Macromolecular nicotinamide composite composition as well as preparation method and application thereof

Abstract

The invention relates to the field of cosmetics, in particular to a macromolecular nicotinamide composite composition as well as a preparation method and application thereof, and solves the problems that in an existing sustained-release system, lipidosome serves as a carrier of nicotinamide, existing composite vesicles are low in mechanical strength under the action of external force, the external force easily causes burst release of nicotinamide due to vesicle breakage, and the nicotinamide is hard to release. The problems that in the prior art, nicotinamide release is unstable, and sensitive skin is damaged are solved, an active composite component and a loading medium are included, and the loading medium is composed of nano-porous particles and a polysaccharide coating wrapping the nano-porous particles, the active composite component is composed of a plant extract, liposome, nicotinamide, ascorbyl glucoside, selenium dioxide and a macromolecular compound, and the nano porous particle is subjected to PEG modification. The nicotinamide sustained-release mask can realize long-term sustained release of nicotinamide, cannot cause sudden release of nicotinamide due to external environment and stress, and is suitable for sensitive skin.

Description

Technical Field

[0001] The present invention relates to the technical field of cosmetics, and in particular to a macromolecular nicotinamide composite composition, a preparation method and an application thereof. Background Art

[0002] Niacinamide (NA) is an antioxidant and the amide form of vitamin B3. It is easily soluble in water and is often used as a whitening ingredient in cosmetics. It has moisturizing properties and can inhibit the transfer of melanosomes from melanocytes to surrounding keratinocytes. It has few side effects. NA is highly water-soluble and extremely hydrophilic. In order to stabilize the effective performance and penetration performance of this core ingredient, niacinamide is usually combined with other molecular components to form a synergistic formula, which can effectively reduce the irritation caused by this substance to the skin.

[0003] Existing studies have used lipid carriers composed of phospholipids and ethanol to effectively improve the stability and skin permeability of niacinamide and provide it with a sustained-release effect. Compared with free niacinamide, it has unparalleled advantages in stability and sustained efficacy. However, the use of lipid-based vesicles to encapsulate niacinamide can lead to unstable release due to the influence of the external environment. For example, under the action of external forces, friction on the skin can cause the vesicles to rupture, causing a sudden release of niacinamide, resulting in local skin sensitivity and difficulty in accurately and continuously releasing the active ingredient. For example, the nanocarrier used in patent document CN118615186A, which contains emulsifiers, polyols, phospholipids, and water, can achieve long-term retention but can be affected by external friction, resulting in a burst release on the target tissue surface. High concentrations of niacinamide can cause local irritation to the skin, and trace amounts of niacin in this burst release can affect and irritate the dermis of sensitive skin, making some people intolerant to this type of niacinamide composition.

[0004] However, materials such as silicon dioxide and zinc oxide used in existing solid carriers are only added in small amounts to reflect and scatter ultraviolet rays, and are unable to form an effective load for ingredients such as niacinamide and produce a sustained-release effect. Summary of the Invention

[0005] In order to solve the problem that liposomes are used as carriers of nicotinamide in existing sustained-release systems, the mechanical strength of the existing composite vesicles is low when subjected to external forces, and the external forces easily cause the vesicles to rupture, resulting in a sudden release of nicotinamide, making the release of nicotinamide unstable and causing damage to sensitive skin, the present invention provides a macromolecular nicotinamide composite composition, a preparation method and application thereof, and the technical solutions adopted by the present invention are as follows: In a first aspect, the present application provides a macromolecular nicotinamide composite composition, comprising an active composite component and a loading medium, wherein the loading medium is composed of nanoporous particles and an externally coated polysaccharide coating; The active compound component is composed of 5-15 parts by weight of a plant extract, 20-30 parts of liposomes, 10-20 parts of nicotinamide, 5-10 parts of ascorbyl glucoside, 1-2 parts of selenium dioxide, and 10-20 parts of a macromolecular complex, and the solvent is 40 parts by weight of deionized water; The nanoporous particles are obtained by cross-linking 50-80 parts of chitosan, 10-30 parts of γ-polyglutamic acid, and 20-50 parts of calcium acetate, and the nanoporous particles are PEG-modified; The polysaccharide coating is pullulan polysaccharide coating, and the weight gain ratio of the polysaccharide coating is 10-15%.

[0006] By using nanoporous particles as the main body for loading the niacinamide active ingredient, the present application has higher mechanical strength and chemical stability than pure liposome bilayers, greatly reducing the risk of particle aggregation and fusion, and thus having better resistance to external environmental influences during storage. Moreover, the internal porous channels of the nanoporous particles can load the active ingredient through physical adsorption, electrostatic effects, etc., which has a stronger release control effect than liposome aqueous encapsulation, and can achieve a smoother and more sustained release. The presence of the nanoporous particles can withstand most external pressure and friction, avoiding the problem of pure liposomes being subjected to external pressure and thus releasing suddenly.

[0007] Before loading, the present application also introduces long polyethylene glycol chains onto the surface of the nanoporous particles, which not only significantly reduces nonspecific aggregation between particles and improves stability, but also facilitates the outward release of the hydrophilic nicotinamide component. The presence of PEG reduces the hydrophobic interaction between nicotinamide and the inner wall of the microspheres, which can significantly increase the release rate of nicotinamide.

[0008] The present application also coats the surface of the nanoporous particles loaded with niacinamide with a pullulan coating. Because the nanoporous particles modified with PEG have a better release efficiency, the liposomes and niacinamide will be lost during storage. Pullulan has good film-forming properties and stability, can regulate the release of niacinamide, helps to prolong the action time of niacinamide on the skin, and has good biocompatibility, which promotes the penetration and absorption of niacinamide.

