Lipid hybrid nanoparticle as well as preparation method and application thereof

Abstract

The invention provides lipid hybrid nanoparticles as well as a preparation method and application thereof, and particularly relates to the technical field of cosmetic intermediates. The lipid hybrid nanoparticle has a core-shell structure, an inner core is a polymer nanoparticle loaded with an anti-aging active matter, and an outer shell is a lipid hybrid layer; the polymer nanoparticles are mainly prepared from a degradable high polymer material, an anti-aging active matter and an emulsifier, the lipid hybrid layer is mainly formed by phospholipid and a fibroblast targeting ligand. The lipid hybrid nanoparticles provided by the invention show outstanding technical advantages in the aspects of improving the chemical stability of anti-aging active matters, enhancing skin permeability, realizing dermis targeted delivery, enhancing biological efficacy and the like, and have a good application prospect.

Description

Technical Field

[0001] This invention relates to the field of cosmetic intermediates technology, and in particular to a lipid hybrid nanoparticle, its preparation method, and its application. Background Technology

[0002] With the aging population and consumers' continued focus on the "appearance economy" and "healthy beauty" concepts, anti-aging has become one of the fastest-growing and most in-demand core areas of the global cosmetics market. Especially for those over 30, facing skin oxidative stress, collagen loss, decreased elasticity, and wrinkle formation caused by multiple factors such as UV radiation, environmental pollution, and life stress, the demand for anti-aging skincare products has shifted from basic moisturizing to higher-level efficacy demands such as precise repair, deep revitalization, and long-term stabilization. High-end cosmetics consumers also demonstrate a strong awareness of scientific skincare, expecting products to not only provide a tangible skin feel but also verifiable biological efficacy and lasting, visible signs of rejuvenation.

[0003] However, current high-end anti-aging products on the market still face significant technological bottlenecks, making it difficult to truly meet consumers' deeper needs. Although many brands claim to use highly active ingredients (such as retinol, Pro-Xylane, Pterostilbene, astaxanthin, and peptides), these ingredients generally suffer from chemical instability, susceptibility to photothermal and oxidative degradation, and limited water or oil solubility leading to poor formulation compatibility. This severely affects their activity retention during storage and efficacy release during actual use. More importantly, most traditional delivery systems (such as ordinary emulsions, microemulsions, and liposomes) have limited penetration capabilities and cannot effectively cross the skin's stratum corneum barrier. This causes active ingredients to remain on the surface of the epidermis or even the stratum corneum, failing to reach the key anti-aging target of dermal fibroblasts. This results in a phenomenon of "high cost, low bioavailability," with actual efficacy far below theoretical expectations.

[0004] Furthermore, some products rely on high concentrations of active ingredients or add irritating penetration enhancers (such as ethanol and certain surfactants) to improve penetration rates. While these may show short-term effects, they can easily cause adverse reactions such as skin barrier damage, redness, and peeling, violating the safety and comfort principles advocated by high-end skincare. Therefore, despite continuous upgrades in packaging, marketing, and pricing of high-end cosmetics, there is still a lack of breakthroughs in core technologies—namely, the stable protection and efficient targeted delivery of active ingredients. This has led to a severe mismatch between market supply and consumers' genuine demand for "efficient, stable, safe, and perceptible" anti-aging solutions.

[0005] In view of this, the present invention is hereby proposed. Summary of the Invention

[0006] The purpose of this invention is to provide a lipid hybrid nanoparticle, its preparation method and application, aiming to solve at least one of the above-mentioned technical problems in the prior art.

[0007] In order to achieve the above-mentioned objectives of the present invention, the following technical solution is adopted: A first aspect of the present invention provides a lipid hybrid nanoparticle having a core-shell structure, wherein the core is a polymer nanoparticle loaded with anti-aging active ingredients and the outer shell is a lipid hybrid layer; the polymer nanoparticle is mainly formed of a biodegradable polymer material, an anti-aging active ingredient and an emulsifier; the lipid hybrid layer is mainly formed of phospholipids and fibroblast-targeting ligands.

[0008] Furthermore, the lipid hybrid nanoparticles have an average particle size of 200~430 nm and a PDI < 0.350.

[0009] And / or, the average particle size of the polymer nanoparticles is 200~450 nm.

[0010] Furthermore, the biodegradable polymer material is selected from at least one of polyglycolic acid (PGA), polylactic acid (PLA), polylactic acid (PLLA), polylactic acid (PDLA), racemic polylactic acid (PDLLA), polycaprolactone (PCL), polylactic acid-glycolic acid copolymer (PLGA), polydioxanone (PDO), polytrimethylene carbonate (PTMC), polyhydroxybutyrate (PHB), polylactic acid-caprolactone copolymer (PLA-PCL), and polycitrate (POC).

[0011] And / or, the anti-aging active ingredient is selected from at least one of retinol, retinol propionate, retinol palmitate, retinol acetate, retinol linoleate, hydroxypinazone retinate, idebenone, astaxanthin, pterostilbene, Dalbergia odorifera bark extract, grape skin extract, resveratrol, curcumin, coenzyme Q10, ferulic acid, tetrahydrocurcumin, and β-carotene.

[0012] And / or, the emulsifier is selected from at least one of polyvinyl alcohol, gum arabic, maltodextrin, poloxamer 407, poloxamer 188, polyglycerol stearate, sucrose stearate, cetyl ether-25, stearyl ether-21, Span-80, polyethylene glycol fatty acid ester, glycerol fatty acid ester, Tween-80, Tween-20, lauryl polyoxyethylene ether-3, PEG-40 hydrogenated castor oil, sodium carboxymethyl cellulose, and hydroxypropyl methylcellulose.

[0013] And / or, the phospholipid is selected from at least one of soybean lecithin, egg yolk lecithin, hydrogenated lecithin, phosphatidylcholine, phosphatidylethanolamine, dipalmitoylphosphatidylcholine (DPPC), and distearate phosphatidylcholine (DSPC).

[0014] And / or, the selected phospholipid contains >90% phosphatidylcholine.

[0015] And / or, the fibroblast-targeting ligand is selected from at least one of RGD peptide and its derivatives, palmitoyl tetrapeptide-7 and its derivatives, palmitoyl pentapeptide-4 (Pal-KTTKS) and its derivatives, P-15 peptide and its derivatives, hexapeptide-11 and its derivatives, REDV peptide and its derivatives, acetyl hexapeptide-8 and its derivatives, TGF-β receptor-binding peptide, YIGSR peptide and its derivatives, fibroblast activation protein targeting peptide (FAPI) and its derivatives, and cell surface glycoprotein CD90.

[0016] Furthermore, the polymer nanoparticles also include hydrophobic anti-sensitivity agents and / or lipophilic antioxidants.

