriers in the application improves the stability of the composition; Comparative Examples 3-5 also showed separation phenomenon in the 48 h heat resistance and cold resistance tests, especially Comparative Example 4, which showed separation phenomenon in the 24 h heat resistance test, indicating that the three carriers in the application depend on each other and form a stable reversible three-dimensional network in space through interaction, and the lack of any carrier will cause a significant decrease in heat resistance and cold resistance stability, proving that the three carriers in the application are indispensable.

[0218] Test Example 3 Safety test

[0219] The compositions prepared in Examples 1-3 and Comparative Examples 1-9 were used as the test objects to conduct human skin patch tests to detect the safety of the compositions. Sixty subjects aged 20-50 years were selected as the test objects and were randomly divided into 12 groups, 5 persons in each group. A third-party testing organization was selected to test the safety, and a suitable patch tester with an area of not more than 50 mm 2 , and a depth of about 1 mm was selected to conduct a closed patch test. Equal amounts of the test objects were respectively added into the patch tester, and the patch tester was attached to the flexor of the forearm of the subject. After 24 h, the test objects were removed, and the skin reactions were observed at 0.5 h, 2 h, 12 h and 24 h after removal, respectively. The results were recorded according to the skin reaction grading standard in the Cosmetic Safety Technology Regulations, and the experimental results were recorded in Table 3.

[0220] Skin reaction grading standard:

[0221] 0: negative reaction;

[0222] 1: suspicious reaction; only weak erythema;

[0223] 2: weak positive reaction (erythema reaction); erythema, infiltration, edema, and possibly papules;

[0224] 3: strong positive reaction (vesicle reaction); erythema, infiltration, edema, papules, and vesicles; the reaction can exceed the test area;

[0225] 4: extremely strong reaction (fusion vesicle reaction); obvious erythema, severe infiltration, edema, fusion vesicles, and the reaction exceeds the test area.

[0226] Table 3: Patch test grading results at different times

[0227]

[0228] As can be seen from Table 3, the compositions prepared in Examples 1-3 and Comparative Examples 1-9 have a score of 0 at 0.5 h, 2 h, 12 h and 24 h, and the subjects do not have skin adverse reactions, indicating that the composition of the present application is safe for the skin and does not have negative effects such as irritation.

[0229] Test Example 4: Moisturizing property test

[0230] 30 volunteers were randomly selected, 15 males and 15 females. The volunteers first washed their forearms, then sat in a constant humidity (25°C, RH 43%) environment for 30 minutes, then divided the left and right arms into regions as controls, each region was 3 cm x 3 cm, the same arm could be marked with multiple regions, and the regions were separated by 1 cm. The same amount of 20 mg of the composition samples prepared by Examples 1-3 and Comparative Examples 4, 6-9 were applied to the test sites, and the moisture content of the test sites was tested using a Corneometer CM825 instrument. The experimental data were repeated 5 times, and the average value of each test was recorded. The average skin hydration rate of 30 volunteers at different time intervals of 0.5 h, 1 h, 2 h, 4 h, 8 h, and 12 h was calculated.

[0231] The skin hydration rate was calculated using the following formula, and the average skin hydration rate of 30 volunteers at different time intervals was calculated. The results are shown in Table 4 and Figure 1 .

[0232] The skin hydration rate calculation formula is as follows:

[0233] W% = (W t -W0) / W0 x 100%

[0234] Where W% is the skin hydration rate; W0 is the moisture content of the blank control at the corresponding time; W t is the moisture content at different time points after the skin test sample is applied.

[0235] Table 4 Moisturizing performance test results

[0236]

[0237] As shown in Table 4 and Figure 1 The results show that the skin hydration rate of Examples 1-3 reaches a relatively high value at 0.5 h. With the increase of skin sweat, the Na + ion concentration reaches a threshold value at around 0.5 h, triggering the rapid release of the moisturizing active ingredients from the nuclear pores in the double-pore MSN within 0.5-2 h, and the hydration rate continues to slowly increase, reaching a maximum value at 2 h. Subsequently, the remaining ubiquinol and HA are slowly released from the large pores within 2-12 h, resulting in a plateau in the water content curve at 0.5-8 h. The hydration rate slightly decreases at 12 h, but it is still above 60% in the entire period of 0.5-12 h, confirming that the combination of the two release mechanisms of the shell pores and the nuclear pores achieves 12 h of continuous hydration.

[0238] Comparative Example 4 did not use a second carrier to encapsulate the moisturizing active ingredient, and reached the maximum hydration rate at 0.5 h, and then rapidly decreased with time, and the hydration rate was only 25.2% after 12 h, indicating that the double-hole MSN encapsulating the moisturizing active ingredient significantly improved the sustained moisturizing performance of the composition.