[0009] Preferably, the macromolecular complex is one or a combination of two or more of hyaluronic acid, quercetin glycoside, tannic acid, sucrose stearate, and octyldodecanol lauroyl glutamate.

[0010] The combination of the macromolecular complex and the nanocarrier of the present application can form a better hydration network through the action of charges, thereby prolonging the residence time on the skin surface.

[0011] Preferably, the plant extract is one of flower extract, leaf extract, plant callus extract or plant yeast fermentation lysate filtrate, and the type of the plant extract is one of honeysuckle extract, alpine edelweiss extract, chamomile extract, rose extract, peach blossom extract or a combination of two or more thereof.

[0012] Plant extracts can synergistically enhance and soothe skin's sensitivity, and can complement the nanoporous particles. The pullulan coating on them can block oxygen oxidation after extending in the solution, significantly enhancing the activity of the active ingredients therein.

[0013] Among them, the alpine edelweiss extract is rich in active ingredients such as edelweiss acid, chlorogenic acid, elissa acid and phytosterols, which can effectively scavenge free radicals, protect DNA, reduce damage caused by strong light, and effectively inhibit the production of melanin, reduce post-inflammatory pigmentation, and inhibit the release of IL-8, IL-6, and TNF-α inflammatory factors, thereby reducing the stimulation of inflammatory acne.

[0014] The above-mentioned plant extracts are mainly extracted from the flowers, leaves and roots of the whole plant through physical or chemical methods, thereby retaining the original components of the plant and not changing its structure. The plant callus extract is derived from the amorphous cells formed under in vitro culture of plant cells and produces special active ingredients under extreme environments; and the plant yeast fermentation lysate filtrate is obtained by filtering the metabolites produced by the co-fermentation of plant raw materials and yeast, which contains amino acids and peptides, converting complex compounds that are difficult to absorb into small molecules.

[0015] Another object of the present application is to provide a method for preparing a macromolecular nicotinamide composite composition, the specific preparation steps of which are as follows: S1. First, PEG is prepared into a solution, and then the nanoporous particles are placed in the PEG solution and stirred for homogenization. After standing for adsorption, solid particles are filtered out, and the solid particles are washed and dried to obtain PEG-modified nanoparticles; S2. The liposomes are prepared into a suspension, and nicotinamide is placed in the liposome suspension, and the suspension is shaken in a water bath to obtain a liposome-nicotinamide complex solution. The PEG-modified nanoparticles obtained in step S1 are added to the liposome-nicotinamide complex solution for loading, and then centrifuged to obtain loaded particles. The loaded particles are dried, and an aqueous solution of pullulan is prepared and sodium tripolyphosphate is added. After adjusting the pH value, the aqueous solution of pullulan is spray-dried to form a pullulan coating on the outside of the loaded particles. S3. Homogeneously combine the plant extract, ascorbyl glucoside, selenium dioxide and the macromolecular complex in deionized water, and add thereto loaded particles coated with pullulan to obtain a macromolecular nicotinamide composition.

[0016] The nanoporous particles used in this application are hydrophobic. Therefore, in order to better disperse in the liquid in the subsequent process and be able to load a sufficient amount of active substance, liposomes are used to form a stable dispersed mixture with nicotinamide during the preparation process, and then loaded into the nanoporous particles, thereby facilitating the entry of nicotinamide into the interior of the nanoporous particles.

[0017] Preferably, the specific steps for preparing the nanoporous particles in step S1 are as follows: Chitosan is placed in an aqueous solution of glacial acetic acid to obtain a chitosan dispersion, γ-polyglutamic acid is placed in water to obtain a γ-polyglutamic acid dispersion, calcium acetate is weighed and placed in the chitosan dispersion, and the γ-polyglutamic acid dispersion is then added dropwise to the chitosan dispersion to react to form colloidal particles, which are freeze-dried and then heat-treated, cooled to room temperature, acid-washed and washed with water, and dried to obtain a nanoporous material; The heat treatment temperature is 600-800°C and the heat treatment time is 3-5h.

[0018] Preferably, the molecular weight of PEG used for PEG modification in step S1 is 200-2000, the concentration of the PEG solution is 1-10 wt %, and the static adsorption time is 4-8 h.

[0019] Preferably, the specific steps for preparing the liposomes in step S2 are as follows: Oleic acid and sodium hydroxide are reacted in deionized water at a molar ratio of 1:1 to obtain an aqueous solution of sodium oleate, wherein the concentration of sodium oleate in deionized water is 5 mg / mL. Carboxymethyl cellulose powder is then placed in deionized water to prepare an aqueous solution of carboxymethyl cellulose with a concentration of 5 mg / mL. The aqueous solution of sodium oleate and the aqueous solution of carboxymethyl cellulose are then mixed at a volume ratio of 1:1, the pH is adjusted to 6.0-7.5, and the mixture is shaken for 24 hours to obtain a liposome suspension.

[0020] Preferably, the vacuum degree of the load in step S2 is -0.1 MPa, the loading time is 30 min, the centrifugal speed is 3000-5000 rpm, the centrifugal time is 10 min, and the concentration of the pullulan is 2 w / v%.

[0021] Preferably, the amount of sodium tripolyphosphate added in step S2 is 0.5 w / v%, and the pH value is adjusted to 5.5-6.0 after addition.