[0017] And / or, the hydrophobic anti-allergen includes at least one of 4-tert-butylcyclohexanol, dihydroagar alkaloids, kava, glycyrrhetinic acid, and glycyrrhetinic acid ester.

[0018] And / or, the fat-soluble antioxidant is selected from at least one of ascorbate tetraisopalmitate, guaiacol, tocopherol, tocopheryl acetate, lipoic acid, butylated hydroxyanisole, butylated hydroxytoluene, tea polyphenols, sarsaparilla acid, quercetin, tinraquinone, and ascorbate palmitate.

[0019] And / or, the lipid hybrid layer may further include a lyophilization protectant and / or a water-soluble stabilizer.

[0020] And / or, the freeze-drying protectant includes at least one of trehalose, sucrose, mannitol, sorbitol, maltitol, inositol, and glycine.

[0021] And / or, the water-soluble stabilizer includes at least one of chelating agents, water-soluble antioxidants, pH buffers, preservatives, and co-emulsifiers.

[0022] And / or, the preservative includes at least one of 1,2-pentanediol, 1,2-hexanediol, octanoyl hydroxamic acid, and sorbic acid.

[0023] Furthermore, based on parts by weight, the polymer nanoparticles are mainly formed from 0.1 to 40 parts of biodegradable polymeric material, 0.1 to 30 parts of anti-aging active ingredient, and 2 to 10 parts of emulsifier.

[0024] And / or, by weight, the lipid hybrid layer is mainly composed of 1 to 10 parts of phospholipids and 0.01 to 1 part of fibroblast-targeting ligands.

[0025] Furthermore, the polymer nanoparticles also include 0.05 to 10 parts of a hydrophobic anti-sensitivity agent and / or 0.5 to 10 parts of a lipid-soluble antioxidant, by weight.

[0026] And / or, by weight, the lipid hybrid layer further includes 10-60 parts of a lyophilization protectant and / or 0.01-15 parts of a water-soluble stabilizer.

[0027] A second aspect of the present invention provides a method for preparing the aforementioned lipid hybrid nanoparticles, comprising the following steps: A. Add biodegradable polymer materials and anti-aging active ingredients to the first organic solvent and mix evenly to obtain a transparent oil phase; add emulsifier to water and mix evenly to obtain a transparent aqueous phase; B. The aqueous phase and oil phase are mixed evenly, and after emulsification and high-pressure homogenization, an emulsion is obtained; then the solvent in the emulsion is removed, and after concentration, washing and drying, polymer nanoparticles are obtained. C. Add phospholipids and fibroblast-targeting ligands to the second organic solution and mix thoroughly to obtain a lipid mixture; D. The polymer nanoparticles are dispersed in the lipid mixture to form a homogeneous liquid to obtain an intermediate; then the intermediate is injected into rapidly stirred water and stirred evenly to obtain an aqueous solution of the intermediate; then the solvent in the aqueous solution of the intermediate is removed to obtain a lipid hybrid nanoparticle suspension; finally, the lipid hybrid nanoparticles are freeze-dried to obtain lipid hybrid nanoparticles.

[0028] Furthermore, the first organic solvent includes at least one of methanol, ethanol, ethyl acetate, isopropanol, n-heptane, and cyclohexane.

[0029] And / or, the second organic solution includes ethanol.

[0030] And / or, in step B, the solvent in the emulsion is removed by stirring at 0~45°C and combined with nitrogen blowing to evaporate the solvent.

[0031] And / or, in step D, the solvent in the intermediate aqueous solution is removed by stirring at 0~45°C and combined with nitrogen blowing to evaporate the solvent.

[0032] Furthermore, in step D, during the preparation of the intermediate aqueous solution, the amount of water used is 10 to 20 times the volume of the intermediate.

[0033] And / or, the pressure of the high-pressure homogenization process is 10,000 to 15,000 psi.

[0034] And / or, the high-pressure homogenization process is performed 1 to 3 times.

[0035] A third aspect of the present invention provides the application of the aforementioned lipid hybrid nanoparticles in the preparation of cosmetics.

[0036] Compared with the prior art, the present invention has at least the following beneficial effects: The lipid hybrid nanoparticles provided by this invention exhibit high stability, maintaining a retention rate of 92.64% after 30 days of storage at 50°C. Regarding transdermal absorption performance, in vitro skin penetration experiments show that the total amount of active ingredients retained in the skin reaches 7.50 µg / cm³ within 8 hours. 2 Cellular uptake experiments showed that lipid hybrid nanoparticles have excellent targeting enrichment capabilities, with SIOD values ​​in HSF cells significantly increased by 317% compared to non-targeted nanoparticles. The lipid hybrid nanoparticles provided by this invention exhibit outstanding technical advantages in improving the chemical stability of anti-aging active ingredients, enhancing skin permeability, achieving targeted delivery to the dermis, and strengthening biological efficacy, and have good application prospects.

[0037] The preparation method provided by this invention is a step-by-step process of first preparing polymer nanoparticles and then coating them with a lipid layer. This process utilizes the good compatibility between biodegradable polymer materials and anti-aging active ingredients in an organic phase, combined with emulsification and high-pressure homogenization, to achieve efficient loading of anti-aging active ingredients and uniform dispersion of polymer nanoparticles. Subsequently, the polymer nanoparticles are dispersed in a lipid mixture containing phospholipids and fibroblast-targeting ligands, followed by aqueous phase injection, solvent removal, and freeze-drying. This process forms a uniform and stable lipid hybrid layer on the surface of the polymer nanoparticles, retaining the high drug loading capacity and controllable drug release of the polymer core, while improving the biocompatibility and dispersion stability of the nanoparticles through the lipid layer. Furthermore, the introduction of fibroblast-targeting ligands endows the nanoparticles with precise targeting delivery capabilities. The entire process is clear, controllable, and highly repeatable, making it suitable for large-scale production.

[0038] The application of lipid hybrid nanoparticles provided by this invention in the preparation of cosmetics, given that these lipid hybrid nanoparticles have the core advantages of high drug loading capacity, strong stability of anti-aging active ingredients, precise targeted delivery and good biocompatibility, can provide cosmetics with efficient, stable, safe and comfortable anti-aging raw materials; and provide high-end functional skin care products with core technical solutions that combine scientific support and performance advantages, significantly enhancing the technological added value and market competitiveness of the products. Attached Figure Description

[0039] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0040] Figure 1 A bar chart of skin retention amount obtained from test example 4; Figure 2 The bar chart shows the skin retention rate obtained from test example 4. Detailed Implementation

[0041] To make the objectives, technical solutions, and advantages of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0042] In the following, the terms “comprising,” “having,” and their cognates, which may be used in various embodiments of the invention, are intended only to indicate a particular feature, number, step, operation, element, component, or combination thereof, and should not be construed as excluding, firstly, the presence of one or more other features, numbers, steps, operations, elements, components, or combinations thereof, or adding the possibility of one or more features, numbers, steps, operations, elements, components, or combinations thereof.