[0239] Comparative Example 6 used a large-pore single-hole MSN instead of a double-hole MSN as the second carrier, and the water content rapidly decreased within 0.5 h to 2 h, and the decrease rate significantly slowed down after 2 h; Comparative Example 7 used a small-pore single-hole MSN instead of a double-hole MSN as the second carrier, and the water content slightly increased within 0.5 h to 2 h, reached a maximum at 2 h, and then rapidly decreased, and the hydration rate was only 33.7% at 12 h. Comparative Examples 6-7 proved that the small-pore core hole rapidly releases the moisturizing active ingredient within 0.5 h to 2 h, which can effectively maintain or even increase the skin water content in the early stage, and the large-pore shell hole tail release can help to prolong the water content plateau, which is beneficial to long-term moisturizing.

[0240] Comparative Example 8 used OTES-HA / B5@MSN without ion plug instead of OTES-plug-HA / B5@MSN, and the water content was basically maintained at a high plateau within 0.5 h to 2 h, and the hydration rate gradually decreased at 2 h to 12 h; Comparative Example 9 used plug-HA / B5@MSN without tail modification instead of OTES-plug-HA / B5@MSN, and the water content gradually increased at 0.5 h to 4 h, and the hydration rate gradually decreased at 4 h to 12 h. Comparative Examples 8-9 showed that the plug and tail modification were beneficial to prolong the release time of the moisturizing active ingredient, thereby prolonging the high water content plateau and achieving the effect of prolonging the moisturizing time.

[0241] The above moisturizing performance test confirmed that the double-hole MSN as the second carrier, the synergistic effect of the four structures of large shell hole, small core hole, plug, and tail modification, achieved high moisturizing rate and long-term moisturizing within 0.5 h to 12 h.

[0242] Test Example 5 Whitening Performance Test

[0243] The content of melanin in the skin is determined by measuring the amount of light of a specific wavelength reflected after irradiation on the human skin, and the rate of change of melanin is used to characterize the whitening effect. The emitter of the probe emits light of three wavelengths of 568 nm, 660 nm, and 880 nm, respectively, to irradiate the skin surface, the receiver measures the reflected light of the skin, and the amount of light absorbed by the skin is determined, so that the rate of change of the skin melanin can be obtained. The test of the rate of change of skin melanin is carried out by using the pigment detector of CK Company in Germany. The measurement range of the probe is 0-999, and the higher the measurement value, the higher the content of melanin in the skin. The number of subjects is 120, which are randomly divided into 8 groups, 10 people in each group, and the whitening performance test of the compositions prepared in Examples 1-3 and Comparative Examples 1-9 is carried out. The test period is 4 weeks, and the test sample is applied to the same area on the inner side of the forearm every day, and the amount of light reflected after irradiation of the test area of the subject at a specific wavelength before the experiment and after 28 days of use is measured to determine the content of melanin in the skin, each sample area is measured 5 times to take the average value, and then the rate of change of melanin is calculated according to the following formula, and the average value is recorded in Table 5.

[0244] The formula for calculating the rate of change of melanin is as follows:

[0245] M% = (M1-M0) / M0x100%

[0246] Wherein, the rate of change of melanin; M0 is the melanin content of the skin before using the test sample; M1 is the melanin content of the skin after using the test sample for 28 days.

[0247] Table 5 Test results of the rate of change of melanin

[0248]

[0249] As can be seen from Table 5, the compositions of Examples 1-3 have achieved significant whitening effect after 28 days of continuous use, and the melanin reduction rate is more than 16%, which shows that the three carriers used in the application are used to load different active ingredients respectively, and the release is interdependent and orderly in time and space, which has a synergistic effect on skin whitening.

[0250] Comparative Example 1 uses an equal amount of α-arbutin instead of nicotinamide, and the total amount of whitening ingredients is basically the same, but the whitening effect is significantly worse, which confirms that the use of multiple whitening ingredients in the application has a synergistic effect, and the synthesis and transport of melanin are inhibited in all directions and all pathways, which has an unexpected technical effect on the improvement of whitening effect.

[0251] Comparative Example 2 directly mixed the three carrier systems with the adjuvants in one pot, and the whitening effect was also obviously weakened compared with Example 1, proving that one-pot method is not conducive to the three carriers to form a stable reversible network in space through various interactions, and the instability of the system leads to the release and effect of the active ingredients, which has an adverse effect, proving that the step S4 of the present application of adding the three carriers step by step and in batches has a beneficial effect on the whitening effect of the composition.