[0022] The macromolecular nicotinamide composite composition provided in the present application can be used in facial masks, shampoos, conditioners and creams, and can achieve a long-term sustained-release effect. The presence of the pullulan polysaccharide coating can also enable the active ingredients to exist for a long time.

[0023] The beneficial effects of the present invention are: Nanoporous particles are used as carriers for niacinamide. The high mechanical strength of the nanoporous particles can resist external pressure and avoid the sudden release of niacinamide, so that people with sensitive skin can also use it without allergic reactions due to the external environment. The nanoporous particles are modified with PEG to improve the release efficiency of niacinamide, and the presence of pullulan coating can also prevent the release rate of niacinamide from being too fast, thereby extending the duration of niacinamide's action. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is a comparative line graph of the 24h release rate and the release rate under 30kPa pressure of the embodiment of the present invention and the comparative example. DETAILED DESCRIPTION

[0025] The following will refer to the attached Figure 1 The embodiments of the present invention are described in detail. It should be understood by those skilled in the art that these embodiments are only used to explain the technical principles of the present invention and are not intended to limit the scope of protection of the present invention.

[0026] Example 1 - Preparation of a macromolecular nicotinamide composite composition S1. Add 60 parts by weight of chitosan to 1% glacial acetic acid solution and stir magnetically for 2 hours to obtain a chitosan dispersion with a concentration of 5wt%. Weigh 20 parts of γ-polyglutamic acid and disperse them in deionized water. Stir in a water bath at 40°C for 1 hour to obtain a γ-polyglutamic acid dispersion with a concentration of 3wt%. Add 30 parts of calcium acetate to the chitosan dispersion. Add the γ-polyglutamic acid dispersion dropwise to the chitosan dispersion at a rate of 10 mL / min until colloidal particles are formed. After freeze-drying, the dried colloidal particles are placed in a heat treatment furnace and heated to 700°C for heat treatment for 4 hours to obtain porous particles. The porous particles are then washed with 0.1M HCl acid solution, washed with deionized water until neutral, and dried with hot air to obtain nanoporous particles.

[0027] PEG with a molecular weight of 1000 was prepared into a 5 wt% aqueous solution, and nanoporous particles were added at a solid-liquid ratio of 1:10. The solution was homogenized at 40°C, allowed to stand for 6 hours, filtered, washed with deionized water, and vacuum dried to obtain PEG-modified nanoparticles.

[0028] S2, oleic acid and sodium hydroxide were added to deionized water in a molar ratio of 1:1, and the mixture was reacted at 70°C for 2 h to obtain a sodium oleate solution with a concentration of 5 mg / mL, and carboxymethyl cellulose powder was prepared into an aqueous solution with a concentration of 5 mg / mL, and then the sodium oleate solution and the aqueous solution of carboxymethyl cellulose were mixed in a volume ratio of 1:1, and the pH of the mixed solution was adjusted to 7.0 with 0.1 M HCl, and the mixture was shaken at room temperature for 24 h to obtain a liposome suspension; 15 parts of nicotinamide were added to the liposome suspension, and the suspension was shaken in a water bath at 40°C for 1 hour to obtain a liposome-nicotinamide complex solution. The PEG-modified nanoparticles prepared in S1 were added to the liposome-nicotinamide complex solution at a solid-liquid ratio of 1:5. The suspension was then vacuum loaded at a vacuum degree of -0.1 MPa for 30 minutes. Nitrogen was then introduced to break the vacuum, and the suspension was centrifuged at a speed of 3000 rpm for 10 minutes. The suspension was then washed with deionized water and dried to obtain loaded particles. A 2% w / v pullulan aqueous solution was prepared, and then 0.5% w / v sodium tripolyphosphate was added. The pH was adjusted to 5.8 using citric acid, and the loaded particles were placed on a fluidized bed. The loaded particles were coated using a spray drying method until the loaded particles gained 12% in weight to obtain a loaded medium.

[0029] S3. 3 parts of honeysuckle extract, 5 parts of alpine edelweiss extract, and 2 parts of chamomile extract are subjected to supercritical CO2 extraction at a pressure of 30 MPa and a temperature of 40°C. The extracts are then mixed with 5 parts of hyaluronic acid, 5 parts of quercetin glycosides, 5 parts of sucrose stearate, 8 parts of ascorbyl glucoside, and 1.5 parts of selenium dioxide, and the mixture is placed in 40 parts of deionized water for homogenization. The loading medium in step S2 is then added and homogenization is continued to obtain a macromolecular niacinamide composite composition.

[0030] Example 2 - Preparation of macromolecular nicotinamide composite composition S1. Add 50 parts by weight of chitosan to 1% glacial acetic acid solution and stir magnetically for 2 hours to obtain a chitosan dispersion with a concentration of 5wt%. Weigh 10 parts of γ-polyglutamic acid and disperse them in deionized water. Stir in a water bath at 40°C for 1 hour to obtain a γ-polyglutamic acid dispersion with a concentration of 3wt%. Add 20 parts of calcium acetate to the chitosan dispersion. Add the γ-polyglutamic acid dispersion dropwise to the chitosan dispersion at a rate of 10 mL / min until colloidal particles are formed. After freeze-drying, the dried colloidal particles are placed in a heat treatment furnace and heated to 600°C for heat treatment for 5 hours to obtain porous particles. The porous particles are then washed with 0.1M HCl acid solution, washed with deionized water until neutral, and dried with hot air to obtain nanoporous particles.