[0043] A first aspect of the present invention provides a lipid hybrid nanoparticle having a core-shell structure, wherein the core is a polymer nanoparticle loaded with anti-aging active ingredients and the outer shell is a lipid hybrid layer; the polymer nanoparticle is mainly formed of a biodegradable polymer material, an anti-aging active ingredient and an emulsifier; the lipid hybrid layer is mainly formed of phospholipids and fibroblast-targeting ligands.

[0044] The lipid hybrid nanoparticles provided by this invention exhibit high stability, maintaining a retention rate of 92.64% after 30 days of storage at 50°C. Regarding transdermal absorption performance, in vitro skin penetration experiments show that the total amount of active ingredients retained in the skin reaches 7.50 µg / cm³ within 8 hours. 2 Cellular uptake experiments showed that lipid hybrid nanoparticles have excellent targeting enrichment capabilities, with SIOD values ​​in HSF cells significantly increased by 317% compared to non-targeted nanoparticles. The lipid hybrid nanoparticles provided by this invention exhibit outstanding technical advantages in improving the chemical stability of anti-aging active ingredients, enhancing skin permeability, achieving targeted delivery to the dermis, and strengthening biological efficacy, and have good application prospects.

[0045] This invention integrates the carrier advantages of biodegradable polymer materials with the targeting characteristics of lipid hybridization technology to construct a precise delivery system for anti-aging active ingredients. Biodegradable polymers (such as polylactic-co-glycolic acid copolymer PLGA, polycaprolactone, etc.) serve as the core carriers encapsulating the anti-aging active ingredients, improving their stability by steric hindrance to isolate them from external factors such as light, temperature, and oxygen. Lipid hybridization technology combines fibroblast-specific targeting agents with anti-aging active ingredient nanoparticles. The fibroblast-targeting ligands, as specific ligands for fibroblast surface receptors, guide the nanoparticles to actively recognize and bind to dermal fibroblasts. Simultaneously, the optimized lipid structure's lipophilicity is highly compatible with the stratum corneum lipid environment, allowing the nanoparticles to penetrate the barrier and reach the dermis, achieving slow release, increasing the accumulation of active ingredients around fibroblasts, improving bioavailability, and reducing irritation. This invention overcomes the problems of insufficient targeting, low utilization of active ingredients, poor stratum corneum penetration, and strong irritation of existing single-agent formulations by increasing the targeting of fibroblasts, providing a more precise and safe solution for skin anti-aging and having great application value in the fields of cosmetics and dermatology.

[0046] Furthermore, the lipid hybrid nanoparticles have an average particle size of 200~430 nm and a PDI < 0.350.

[0047] And / or, the average particle size of the polymer nanoparticles is 200~450 nm.

[0048] Furthermore, the biodegradable polymer material is selected from at least one of polyglycolic acid (PGA), polylactic acid (PLA), polylactic acid (PLLA), polylactic acid (PDLA), racemic polylactic acid (PDLLA), polycaprolactone (PCL), polylactic acid-glycolic acid copolymer (PLGA), polydioxanone (PDO), polytrimethylene carbonate (PTMC), polyhydroxybutyrate (PHB), polylactic acid-caprolactone copolymer (PLA-PCL), and polycitrate (POC).

[0049] And / or, the anti-aging active ingredient is selected from at least one of retinol, retinol propionate, retinol palmitate, retinol acetate, retinol linoleate, hydroxypinazone retinate, idebenone, astaxanthin, pterostilbene, Dalbergia odorifera bark extract, grape skin extract, resveratrol, curcumin, coenzyme Q10, ferulic acid, tetrahydrocurcumin, and β-carotene.

[0050] And / or, the emulsifier is selected from at least one of polyvinyl alcohol, gum arabic, maltodextrin, poloxamer 407, poloxamer 188, polyglycerol stearate, sucrose stearate, cetyl ether-25, stearyl ether-21, Span-80, polyethylene glycol fatty acid ester, glycerol fatty acid ester, Tween-80, Tween-20, lauryl polyoxyethylene ether-3, PEG-40 hydrogenated castor oil, sodium carboxymethyl cellulose, and hydroxypropyl methylcellulose.

[0051] And / or, the phospholipid is selected from at least one of soybean lecithin, egg yolk lecithin, hydrogenated lecithin, phosphatidylcholine, phosphatidylethanolamine, dipalmitoylphosphatidylcholine (DPPC), and distearate phosphatidylcholine (DSPC).

[0052] And / or, the selected phospholipid contains >90% phosphatidylcholine.

[0053] And / or, the fibroblast-targeting ligand is capable of specifically recognizing receptors on the surface of fibroblasts to achieve targeted selection, specifically selected from at least one of RGD peptide and its derivatives, palmitoyl tetrapeptide-7 and its derivatives, palmitoyl pentapeptide-4 (Pal-KTTKS) and its derivatives, P-15 peptide and its derivatives, hexapeptide-11 and its derivatives, REDV peptide and its derivatives, acetyl hexapeptide-8 and its derivatives, TGF-β receptor-binding peptide, YIGSR peptide and its derivatives, fibroblast activation protein targeting peptide (FAPI) and its derivatives, and cell surface glycoprotein CD90.

[0054] In some embodiments of the present invention, RGD peptides and their derivatives are typically, but not limited to, RGD cyclic peptides, RGDS peptides, GRGDS peptides, or RGD linear peptides.

[0055] Furthermore, the polymer nanoparticles also include hydrophobic anti-sensitivity agents and / or lipophilic antioxidants, thereby achieving a synergistic anti-sensitivity effect with the active ingredients. The addition of lipophilic antioxidants can effectively protect the anti-aging active ingredients from oxidative degradation.

[0056] The hydrophobic anti-allergy agent is a commonly used soothing agent in the field. This invention does not have any special limitations, and researchers in the field can choose according to actual needs. Typically, but not limitingly, the hydrophobic anti-allergy agent includes at least one of 4-tert-butylcyclohexanol, dihydroagar alkaloids, kava, glycyrrhetinic acid, and glycyrrhetinic acid ester.

[0057] And / or, the fat-soluble antioxidant is selected from at least one of ascorbate tetraisopalmitate, guaiacol, tocopherol, tocopheryl acetate, lipoic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tea polyphenols, sarsaparilla acid, quercetin, tinraquinone, and ascorbate palmitate.

[0058] And / or, the lipid hybrid layer may further include a lyophilization protectant and / or a water-soluble stabilizer.

[0059] And / or, the freeze-drying protectant includes at least one of trehalose, sucrose, mannitol, sorbitol, maltitol, inositol, and glycine.