[0252] Comparative Example 3 does not use liposomes (first carrier) for encapsulation, Comparative Example 4 does not use the second carrier for encapsulation of the moisturizing active ingredient, Comparative Example 4 does not use double-hole MSN (second carrier) for encapsulation, and Comparative Example 5 does not use PLAG microspheres (third carrier) for encapsulation. The whitening effect is obviously weakened compared with Example 1, which shows that the three carriers of the present application depend on each other, form a stable reversible three-dimensional network in space through interaction, and realize good whitening effect through the ordered release of active ingredients at different times and different rates. The lack of any carrier will lead to a significant decrease in its whitening effect, proving that the three carriers of the present application are indispensable.

[0253] Comparative Example 6 uses large-pore single-hole MSN instead of double-hole MSN as the second carrier, Comparative Example 7 uses small-pore single-hole MSN instead of double-hole MSN as the second carrier, Comparative Example 8 uses OTES-HA / B5@MSN without ion plug instead of OTES-plug-HA / B5@MSN, and Comparative Example 9 uses plug-HA / B5@MSN without tail modification instead of OTES-plug-HA / B5@MSN. Comparative Examples 6-9 differ from Example 1 in that the structure of the second carrier is different, and the main effect difference should theoretically also be reflected in the efficacy of the moisturizing active ingredient encapsulated by the second carrier, i.e., in the moisturizing effect. However, the above whitening efficacy test results prove that Comparative Examples 6-9 not only have a decrease in moisturizing performance, but also have a decrease in whitening effect to varying degrees. This again proves that the three carriers of the present application depend on each other, form a stable reversible three-dimensional network in space through interaction, and realize ordered release of active ingredients at different times and different rates. Changes in the carriers will change the three-dimensional spatial network of the composition of the present application to a certain extent, thereby adversely affecting the whitening and moisturizing effect through stability, release time and release rate.

[0254] Test Example 6 Irritation Test

[0255] The compositions prepared in Examples 1-3 and Comparative Examples 1-9 were sampled respectively, and tested according to the test method of SN / T 2329-2009 "Chicken embryo chorioallantoic membrane blood vessel test for eye irritation of cosmetics", and the results are shown in Table 6.

[0256] Table 6 Results of Irritation Test

[0257]

[0258] From Table 6, it can be seen that the NC values of Examples 1-3 and Comparative Examples 1-9 are all at a low level, indicating that the compositions prepared by Examples 1-3 and Comparative Examples 1-9 are all substantially non-irritating, especially Examples 1-3, with NC values as low as 0.3-0.4, which are very mild and can be applied to sensitive skin for whitening and moisturizing needs.

[0259] The above detailed description of the specific embodiments, the purpose, technical solutions and beneficial effects of the present application are further described in detail, and it should be understood that the above description is only a specific embodiment of the present application and is not used to limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A whitening moisturizing composition characterized in that: Comprise: (i) at least one whitening active ingredient; (ii) at least one moisturizing active ingredient; (iii) a multi-level carrier system, the multi-level carrier system comprising: a first carrier for encapsulating and releasing the whitening active ingredient, a second carrier for encapsulating and releasing the moisturizing active ingredient, a third carrier for encapsulating and releasing the whitening active ingredient and / or the moisturizing active ingredient; wherein the first carrier is a liposome, the second carrier is mesoporous silica, and the third carrier is a PLGA microsphere; the first carrier, the second carrier and the third carrier release the encapsulated active ingredients at different time stages, respectively; the first carrier releases the encapsulated active ingredient within 0-0.5h; the second carrier releases the encapsulated active ingredient within 0.5-12h; and the third carrier releases the encapsulated active ingredient within 2-12h; the composition forms a hybrid aggregate with "PLGA as the large core-MSN as the satellite-Lip as the shell".

2. The composition of claim 1, wherein: The mesoporous silica is a dual-pore MSN containing 2-4nm core pores and 8-10nm shell pores.

3. The composition according to claim 1 or 2, characterized in that: The whitening active ingredient includes one or more of niacinamide, arbutin, glabridin, rhodiola extract, resveratrol, kojic acid, mandelic acid, vitamin C and derivatives thereof.

4. The composition according to claim 1 or 2, characterized in that: The moisturizing active ingredient includes one or more of sodium hyaluronate, panthenol, glycerol, amino acid mixture, and ectoin.