[0031] PEG with a molecular weight of 200 was prepared into a 1 wt% aqueous solution, and nanoporous particles were added at a solid-liquid ratio of 1:10. The solution was homogenized at 40°C, allowed to stand for 4 hours, and then filtered. The solution was washed with deionized water and vacuum dried to obtain PEG-modified nanoparticles.

[0032] S2, oleic acid and sodium hydroxide were added to deionized water in a molar ratio of 1:1, and the mixture was reacted at 70°C for 2 h to obtain a sodium oleate solution with a concentration of 5 mg / mL, and carboxymethyl cellulose powder was prepared into an aqueous solution with a concentration of 5 mg / mL, and then the sodium oleate solution and the aqueous solution of carboxymethyl cellulose were mixed in a volume ratio of 1:1, and the pH of the mixed solution was adjusted to 6.0 with 0.1 M HCl, and the mixture was shaken at room temperature for 24 h to obtain a liposome suspension; 10 parts of nicotinamide were added to the liposome suspension, and the suspension was shaken in a water bath at 40°C for 1 hour to obtain a liposome-nicotinamide complex solution. The PEG-modified nanoparticles prepared in S1 were added to the liposome-nicotinamide complex solution at a solid-liquid ratio of 1:5. The suspension was then vacuum loaded at a vacuum degree of -0.1 MPa for 30 minutes. Nitrogen was then introduced to break the vacuum, and the suspension was centrifuged at a speed of 3000 rpm for 10 minutes. The suspension was then washed with deionized water and dried to obtain loaded particles. A 2% w / v pullulan aqueous solution was prepared, and then 0.5% w / v sodium tripolyphosphate was added. The pH was adjusted to 5.5 using citric acid, and the loaded particles were placed on a fluidized bed. The loaded particles were coated using a spray drying method until the loaded particles gained 10% in weight to obtain a loaded medium.

[0033] S3. 2 parts of Leontopodium alpinum extract and 3 parts of rose extract are subjected to supercritical CO2 extraction at a pressure of 30 MPa and a temperature of 40°C. The extracts are then mixed with 5 parts of hyaluronic acid, 5 parts of octyldodecanol lauroyl glutamate, 5 parts of ascorbyl glucoside, and 1 part of selenium dioxide, placed in 40 parts of deionized water, and homogenized. The loading medium in step S2 is then added and homogenization is continued to obtain a macromolecular niacinamide composite composition.

[0034] Example 3 - Preparation of macromolecular nicotinamide composite composition S1. Add 80 parts by weight of chitosan to 1% glacial acetic acid solution and stir magnetically for 2 hours to obtain a chitosan dispersion with a concentration of 5wt%. Weigh 30 parts of γ-polyglutamic acid and disperse them in deionized water. Stir in a water bath at 40°C for 1 hour to obtain a γ-polyglutamic acid dispersion with a concentration of 3wt%. Add 50 parts of calcium acetate to the chitosan dispersion. Add the γ-polyglutamic acid dispersion dropwise to the chitosan dispersion at a rate of 10 mL / min until colloidal particles are formed. After freeze-drying, the dried colloidal particles are placed in a heat treatment furnace and heated to 800°C for heat treatment for 3 hours to obtain porous particles. The porous particles are then washed with 0.1M HCl acid solution, washed with deionized water until neutral, and dried with hot air to obtain nanoporous particles.

[0035] PEG with a molecular weight of 2000 was prepared into a 10 wt% aqueous solution, and nanoporous particles were added at a solid-liquid ratio of 1:10. The solution was homogenized at 40°C, allowed to stand for 8 hours, filtered, washed with deionized water, and vacuum dried to obtain PEG-modified nanoparticles.

[0036] S2, oleic acid and sodium hydroxide were added to deionized water in a molar ratio of 1:1, and the mixture was reacted at 70°C for 2 h to obtain a sodium oleate solution with a concentration of 5 mg / mL, and carboxymethyl cellulose powder was prepared into an aqueous solution with a concentration of 5 mg / mL, and then the sodium oleate solution and the aqueous solution of carboxymethyl cellulose were mixed in a volume ratio of 1:1, and the pH of the mixed solution was adjusted to 7.5 with 0.1 M HCl, and the mixture was shaken at room temperature for 24 h to obtain a liposome suspension; 20 parts of nicotinamide were added to the liposome suspension, and the suspension was shaken in a water bath at 40°C for 1 hour to obtain a liposome-nicotinamide complex solution. The PEG-modified nanoparticles prepared in S1 were added to the liposome-nicotinamide complex solution at a solid-liquid ratio of 1:5. The suspension was then vacuum loaded at a vacuum degree of -0.1 MPa for 30 minutes. Nitrogen was then introduced to break the vacuum, and the suspension was centrifuged at a speed of 3000 rpm for 10 minutes. The suspension was then washed with deionized water and dried to obtain loaded particles. A 2% w / v pullulan aqueous solution was prepared, and then 0.5% w / v sodium tripolyphosphate was added. The pH was adjusted to 6.0 using citric acid, and the loaded particles were placed on a fluidized bed. The loaded particles were coated using a spray drying method until the loaded particles gained 15% in weight to obtain a loaded medium.

[0037] S3. 10 parts of Leontopodium alpinum extract and 5 parts of peach blossom extract are subjected to supercritical CO2 extraction at a pressure of 30 MPa and a temperature of 40°C. The mixture is then mixed with 20 parts of a macromolecular complex, 10 parts of ascorbyl glucoside, and 2 parts of selenium dioxide, placed in 40 parts of deionized water, and homogenized. The loading medium in step S2 is then added and homogenization is continued to obtain a macromolecular nicotinamide composite composition.