[0060] The water-soluble stabilizer is an adjuvant. This invention does not impose any special restrictions, and researchers in the field can choose it according to actual needs. Typically, but not limitingly, the water-soluble stabilizer includes at least one of chelating agents, water-soluble antioxidants, pH buffers, preservatives, and co-emulsifiers.

[0061] The preservative includes at least one selected from 1,2-pentanediol, 1,2-hexanediol, octanoyl hydroxamic acid, and sorbic acid. Further, by weight, the polymer nanoparticles are mainly formed from 0.1-40 parts of biodegradable polymer material, 0.1-30 parts of anti-aging active ingredient, and 2-10 parts of emulsifier.

[0062] Typical, but not limiting, the biodegradable polymer material may be 0.1 parts, 1 part, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, or 40 parts, or any value within the range of 0.1 to 40 parts; the anti-aging active ingredient may be 0.1 parts, 1 part, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, or 30 parts, or any value within the range of 0.1 to 30 parts; the emulsifier may be 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, or 10 parts, or any value within the range of 2 to 10 parts.

[0063] And / or, by weight, the lipid hybrid layer is mainly composed of 1 to 10 parts of phospholipids and 0.01 to 1 part of fibroblast-targeting ligands.

[0064] Typically, but not limitingly, the phospholipids can be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, or 10 parts, or any value in the range of 1 to 10 parts; the fibroblast-targeting ligands can be 0.01 parts, 0.05 parts, 0.1 parts, 0.2 parts, 0.3 parts, 0.4 parts, 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts, 0.9 parts, or 1 part, or any value in the range of 0.01 to 1 part.

[0065] Furthermore, the polymer nanoparticles also include 0.05 to 20 parts of a hydrophobic anti-sensitivity agent and / or 0.5 to 10 parts of a lipid-soluble antioxidant, by weight.

[0066] Typical, but not limiting, the weight parts of hydrophobic antisensitizing agents may be, for example, 0.05 parts, 0.1 parts, 0.5 parts, 1 part, 5 parts, 10 parts, 15 parts, or 20 parts, or any value within the range of 0.05 to 20 parts; the weight parts of lipid-soluble antioxidants may be, for example, 0.5 parts, 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, or 10 parts, or any value within the range of 0.5 to 10 parts.

[0067] And / or, by weight, the lipid hybrid layer further includes 10-60 parts of a lyophilization protectant and / or 0.01-15 parts of a water-soluble stabilizer.

[0068] Lyophilization protectants are used during the freeze-drying process to prevent nanoparticles from agglomerating, breaking, or collapsing due to ice crystal formation, dehydration stress, and interfacial effects, thereby maintaining the physical stability and dispersibility of the nanoparticles. By forming a glassy matrix at low temperatures, lyophilization protectants can encapsulate and support the nanoparticle structure, effectively protecting its core-shell integrity and the chemical stability of the loaded active ingredients.

[0069] Typical, but not limiting, the lyophilization protectant may be, for example, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, or 60 parts, or any value within the range of 10 to 60 parts; the water-soluble stabilizer may be, for example, 0.01 parts, 0.05 parts, 0.1 parts, 0.5 parts, 1 part, 5 parts, 10 parts, 15 parts, or 20 parts, or any value within the range of 0.01 to 15 parts.

[0070] The lipid hybrid nanoparticles provided by this invention effectively improve the problems of anti-aging active ingredients (such as retinol, pterostilbene, astaxanthin, etc.) being sensitive to light, heat, and oxygen and easily degradable, having low compatibility with water / oil-based formulations, and being difficult to reach dermal fibroblasts through transdermal delivery. They significantly enhance the stability and formulation compatibility of the anti-aging active ingredient system and improve its targeted delivery efficiency to the dermis. By utilizing the stable encapsulation properties of biodegradable polymers and the dual advantages of targeted and permeation-enhancing lipid hybrid technology, a novel precision delivery system for anti-aging active ingredients is constructed. This system not only improves the stability of anti-aging active ingredients during production and storage but also enhances their penetration ability in the stratum corneum and the targeted enrichment effect on dermal fibroblasts. This allows the anti-aging active ingredients to accumulate efficiently around fibroblasts, fully activating cell activity and promoting collagen synthesis.

[0071] A second aspect of the present invention provides a method for preparing the aforementioned lipid hybrid nanoparticles, comprising the following steps: A. Add biodegradable polymer materials and anti-aging active ingredients to the first organic solvent and mix evenly to obtain a transparent oil phase; add emulsifier to water and mix evenly to obtain a transparent aqueous phase; B. The aqueous phase and oil phase are mixed evenly, and after emulsification and high-pressure homogenization, an emulsion is obtained; then the solvent in the emulsion is removed, and after concentration, washing and drying, polymer nanoparticles are obtained. C. Add phospholipids and fibroblast-targeting ligands to the second organic solution and mix thoroughly to obtain a lipid mixture; D. The polymer nanoparticles are dispersed in the lipid mixture to form a homogeneous liquid to obtain an intermediate; then the intermediate is injected into rapidly stirred water and stirred evenly to obtain an aqueous solution of the intermediate; then the solvent in the aqueous solution of the intermediate is removed to obtain a lipid hybrid nanoparticle suspension; finally, the lipid hybrid nanoparticles are freeze-dried to obtain lipid hybrid nanoparticles.

[0072] The preparation method provided by this invention is a step-by-step process of first preparing polymer nanoparticles and then coating them with a lipid layer. This process utilizes the good compatibility between biodegradable polymer materials and anti-aging active ingredients in an organic phase, combined with emulsification and high-pressure homogenization, to achieve efficient loading of anti-aging active ingredients and uniform dispersion of polymer nanoparticles. Subsequently, the polymer nanoparticles are dispersed in a lipid mixture containing phospholipids and fibroblast-targeting ligands, followed by aqueous phase injection, solvent removal, and freeze-drying. This process forms a uniform and stable lipid hybrid layer on the surface of the polymer nanoparticles, retaining the high drug loading capacity and controllable drug release of the polymer core, while improving the biocompatibility and dispersion stability of the nanoparticles through the lipid layer. Furthermore, the introduction of fibroblast-targeting ligands endows the nanoparticles with precise targeting delivery capabilities. The entire process is clear, controllable, and highly repeatable, making it suitable for large-scale production.

[0073] In step D, polymer nanoparticles are dispersed in an organic solvent (such as ethanol) containing phospholipids and fibroblast-targeting ligands to form a homogeneous intermediate. The purpose is to fully wet the lipid material and adsorb it onto the surface of the polymer nanoparticles. Subsequently, this intermediate is rapidly injected into a large volume of rapidly stirred water. Utilizing the principle that the sudden entry of the solvent into the aqueous phase causes a sharp decrease in solubility, the phospholipids and targeting ligands spontaneously assemble on the surface of the polymer nanoparticles to form a lipid layer, achieving "lipid hybrid" coating. Then, residual organic solvent is removed by stirring combined with nitrogen blowing to ensure system stability and complete the self-assembly process, resulting in a lipid hybrid nanoparticle suspension. Finally, lyophilization is performed, and a lyophilization protectant is added to prevent nanoparticle aggregation, resulting in a dry, stable, easy-to-store, and easily reconstituted powdered final product.