5. A process for the preparation of a whitening moisturizing composition as claimed in any one of claims 1 to 4, characterized in that: The steps include: S1, forming a first carrier and encapsulating a whitening active ingredient; S2, forming a second carrier and encapsulating a moisturizing active ingredient; S3, forming a third carrier and encapsulating a whitening active ingredient and / or a moisturizing active ingredient; S4, mixing the encapsulated first carrier, second carrier and third carrier with excipients to obtain a synergistic composition that releases the encapsulated active ingredients at different time stages, respectively.

6. The method of claim 5, wherein: The step S2 specifically includes: S21, core liquid and shell liquid preparation: mixing template agent A with alkali solution to obtain A core liquid, and mixing template agent B with acid solution to obtain B shell liquid; S22, low-temperature nucleation: quickly adding a portion of tetraethyl orthosilicate (TEOS) to the A core liquid under water bath stirring, centrifuging and washing after reaction to obtain primary core particles; S23, shell growth at elevated temperature: dispersing the primary core particles in the B shell liquid, heating, and adding the remaining portion of TEOS dropwise, continuing to react until the solution shows obvious Tyndall effect, centrifuging and washing to obtain primary core-shell silica; S24, template removal: drying, calcining and cooling the primary core-shell silica to obtain dual-pore MSN; S25, amino modification: dispersing the dual-pore MSN in an organic solvent, adding amino silane after heating and stirring activation, continuing to stir, high-speed centrifuging, washing, and vacuum drying to obtain amino-modified dual-pore MSN; S26, preparation of a moisturizing active solution: adding a moisturizing active ingredient to PBS buffer solution, stirring and dissolving to obtain a PBS solution of the moisturizing active ingredient; S27, vacuum impregnation: the PBS solution is added to the amino-modified dual-hole MSNs, the liquid surface completely covers the particles, vacuum is drawn at room temperature, then normal pressure is restored to carry out the pumping and discharging cycle, and the liquid is fully introduced into the pores; the pumping and discharging cycle is repeated for 3-5 times, centrifugation is carried out, and washing is performed to obtain the MSN wet particles loaded with the moisturizing active ingredient; S28, ion plug: the sodium sulfate solution is slowly added dropwise into the chitosan solution under stirring to form a chitosan-sulfate complex colloid; the MSN wet particles loaded with the moisturizing active ingredient are added into the above-mentioned colloid, and oscillation is performed to make the complex deposit on the shell pore of the MSN wet particles; centrifugation is performed, and washing is performed to obtain the plug-MSN wet particles loaded with the moisturizing active ingredient; S29, hydrophobic tail modification: the plug-MSN wet particles loaded with the moisturizing active ingredient are dispersed in an organic solvent, OTES is added, and reflux reaction is performed, followed by centrifugation and washing, and vacuum drying to obtain the hydrophobic tail modification-MSN wet particles loaded with the moisturizing active ingredient.

7. The method of claim 5, wherein: The step S3 specifically comprises: S31, the PLGA copolymer is dissolved in an organic solvent to obtain a transparent viscous oil phase, and the porogen, whitening active ingredient and / or moisturizing active ingredient are added into water to be dissolved under stirring to obtain an inner water phase; S32, the inner water phase is slowly poured into the oil phase, and emulsification is immediately performed by using a high-speed dispersion homogenizer to form a white viscous primary emulsion, which is immediately transferred to an ice bath; S33, purified water is added into polyvinyl alcohol to be dissolved under stirring at room temperature to obtain an outer water phase; the outer water phase is pre-cooled, mechanical stirring is started, and the primary emulsion in the ice bath is slowly added dropwise into the outer water phase; after the dropwise addition is completed, the stirring speed is immediately increased to form a white emulsion of double emulsion; S34, the double emulsion is transferred to room temperature magnetic stirring, and the organic solvent is volatilized under open stirring; after the volatilization is completed, washing is performed with deionized water, and the white precipitate is collected after each washing to obtain a microsphere wet cake; S35, the microsphere wet cake is dispersed in a mannitol solution, and vacuum freeze-drying is performed.

8. The method of any one of claims 5-7, wherein: The step S4 specifically comprises: S41, the first carrier after loading is stirred in a water bath to form a gentle vortex, and the third carrier after loading is added in portions while the stirring is continuously performed; S42, the heating is turned off, the stirring is maintained, and the second carrier after loading is added in portions with an interval of 5-10 min each time; S43, the stirring is maintained, the pre-swollen and cooled gellan gum pre-gel is slowly poured into the barrel, and the stirring is continuously performed to form a reversible gel network to obtain a concentrated hybrid slurry; S44, the base material is added into the concentrated hybrid slurry under stirring, the cooling cycle is started, the temperature of the liquid is reduced to 25℃, the pH is adjusted to 6.0, and filtration is performed to obtain the whitening and moisturizing composition.

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