[0038] The plant extracts used in the above examples are obtained by mixing flower extracts, leaf extracts, plant callus extracts or plant yeast fermentation lysate filtrates in a ratio of 1:1:0.5:5.

[0039] Comparative Example 1—Nanoporous particles not modified with PEG S1. Add 60 parts by weight of chitosan to 1% glacial acetic acid solution and stir magnetically for 2 hours to obtain a chitosan dispersion with a concentration of 5wt%. Weigh 20 parts of γ-polyglutamic acid and disperse them in deionized water. Stir in a water bath at 40°C for 1 hour to obtain a γ-polyglutamic acid dispersion with a concentration of 3wt%. Add 30 parts of calcium acetate to the chitosan dispersion. Add the γ-polyglutamic acid dispersion dropwise to the chitosan dispersion at a rate of 10 mL / min until colloidal particles are formed. After freeze-drying, the dried colloidal particles are placed in a heat treatment furnace and heated to 700°C for heat treatment for 4 hours to obtain porous particles. The porous particles are then washed with 0.1M HCl acid solution, washed with deionized water until neutral, and dried with hot air to obtain nanoporous particles.

[0040] S2, oleic acid and sodium hydroxide were added to deionized water in a molar ratio of 1:1, and the mixture was reacted at 70°C for 2 h to obtain a sodium oleate solution with a concentration of 5 mg / mL, and carboxymethyl cellulose powder was prepared into an aqueous solution with a concentration of 5 mg / mL, and then the sodium oleate solution and the aqueous solution of carboxymethyl cellulose were mixed in a volume ratio of 1:1, and the pH of the mixed solution was adjusted to 7.0 with 0.1 M HCl, and the mixture was shaken at room temperature for 24 h to obtain a liposome suspension; 15 parts of nicotinamide were added to the liposome suspension, and the suspension was shaken in a water bath at 40°C for 1 hour to obtain a liposome-nicotinamide composite solution. The nanoporous particles prepared in S1 were added to the liposome-nicotinamide composite solution at a solid-liquid ratio of 1:5. The suspension was then vacuum loaded at a vacuum degree of -0.1 MPa for 30 minutes. Nitrogen was then introduced to break the vacuum, and the suspension was centrifuged at a speed of 3000 rpm for 10 minutes. The suspension was then washed with deionized water and dried to obtain loaded particles. A 2% w / v pullulan aqueous solution was prepared, and then 0.5% w / v sodium tripolyphosphate was added. The pH was adjusted to 5.8 using citric acid, and the loaded particles were placed on a fluidized bed. The loaded particles were coated using a spray drying method until the loaded particles gained 12% in weight to obtain a loaded medium.

[0041] The remaining steps are the same as those in Example 1.

[0042] Comparative Example 2 - Nanoparticles using silica particles S1. Prepare a 5 wt% aqueous solution of PEG with a molecular weight of 1000, add 90 parts by weight of silica particles with a particle size of 200 nm at a solid-liquid ratio of 1:10, homogenize at 40°C, let stand for 6 hours, filter, rinse with deionized water, and vacuum dry to obtain PEG-modified silica nanoparticles.

[0043] S2, oleic acid and sodium hydroxide were added to deionized water in a molar ratio of 1:1, and the mixture was reacted at 70°C for 2 h to obtain a sodium oleate solution with a concentration of 5 mg / mL, and carboxymethyl cellulose powder was prepared into an aqueous solution with a concentration of 5 mg / mL, and then the sodium oleate solution and the aqueous solution of carboxymethyl cellulose were mixed in a volume ratio of 1:1, and the pH of the mixed solution was adjusted to 7.0 with 0.1 M HCl, and the mixture was shaken at room temperature for 24 h to obtain a liposome suspension; 15 parts of nicotinamide were added to the liposome suspension, and the suspension was shaken in a water bath at 40°C for 1 hour to obtain a liposome-nicotinamide complex solution. The PEG-modified silica nanoparticles prepared in S1 were added to the liposome-nicotinamide complex solution at a solid-liquid ratio of 1:5. The suspension was then vacuum loaded at a vacuum degree of -0.1 MPa for 30 minutes. Nitrogen was then introduced to break the vacuum, and the suspension was centrifuged at a speed of 3000 rpm for 10 minutes. The suspension was then washed with deionized water and dried to obtain loaded particles. A 2% w / v pullulan aqueous solution was prepared, and then 0.5% w / v sodium tripolyphosphate was added. The pH was adjusted to 5.8 using citric acid, and the loaded particles were placed on a fluidized bed. The loaded particles were coated using a spray drying method until the loaded particles gained 12% in weight to obtain a loaded medium.

[0044] The remaining steps are the same as those in Example 1.

[0045] Comparative Example 3 - Nanoparticles using zinc oxide particles S1. Prepare a 5 wt% aqueous solution of PEG with a molecular weight of 1000, add 80 parts by weight of zinc oxide particles with a particle size of 150 nm at a solid-liquid ratio of 1:10, homogenize at 40°C, let stand for 6 hours, filter, rinse with deionized water, and vacuum dry to obtain PEG-modified zinc oxide particles.