[0074] Furthermore, the first organic solvent includes at least one of methanol, ethanol, ethyl acetate, isopropanol, n-heptane, and cyclohexane.

[0075] And / or, the second organic solution includes ethanol.

[0076] This invention does not specifically limit the amount of the first organic solvent and the second organic solvent. In practical applications, the amount that can dissolve the target substance and is easy to remove is preferred.

[0077] And / or, in step B, the solvent in the emulsion is removed by stirring at 0~45°C and combined with nitrogen blowing to evaporate the solvent.

[0078] And / or, in step D, the solvent in the intermediate aqueous solution is removed by stirring at 0~45°C and combined with nitrogen blowing to evaporate the solvent.

[0079] Furthermore, in step D, during the preparation of the intermediate aqueous solution, the amount of water used is 10 to 20 times the volume of the intermediate. Typically, but not limitingly, the amount of water used can be, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 times, or any value within the range of 10 to 20 times.

[0080] And / or, the pressure of the high-pressure homogenization process is 10,000 to 15,000 psi. Typically, but not limitingly, the pressure can be, for example, 10,000 psi, 10,500 psi, 11,000 psi, 11,500 psi, 12,000 psi, 12,500 psi, 13,000 psi, 13,500 psi, 14,000 psi, 14,500 psi, or 15,000 psi, or any value within the range of 10,000 to 15,000 psi.

[0081] And / or, the high-pressure homogenization process is performed 1 to 3 times. Typically, but not limitingly, the number of times can be, for example, 1, 2, or 3 times.

[0082] A third aspect of the present invention provides the application of the aforementioned lipid hybrid nanoparticles in the preparation of cosmetics.

[0083] The application of lipid hybrid nanoparticles provided by this invention in the preparation of cosmetics, given that these lipid hybrid nanoparticles have the core advantages of high drug loading capacity, strong stability of anti-aging active ingredients, precise targeted delivery and good biocompatibility, can provide cosmetics with efficient, stable, safe and comfortable anti-aging raw materials; and provide high-end functional skin care products with core technical solutions that combine scientific support and performance advantages, significantly enhancing the technological added value and market competitiveness of the products.

[0084] The present invention is further illustrated below with specific embodiments and comparative examples. However, it should be understood that these embodiments are merely for illustrative purposes and should not be construed as limiting the invention in any way. Unless otherwise specified, the raw materials used in the embodiments and comparative examples of the present invention were carried out under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products.

[0085] Example 1 This embodiment provides a lipid hybrid nanoparticle, and the specific preparation process is as follows: 1. Weigh 2g of polylactic-co-glycolic acid copolymer (PLGA), 5g of polycaprolactone (PCL), 5g of retinol, and 0.5g of tocopherol. Add appropriate amounts of ethyl acetate and ethanol, and stir to dissolve to prepare the oil phase. Weigh 2g of polyvinyl alcohol and dissolve it in water to prepare the aqueous phase. Mix the oil and aqueous phases for 5 minutes to emulsify, then homogenize twice under high pressure at 12000psi. Subsequently, evaporate the solvent under stirring and nitrogen blowing conditions at 45℃, and then freeze-dry in a vacuum freeze dryer to obtain polymer nanoparticles loaded with active ingredients.

[0086] 2. Weigh 1g of phosphatidylcholine and 0.05g of palmitoyl pentapeptide-4 (Pal-KTTKS), add ethanol to dissolve and prepare a lipid mixture.

[0087] 3. Disperse the polymer nanoparticles loaded with active ingredients obtained in step 1 above in a lipid mixture, stir evenly, and then slowly inject them into 15 times the volume of water with rapid stirring. Under stirring and nitrogen blowing conditions at 30°C, the solvent is evaporated to obtain a suspension. Add 20g of mannitol and 3g of 1,2-pentanediol, stir to dissolve, and then freeze-dry under vacuum to obtain the lipid hybrid nanoparticle product.

[0088] Example 2 This embodiment provides a lipid hybrid nanoparticle. Unlike Example 1, 2g of polylactic acid-glycolic acid copolymer (PLGA) and 5g of polycaprolactone (PCL) are replaced with 1g of polylactic acid (PLLA) and 2g of polylactic acid-glycolic acid copolymer (PLGA), 0.5g of tocopherol is replaced with 0.8g of teradycin, and 0.05g of palmitoyl pentapeptide-4 (Pal-KTTKS) is replaced with 0.1g of RGD cyclic peptide. The remaining raw materials and preparation methods are the same as in Example 1 and will not be repeated here.

[0089] Example 3 This embodiment provides a lipid hybrid nanoparticle. Unlike Example 1, 2g of polylactic acid-glycolic acid copolymer (PLGA) and 5g of polycaprolactone (PCL) are replaced with 5g of polylactic acid-caprolactone copolymer (PLA-PCL) and 4g of polycitrate (POC), 5g of retinol is replaced with 6g of hydroxypinazone retinate, and 0.05g of palmitoyl pentapeptide-4 (Pal-KTTKS) is replaced with 0.2g of palmitoyl tetrapeptide-7 and 0.1g of REDV peptide. The remaining raw materials and preparation methods are the same as in Example 1 and will not be repeated here.

[0090] Example 4 This embodiment provides a lipid hybrid nanoparticle. The difference from Example 1 is that 2g of polylactic acid-glycolic acid copolymer (PLGA) and 5g of polycaprolactone (PCL) are replaced with 3g of polylactic acid (PLLA), 2g of polydioxanone and 2g of polycaprolactone (PCL), and 0.05g of palmitoyl pentapeptide-4 (Pal-KTTKS) is replaced with 0.05g of P-15 peptide. The remaining raw materials and preparation methods are the same as in Example 1, and will not be repeated here.

[0091] Example 5 This embodiment provides a lipid hybrid nanoparticle. The difference from Example 1 is that 1g of phosphatidylcholine is replaced with 3g of dipalmitoylphosphatidylcholine, and 0.05g of palmitoyl pentapeptide-4 (Pal-KTTKS) is replaced with 0.1g of hexapeptide-11 and 0.01g of palmitoyl pentapeptide-4 (Pal-KTTKS). The other raw materials and preparation methods are the same as in Example 1, and will not be repeated here.

[0092] Example 6 This embodiment provides a lipid hybrid nanoparticle. The difference from Example 1 is that the high-pressure homogenization parameter is modified to 15000 psi, and the homogenization is performed 3 times. The other raw materials and preparation methods are the same as in Example 1, and will not be described again here.

[0093] Example 7 This embodiment provides a lipid hybrid nanoparticle. The difference from Example 1 is that 20g of mannitol is replaced with 5g of trehalose and 12g of sucrose. The other raw materials and preparation methods are the same as in Example 1, and will not be repeated here.

[0094] Example 8 This embodiment provides a lipid hybrid nanoparticle. The difference from Example 1 is that 0.5g of glycyrrhetinic acid and 0.5g of 4-tert-butylcyclohexanol are added to the oil phase in step 1. The other raw materials and preparation methods are the same as in Example 1, and will not be repeated here.

[0095] Example 9 This embodiment provides a lipid hybrid nanoparticle. Unlike Example 1, in step 3, 0.5g of chelating agent (EDTA-2Na) is added to 15 times the volume of water that is rapidly stirred. The other raw materials and preparation methods are the same as in Example 1, and will not be repeated here.

[0096] Example 10 This embodiment provides a lipid hybrid nanoparticle. Unlike Example 1, in step 3, 15 times the volume of water with rapid stirring is added with 50 mM pH buffer (citric acid / disodium hydrogen phosphate system). The other raw materials and preparation methods are the same as in Example 1, and will not be repeated here.

[0097] Example 11 This embodiment provides a lipid hybrid nanoparticle. Unlike Example 1, in step 3, 1g of water-soluble antioxidant (ascorbic acid) is added to 15 times the volume of water that is rapidly stirred. The other raw materials and preparation methods are the same as in Example 1, and will not be repeated here.

[0098] Example 12 This embodiment provides a lipid hybrid nanoparticle. The difference from Example 1 is that 5g of retinol is replaced with palmetto bark extract, and 0.05g of palmitoyl pentapeptide-4 (Pal-KTTKS) is replaced with 1g of palmitoyl pentapeptide-4 (Pal-KTTKS). The other raw materials and preparation methods are the same as in Example 1, and will not be repeated here.

[0099] Example 13 This embodiment provides a lipid hybrid nanoparticle. The difference from Example 1 is that 5g of retinol is replaced with 3g of retinyl linoleate and 3g of retinyl palmitate, and 0.05g of palmitoyl pentapeptide-4 (Pal-KTTKS) is replaced with 0.05g of RGD linear peptide. The other raw materials and preparation methods are the same as in Example 1, and will not be repeated here.

[0100] Example 14 This embodiment provides a lipid hybrid nanoparticle. The difference from Example 1 is that 5g of retinol is replaced with astaxanthin, and 0.05g of palmitoyl pentapeptide-4 (Pal-KTTKS) is replaced with 0.02g of YIGSR peptide. The other raw materials and preparation methods are the same as in Example 1, and will not be repeated here.

[0101] Example 15 This embodiment provides a lipid hybrid nanoparticle. The difference from Example 1 is that 5g of retinol is replaced with idebenone, and 0.05g of palmitoyl pentapeptide-4 (Pal-KTTKS) is replaced with 0.1g of acetyl hexapeptide-8 and 0.02g of YIGSR peptide. The other raw materials and preparation methods are the same as in Example 1, and will not be repeated here.

[0102] Example 16 This embodiment provides a lipid hybrid nanoparticle. The difference from Example 1 is that 5g of retinol is replaced with β-carotene, and 0.05g of palmitoyl pentapeptide-4 (Pal-KTTKS) is replaced with 0.1g of acetyl hexapeptide-8 and 0.05g of fibroblast activation protein targeting peptide (FAPI). The remaining raw materials and preparation methods are the same as in Example 1, and will not be repeated here.

[0103] Comparative Example 1 This comparative example provides a liposome, and the specific preparation process is as follows: 5g retinol, 1g phosphatidylcholine, 0.5g tocopherol, and 0.05g palmitoyl pentapeptide-4 (Pal-KTTKS) are dissolved in ethanol to obtain an oil phase. 2g polyvinyl alcohol and 20g lyophilization protectant are dissolved in water to obtain an aqueous phase. The oil phase is slowly injected into the rapidly stirred aqueous phase, and the solvent is evaporated under stirring and nitrogen blowing conditions at 30°C to obtain a homogeneous liquid, which is the liposome.

[0104] Comparative Example 2 This comparative example provides a lipid hybrid nanoparticle. Unlike Example 1, palmitoyl pentapeptide-4 (Pal-KTTKS) is not added in step 2. The other raw materials and preparation methods are the same as in Example 1, and will not be repeated here.

[0105] Comparative Example 3 This comparative example provides a polymer nanoparticle loaded with an active ingredient. The preparation method is exactly the same as step 1 of Example 1, and will not be repeated here.

[0106] Comparative Example 4 This comparative example provides a lipid hybrid nanoparticle. Unlike Example 1, retinol is not added in step 1. The other raw materials and preparation methods are the same as in Example 1, and will not be repeated here.

[0107] Comparative Example 5 This comparative example provides an anti-aging composition, which is obtained by uniformly mixing 2g of polylactic-co-glycolic acid copolymer (PLGA), 5g of polycaprolactone (PCL), 5g of retinol, 0.5g of tocopherol, 2g of polyvinyl alcohol, 1g of phosphatidylcholine, 0.05g of palmitoyl pentapeptide-4 (Pal-KTTKS), and 20g of mannitol.

[0108] Comparative Example 6 This comparative example provides a self-made retinol lipid nanoparticle, the raw materials of which are shown in Table 1 below.

[0109] Table 1 Raw Material Composition

[0110] The specific preparation method is as follows: 1. Mix solid lipids with hydrogenated lecithin, place in a 75°C constant temperature water bath, stir to dissolve, and use as the solid lipid phase.

[0111] 2. Take liquid lipids, tocopherol and retinol, mix them, place them in a 50℃ constant temperature water bath, and stir magnetically until the retinol is completely dissolved to obtain the liquid lipid phase.

[0112] 3. Slowly add the liquid lipid phase to the solid lipid phase and stir continuously for 5 minutes to obtain the mixed lipid phase.

[0113] 4. Add the surfactant to deionized water, heat to above 80°C, and magnetically stir at 500 rpm until completely dissolved to obtain the aqueous phase. Finally, emulsify the mixed lipid phase and aqueous phase for 5 minutes, and homogenize twice under high pressure at 12000 psi to obtain retinol lipid nanoparticles.

[0114] Test Example 1: Particle Size Test The products obtained from the examples and comparative examples were dispersed in laboratory pure water to obtain a 1% pure water dispersion. The particle size and PDI were then tested using a BeNano 180 zeta Pro particle size analyzer. The test conditions were: 25°C, equilibration time 120s, and test angle 173°. The specific data are shown in Table 2.