[0046] S2, oleic acid and sodium hydroxide were added to deionized water in a molar ratio of 1:1, and the mixture was reacted at 70°C for 2 h to obtain a sodium oleate solution with a concentration of 5 mg / mL, and carboxymethyl cellulose powder was prepared into an aqueous solution with a concentration of 5 mg / mL, and then the sodium oleate solution and the aqueous solution of carboxymethyl cellulose were mixed in a volume ratio of 1:1, and the pH of the mixed solution was adjusted to 7.0 with 0.1 M HCl, and the mixture was shaken at room temperature for 24 h to obtain a liposome suspension; 15 parts of nicotinamide were added to the liposome suspension, and the suspension was shaken in a water bath at 40°C for 1 hour to obtain a liposome-nicotinamide complex solution. The PEG-modified zinc oxide particles prepared in S1 were added to the liposome-nicotinamide complex solution at a solid-liquid ratio of 1:5. The suspension was then vacuum loaded at a vacuum degree of -0.1 MPa for 30 minutes. Nitrogen was then introduced to break the vacuum, and the suspension was centrifuged at a speed of 3000 rpm for 10 minutes. The suspension was washed with deionized water and dried to obtain loaded particles. A 2% w / v pullulan aqueous solution was prepared, and then 0.5% w / v sodium tripolyphosphate was added. The pH was adjusted to 5.8 using citric acid, and the loaded particles were placed on a fluidized bed. The loaded particles were coated using a spray drying method until the loaded particles gained 12% in weight to obtain a loaded medium.

[0047] The remaining steps are the same as those in Example 1.

[0048] Comparative Example 4—No Nanoporous Particles Used S1. Oleic acid and sodium hydroxide were added to deionized water in a molar ratio of 1:1, and the mixture was reacted at 70°C for 2 h to obtain a sodium oleate solution with a concentration of 5 mg / mL. Carboxymethyl cellulose powder was prepared into an aqueous solution with a concentration of 5 mg / mL. The sodium oleate solution and the aqueous solution of carboxymethyl cellulose were then mixed in a volume ratio of 1:1. The pH of the mixed solution was adjusted to 7.0 with 0.1 M HCl, and the mixture was shaken at room temperature for 24 h to obtain a liposome suspension. 15 parts of nicotinamide were added to the liposome suspension, shaken in a water bath at 40°C for 1 hour to obtain a liposome-nicotinamide complex solution, a 2% w / v pullulan aqueous solution was prepared, and then 0.5% w / v sodium tripolyphosphate was added. The pH was adjusted to 5.8 using citric acid, and the liposome suspension and the pullulan aqueous solution were mixed in a volume ratio of 85:15 to obtain a loaded mixed solution.

[0049] S2. 3 parts of honeysuckle extract, 5 parts of alpine edelweiss extract, and 2 parts of chamomile extract are subjected to supercritical CO2 extraction at a pressure of 30 MPa and a temperature of 40°C. The extracts are then mixed with 5 parts of hyaluronic acid, 5 parts of quercetin glycoside, 5 parts of sucrose stearate, 8 parts of ascorbyl glucoside, and 1.5 parts of selenium dioxide, and the mixture is placed in 40 parts of deionized water for homogenization. The loaded mixed solution in step S1 is then added and homogenization is continued to obtain a macromolecular niacinamide composite composition.

[0050] Comparative Example 5: Pullulan coating not constructed S1. Add 60 parts by weight of chitosan to 1% glacial acetic acid solution and stir magnetically for 2 hours to obtain a chitosan dispersion with a concentration of 5wt%. Weigh 20 parts of γ-polyglutamic acid and disperse them in deionized water. Stir in a water bath at 40°C for 1 hour to obtain a γ-polyglutamic acid dispersion with a concentration of 3wt%. Add 30 parts of calcium acetate to the chitosan dispersion. Add the γ-polyglutamic acid dispersion dropwise to the chitosan dispersion at a rate of 10 mL / min until colloidal particles are formed. After freeze-drying, the dried colloidal particles are placed in a heat treatment furnace and heated to 700°C for heat treatment for 4 hours to obtain porous particles. The porous particles are then washed with 0.1M HCl acid solution, washed with deionized water until neutral, and dried with hot air to obtain nanoporous particles.

[0051] PEG with a molecular weight of 1000 was prepared into a 5 wt% aqueous solution, and nanoporous particles were added at a solid-liquid ratio of 1:10. The solution was homogenized at 40°C, allowed to stand for 6 hours, filtered, washed with deionized water, and vacuum dried to obtain PEG-modified nanoparticles.

[0052] S2, oleic acid and sodium hydroxide were added to deionized water in a molar ratio of 1:1, and the mixture was reacted at 70°C for 2 h to obtain a sodium oleate solution with a concentration of 5 mg / mL, and carboxymethyl cellulose powder was prepared into an aqueous solution with a concentration of 5 mg / mL, and then the sodium oleate solution and the aqueous solution of carboxymethyl cellulose were mixed in a volume ratio of 1:1, and the pH of the mixed solution was adjusted to 7.0 with 0.1 M HCl, and the mixture was shaken at room temperature for 24 h to obtain a liposome suspension; 15 parts of nicotinamide were added to the liposome suspension, and the suspension was shaken in a water bath at 40°C for 1 hour to obtain a liposome-nicotinamide complex solution. The PEG-modified nanoparticles prepared in S1 were added to the liposome-nicotinamide complex solution at a solid-liquid ratio of 1:5. The suspension was then vacuum loaded at a vacuum degree of -0.1 MPa for 30 minutes. Nitrogen was then introduced to break the vacuum, and the suspension was centrifuged at a speed of 3000 rpm for 10 minutes. The suspension was then washed with deionized water and dried to obtain loaded particles. S3. 3 parts of honeysuckle extract, 5 parts of alpine edelweiss extract, and 2 parts of chamomile extract are subjected to supercritical CO2 extraction at a pressure of 30 MPa and a temperature of 40°C. The extracts are then mixed with 5 parts of hyaluronic acid, 5 parts of quercetin glycoside, 5 parts of sucrose stearate, 8 parts of ascorbyl glucoside, and 1.5 parts of selenium dioxide, and the mixture is placed in 40 parts of deionized water for homogenization. The loaded particles in step S2 are then added and homogenization is continued to obtain a macromolecular niacinamide composite composition.

[0053] Experiments and Data: The macromolecular nicotinamide composite compositions prepared in the above examples and comparative examples were subjected to pressure release test, skin irritation test and leakage rate test.

[0054] 24h release rate test: The macromolecular nicotinamide composite composition was placed in a USP IV flow cell system, the release medium was PBS buffer, the flow rate was 8mL / min, and the effluent was collected at 0.5, 1, 2, 4, 8, 12, and 24h time points, and the cumulative release rate was then calculated: Cumulative release rate = ∑(concentration × flow rate × time interval) / total amount of nicotinamide × 100% Release rate under no pressure, unit: %.

[0055] Release test under pressure: Using a Franz diffusion cell with an integrated pneumatic piston, the release rate was measured at a pressure of 30 kPa. The macromolecular nicotinamide composite composition was spread evenly on the transdermal membrane surface of the diffusion cell to a nicotinamide loading of 1.0 mg / cm2. The receptor fluid was PBS with a pH of 5.5. A cylindrical head was used to apply pressure at 30 kPa for 10 seconds, followed by a 1-minute relaxation. This was repeated 10 times. Real-time dialysis sampling (after each pressurization) was performed to measure the nicotinamide concentration. Release rate = release amount during pressurization period / total amount of niacinamide × 100%, unit: %.

[0056] Skin irritation test: EpiDerm 3D skin model (EPI-200) was used to measure IL-1α release and detect the release of inflammatory factor IL-1α (ELISA, increase ≤ 1.5 times the control). The negative control was PBS buffer (pH 5.5, benchmark). The macromolecular nicotinamide complex composition was applied to the surface of the skin model and incubated at 37°C for 24 hours. The culture medium was then collected and centrifuged to obtain the supernatant. The ELISA operation was performed and the IL-1α concentration was measured according to the kit instructions. The multiple = IL-1α concentration in the test group / IL-1α concentration in the negative control group The positive control was 5% free nicotinamide, and the positive control multiple was 3.2, unit: times (control).

[0057] Human patch pressure test: ISO 10993-10:2010 (Medical device skin irritation test), erythema / edema score, ≤1 is qualified.

[0058] Leakage rate test: centrifugal leakage rate at 10000rpm, unit: %.

[0059] The test data is shown in Table 1 below: The 24h release rate and the release rate under 30kPa pressure in Table 1 are plotted as a line graph to compare the relationship between the two. Figure 1 shown.

[0060] Analysis: According to the data in Table 1, the macromolecular niacinamide composite compositions of Examples 1, 2, and 3 all exhibited good leakage and release rates during centrifugation and 30 kPa pressure tests. Therefore, they are not affected by external forces and do not cause sudden release, making them suitable for people with sensitive skin.

[0061] According to the data in Table 1, the release rate of the macromolecular nicotinamide composite composition prepared in Comparative Example 1 is low under no pressure, and the effect is poor. Although the other test results are good, the nicotinamide does not act on the skin target, so it is ineffective and the active substance is wasted. The difference between Comparative Example 1 and Example 1 is that the nanoparticles are not modified with PEG. Therefore, it can be proved that PEG modification can reduce the locking of the nanoparticles themselves on the liposomes and nicotinamide, facilitate the release of the active ingredient nicotinamide, and thus produce excellent effects.

[0062] According to the data in Table 1, the macromolecular nicotinamide composite compositions prepared in Comparative Examples 2 and 3 have excellent release rates and good effects under no-pressure conditions. However, they exhibit poor performance during centrifugation and 30 kPa pressure tests, making them difficult to resist the influence of the external environment and prone to sudden release due to external forces. This can cause allergic reactions in the skin and release a large amount of inflammatory factors, making them unsuitable for people with sensitive skin. The difference between Comparative Examples 2 and 3 and Example 1 is that the nanoparticles used are silicon dioxide and zinc oxide particles. Existing nanoparticles have poor coating capabilities and are difficult to load with liposomes and nicotinamide.

[0063] According to the data in Table 1, the macromolecular niacinamide composite composition prepared in Comparative Example 4 also has an excellent release rate and good effect under no pressure, but shows poor performance when subjected to centrifugation and 30 kPa pressure tests, and its burst release is the largest. The difference between Comparative Example 4 and Example 1 is that nanoporous particles are not used. This proves that the presence of nanoporous particles can effectively resist the influence of the external environment and is not affected by external forces, thereby ensuring that the niacinamide component will not be released suddenly and will not cause skin intolerance.

[0064] According to the data in Table 1, the macromolecular nicotinamide composite composition prepared in Comparative Example 5 has a good pressure-free release rate, but performs generally well under 1000 rpm centrifugation and has a low release rate in a 30 kPa pressure test, while the release of inflammatory factors also increases to a certain extent. The difference between Comparative Example 5 and Example 1 is that a pullulan coating is not constructed. Therefore, it can be confirmed that the presence of the pullulan coating can indirectly affect the release effect of the nanoporous particles, partially inhibiting the release rate of nicotinamide from the nanoporous particles and maintaining normal release.