[0115] Table 2 Initial appearance and particle size characterization of the examples and comparative examples

[0116] As can be seen from Table 2, Example 1 has uniform particle size (small PDI) and stable appearance (no clumping when dry); Comparative Example 5 (physical mixing) cannot form a uniform system; Comparative Examples 2 and 3 have particle size and PDI that are close to Example 1; Comparative Example 4 (blank carrier) has no active material loading and its particle size is slightly smaller than that of Example 1.

[0117] Test Example 2: Stability Test Example 1 and Comparative Examples 1-6 were sealed in a nitrogen atmosphere and then placed at room temperature for 30 days. The appearance changes of the products were observed visually and the particle size changes were tested at room temperature and under non-direct sunlight. The specific data are shown in Table 3.

[0118] Table 3. Appearance and particle size of the examples and comparative examples after 30 days.

[0119] As shown in Table 3, Example 1 exhibits a stable structure, remaining dry after 30 days with minimal particle size variation and a low PDI level, indicating high stability. Comparative Examples 1 and 6 show significantly darker colors and a significantly increased PDI, suggesting that the liposomes and solid lipid nanoparticles may undergo Austronstein ripening, leading to particle aggregation and system instability. Comparative Examples 2 and 4 demonstrate stability similar to Example 1, indicating that the introduction of the targeting agent and active ingredient does not significantly affect stability. Comparative Example 5 lacks a stable nanostructure, exhibiting severe discoloration and clumping after 30 days, making system instability difficult. Comparative Example 3 shows a slight increase in particle size and a significant increase in PDI, suggesting that without the protection of a lipid layer, slight aggregation may occur between solid polymer particles.

[0120] Test Example 3: Retention Rate Test Example 1 and Comparative Examples 1-6 were sealed in a nitrogen atmosphere and then placed at different temperatures for 30 days. The content of active ingredients was determined by high performance liquid chromatography and the retention rate was calculated. The specific data are shown in Table 4.

[0121] Table 4. 30-day retention rate of the examples and comparative examples.

[0122] As can be seen from Table 4, each embodiment exhibits good retention rate under various temperature conditions, especially under high temperature conditions, and the retention rate remains above 90% after 30 days of storage at 50°C.

[0123] The retention rate of Comparative Example 1 was significantly lower than that of Example 1 because it lacked the protection of the polymer layer; Comparative Example 3 had reduced protection due to the lack of a lipid hybrid layer, and its retention rate was slightly lower than that of Example 1; Comparative Example 5 did not form a stable nanostructure, and its retention rate showed a rapid downward trend with increasing temperature; Comparative Example 6 had a retention rate close to that of Example 1 at low temperatures (-20℃, 4℃, room temperature), but its stability dropped sharply at high temperatures, with a retention rate of only 58.11% at 50℃ after 30 days.

[0124] Test Example 4: Permeability Test A Franz cell diffusion system was used, with pigskin fixed between the receiving and supply cells. Experimental conditions included a temperature of 37℃, a stirring speed of 600 rpm, and a permeation time of 8 hours. The receiving cell was filled with the release medium, phosphate buffer (pH 7.4). 0.1 g of sample was applied to the skin surface, and the permeated receiving solution was collected. The cumulative retinol permeation amount in the receiving solution at each time point was quantitatively analyzed by high-performance liquid chromatography (HPLC). After 8 hours of permeation, the stratum corneum, active epidermis, and dermis were separated using an adhesive tape peeling method. Each layer was thoroughly minced, and the retinol remaining was extracted with acetonitrile. The retinol content in the skin abrasion solution was detected and analyzed by HPLC.

[0125] The significance was as follows when comparing sample groups: This means that a p-value < 0.05 indicates that... A p-value < 0.001 indicates that... ,get Figure 1 and Figure 2 Specific data are shown in Table 5.

[0126] Table 5 Summary of Skin Retention Results of Retinol in Samples

[0127] As shown in Table 5, there are significant differences in the skin retention properties of retinol among different samples, as detailed below: Comparative Example 5 performed the worst, with an average retention of only 0.49 µg / cm³ in the dermis. 2 The total retention was 2.70 µg / cm³. 2 With a total retention rate of only 1.98%, the free system has difficulty effectively penetrating into the deep layers of the skin, making it impossible to achieve deep delivery of retinol.

[0128] Comparative Example 6 showed moderate performance, with a dermal retention rate of 1.68 µg / cm³. 2 The total retention rate reached 5.09 µg / cm³. 2 Although its total retention was significantly increased by 88.38% compared to control 5 (P<0.01), it could not concentrate retinol in the dermal layer due to the lack of targeted delivery capability.

[0129] Comparative Examples 1, 2, and 3 showed lower performance than Example 1. The dermal retention rate of Comparative Example 1 was 1.86 µg / cm³. 2 Total retention: 4.03 µg / cm³ 2 Comparative Example 2 showed a dermal retention rate of 2.53 µg / cm³. 2 Total retention: 5.46 µg / cm³ 2 Comparative Example 3 showed a dermal retention rate of 2.05 µg / cm³. 2 Total retention: 4.40 µg / cm³ 2 Comparative Examples 1, 2, and 3 are all nanocarriers, which can improve the permeation of active ingredients. However, Comparative Examples 1 and 3 have simple structures and insufficient transdermal performance.

[0130] Example 1 showed the best performance: its retinol retention in the dermis reached 3.69 µg / cm³. 2 Compared to control sample 5, the concentration increased by 660.92%, and compared to control sample 6, the concentration increased by 120.33%; the total retention was 7.50 µg / cm³.2 Compared to Comparative Example 5, the performance was improved by 177.52%, and compared to Comparative Example 6, the performance was improved by 47.32%. This result fully demonstrates that the lipid hybrid nanoparticles of the present invention can efficiently guide retinol to target and accumulate in the dermis, and their performance is significantly better than that of free retinol systems and conventional retinol lipid nanoparticles that lack active targeting.

[0131] Test Example 5: Target Performance Test Comparative Examples 1 and 2 were prepared into aqueous dispersions with the same retinol concentration. HaCaT, HSF, and A375 cells were then cultured at a concentration of 8 × 10⁻⁶. 3 The cells were seeded at a density of 1 cell per well into 96-well plates and incubated overnight. After pre-incubation with culture medium, the samples were drug-treated when the cells reached the appropriate plating rate. Drug-free culture medium was added to the blank control wells. After drug-treated incubation, the supernatant was discarded, and the cells were washed with PBS, fixed, permeabilized, and stained with phalloidin and DAPI. Single-cell fluorescence density (SIOD) data were obtained by taking pictures under a fluorescence microscope. The specific data are shown in Table 6.

[0132] Table 6 Summary of Single-Cell Fluorescence Density (SIOD) Data Analysis Results

[0133] Note: Significance is based on This means that a p-value < 0.05 indicates that... A p-value < 0.01 indicates that... .