[0065] Thus far, the technical solutions of the present invention have been described in conjunction with the preferred embodiments shown in the accompanying drawings. However, it will be readily understood by those skilled in the art that the scope of protection of the present invention is obviously not limited to these specific embodiments. Without departing from the principles of the present invention, those skilled in the art may make equivalent changes or substitutions to the relevant technical features, and the technical solutions after such changes or substitutions will fall within the scope of protection of the present invention.

Claims

1. A macromolecular nicotinamide composite composition, characterized in that: The invention comprises an active composite component and a loading medium, wherein the loading medium is composed of nanoporous particles and a polysaccharide coating on the outside; The active compound component is composed of 5-15 parts by weight of a plant extract, 20-30 parts of liposomes, 10-20 parts of nicotinamide, 5-10 parts of ascorbyl glucoside, 1-2 parts of selenium dioxide, and 10-20 parts of a macromolecular complex, and the solvent is 40 parts by weight of deionized water; The nanoporous particles are obtained by cross-linking 50-80 parts of chitosan, 10-30 parts of γ-polyglutamic acid, and 20-50 parts of calcium acetate, and the nanoporous particles are PEG-modified; The polysaccharide coating is pullulan polysaccharide coating, and the weight gain ratio of the polysaccharide coating is 10-15%.

2. A macromolecular nicotinamide composite composition according to claim 1, characterized in that: The macromolecular complex is one or a combination of two or more of hyaluronic acid, quercetin glycoside, tannic acid, sucrose stearate, and octyldodecanol lauroyl glutamate.

3. The macromolecular nicotinamide composite composition according to claim 1, characterized in that: The plant extract is one of flower extract, leaf extract, plant callus extract or plant yeast fermentation lysate filtrate, and the type of the plant extract is one of honeysuckle extract, alpine edelweiss extract, chamomile extract, rose extract, peach blossom extract or a combination of two or more thereof.

4. The method for preparing a macromolecular nicotinamide composite composition according to any one of claims 1 to 3, characterized in that: The specific preparation steps are as follows: S1. First, PEG is prepared into a solution, and then the nanoporous particles are placed in the PEG solution and stirred for homogenization. After standing for adsorption, solid particles are filtered out, and the solid particles are washed and dried to obtain PEG-modified nanoparticles; S2. The liposomes are prepared into a suspension, and nicotinamide is placed in the liposome suspension, and the suspension is shaken in a water bath to obtain a liposome-nicotinamide complex solution. The PEG-modified nanoparticles obtained in step S1 are added to the liposome-nicotinamide complex solution for loading, and then centrifuged to obtain loaded particles. The loaded particles are dried, and an aqueous solution of pullulan is prepared and sodium tripolyphosphate is added. After adjusting the pH value, the aqueous solution of pullulan is spray-dried to form a pullulan coating on the outside of the loaded particles. S3. Homogeneously combine the plant extract, ascorbyl glucoside, selenium dioxide and the macromolecular complex in deionized water, and add thereto loaded particles coated with pullulan to obtain a macromolecular nicotinamide composition.

5. The method for preparing a macromolecular nicotinamide composite composition according to claim 4, characterized in that: The specific steps for preparing the nanoporous particles in step S1 are as follows: Chitosan is placed in an aqueous solution of glacial acetic acid to obtain a chitosan dispersion, γ-polyglutamic acid is placed in water to obtain a γ-polyglutamic acid dispersion, calcium acetate is weighed and placed in the chitosan dispersion, and the γ-polyglutamic acid dispersion is then added dropwise to the chitosan dispersion to react to form colloidal particles, which are freeze-dried and then heat-treated, cooled to room temperature, acid-washed and washed with water, and dried to obtain a nanoporous material; The heat treatment temperature is 600-800°C and the heat treatment time is 3-5h.

6. The method for preparing a macromolecular nicotinamide composite composition according to claim 4, characterized in that: The molecular weight of PEG used for PEG modification in step S1 is 200-2000, the concentration of the PEG solution is 1-10 wt %, and the static adsorption time is 4-8 h.

7. The method for preparing a macromolecular nicotinamide composite composition according to claim 4, characterized in that: The specific steps for preparing liposomes in step S2 are as follows: Oleic acid and sodium hydroxide are reacted in deionized water at a molar ratio of 1:1 to obtain an aqueous solution of sodium oleate, wherein the concentration of sodium oleate in deionized water is 5 mg / mL. Carboxymethyl cellulose powder is then placed in deionized water to prepare an aqueous solution of carboxymethyl cellulose with a concentration of 5 mg / mL. The aqueous solution of sodium oleate and the aqueous solution of carboxymethyl cellulose are then mixed at a volume ratio of 1:1, the pH is adjusted to 6.0-7.5, and the mixture is shaken for 24 hours to obtain a liposome suspension.

8. The method for preparing a macromolecular nicotinamide composite composition according to claim 4, characterized in that: In step S2, the vacuum degree of the load is -0.1 MPa, the load time is 30 min, the centrifugal speed is 3000-5000 rpm, the centrifugal time is 10 min, and the concentration of the pullulan is 2 w / v%.

9. The method for preparing a macromolecular nicotinamide composite composition according to claim 4, characterized in that: In step S2, the amount of sodium tripolyphosphate added is 0.5 w / v%, and the pH value is adjusted to 5.5-6.0 after addition.

10. Use of the macromolecular nicotinamide composite composition according to any one of claims 1 to 3 in facial masks, shampoos and facial creams.

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