[0134] The experimental results show that Example 1 has HSF cell-specific uptake. Its uptake effect (SIOD value) in HaCaT cells and A375 cells is not significantly different from that in Comparative Example 2. However, in HSF cells, the SIOD value is significantly increased by 317% compared with the non-targeted nanoparticles (P < 0.01). This confirms the effectiveness of the targeted design of Example 1 due to the introduction of fibroblast-specific targeting ligands. It also provides a basis for its subsequent application in skin repair, anti-aging and other scenarios that require precise action on HSF cells. It can reduce non-specific effects on other skin cells and significantly improve the efficacy and biosafety in the application process.

[0135] Test Example 6: Security Test Follow the guidelines outlined in the "Expert Consensus on Clinical Application of Patch Testing (2020 Revised Edition)".

[0136] (1) Sample preparation: blank, 0.1% SDS positive control, Example 1 containing 0.1% retinol, Comparative Example 5, Comparative Example 6; (2) Subjects: a total of 30 people, 10 males and 20 females, aged 22 to 42 years, who met the subject voluntary selection criteria.

[0137] (3) Patch test method: Select qualified patch test equipment and use the closed patch test method. After random blinding, place the test substance in the patch test device at a quantitative level of 0.020mL~0.025mL. Apply the low-allergenic adhesive tape to one side of the upper back of the subject. Remove the test substance after 48 hours. Observe the skin reaction at 0.5, 24, 48 and 72 hours after removal. Record the results according to the recommendations of the International Contact Dermatitis Study Group (ICDRG). The results are shown in Table 7.

[0138] Table 7. Statistical results of adverse reactions to 48-hour closed patch treatment.

[0139] Patch results - the following is a ranking of mildness: Dimension 1: Peak number of adverse reactions in four time periods: The lower the peak, the milder the adverse reaction: Example 1 > Comparative Example 6 > Comparative Example 5.

[0140] Dimension 2: Total number of adverse reactions in four time periods: The lower the total, the milder the adverse reaction: Example 1 > Comparative Example 6 > Comparative Example 5.

[0141] Example 1 exhibited excellent skin tolerance: during the four observation time points of the 48-hour closed patch test, the peak nonspecific skin irritation occurred in only 2 cases, with a low overall adverse reaction rate. Furthermore, the irritation was transient, completely subsiding within 72 hours with no risk of persistent irritation. Comparative Example 5, due to its low skin biocompatibility, experienced severe nonspecific skin irritation, resulting in a significantly higher overall adverse reaction rate (15 cases), and exhibited the worst skin tolerance. Comparative Example 6 had a skin irritation index between the two, demonstrating moderate skin mildness. The lipid-hybrid nanoparticles provided by this invention can effectively improve the skin tolerance of the formulation, significantly outperforming free systems and non-targeted technologies.

[0142] In summary, the composite system provided by this invention, consisting of a core constructed from biodegradable polymer materials and a lipid hybrid outer layer, not only significantly improves the storage stability and skin penetration efficiency of anti-aging active ingredients, but also enables the slow and controllable release of active ingredients. With the dual benefits of improved bioavailability and enhanced targeting, it exhibits significant anti-aging efficacy while also possessing excellent safety and high application efficiency, providing reliable technical support for the precise delivery and efficient performance of anti-aging active ingredients.

[0143] Finally, it should be noted that the above-described embodiments are merely specific implementations of the present invention, used to illustrate the technical solutions of the present invention, and not to limit it. The scope of protection of the present invention is not limited thereto. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that any person skilled in the art can still modify or easily conceive of changes to the technical solutions described in the foregoing embodiments within the technical scope disclosed in the present invention, or make equivalent substitutions for some of the technical features; and these modifications, changes, or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention, and should all be covered within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A lipid hybrid nanoparticle, characterized in that, It has a core-shell structure, with the core being polymer nanoparticles loaded with anti-aging active ingredients and the outer shell being a lipid hybrid layer; The polymer nanoparticles are mainly formed from biodegradable polymer materials, anti-aging active ingredients, and emulsifiers. The lipid hybrid layer is mainly formed by phospholipids and fibroblast-targeting ligands.

2. The lipid hybrid nanoparticles according to claim 1, characterized in that, The average particle size is 200~430nm, and the PDI is <0.350; And / or, the average particle size of the polymer nanoparticles is 200~450 nm.

3. The lipid hybrid nanoparticles according to claim 1, characterized in that, The biodegradable polymer material is selected from at least one of polyglycolic acid, polylactic acid, L-polylactic acid, D-polylactic acid, racemic polylactic acid, polycaprolactone, polylactic acid-glycolic acid copolymer, polydioxanone, polytrimethylene carbonate, polyhydroxybutyrate, polylactic acid-caprolactone copolymer, and polycitrate. And / or, the anti-aging active ingredient is selected from at least one of retinol, retinol propionate, retinol palmitate, retinol acetate, retinol linoleate, hydroxypinazone retinate, idebenone, astaxanthin, pterostilbene, Dalbergia odorifera bark extract, grape skin extract, resveratrol, curcumin, coenzyme Q10, ferulic acid, tetrahydrocurcumin, and β-carotene; And / or, the emulsifier is selected from at least one of polyvinyl alcohol, gum arabic, maltodextrin, poloxamer 407, poloxamer 188, polyglycerol stearate, sucrose stearate, cetyl alcohol polyether-25, stearyl alcohol polyether-21, Span-80, polyethylene glycol fatty acid ester, glycerol fatty acid ester, Tween-80, Tween-20, lauryl alcohol polyoxyethylene ether-3, PEG-40 hydrogenated castor oil, sodium carboxymethyl cellulose, and hydroxypropyl methylcellulose; And / or, the phospholipid is selected from at least one of soybean lecithin, egg yolk lecithin, hydrogenated lecithin, phosphatidylcholine, phosphatidylethanolamine, dipalmitoylphosphatidylcholine, and distearate phosphatidylcholine; And / or, the selected phospholipid contains >90% phosphatidylcholine; And / or, the fibroblast-targeting ligand is selected from at least one of RGD peptide and its derivatives, palmitoyl tetrapeptide-7 and its derivatives, palmitoyl pentapeptide-4 and its derivatives, P-15 peptide and its derivatives, hexapeptide-11 and its derivatives, REDV peptide and its derivatives, acetyl hexapeptide-8 and its derivatives, TGF-β receptor-binding peptide, YIGSR peptide and its derivatives, fibroblast activation protein targeting peptide and its derivatives, and cell surface glycoprotein CD90.

4. The lipid hybrid nanoparticles according to any one of claims 1 to 3, characterized in that, The polymer nanoparticles also include hydrophobic anti-sensitivity agents and / or lipophilic antioxidants; And / or, the hydrophobic anti-allergen includes at least one of 4-tert-butylcyclohexanol, dihydroagar alkaloids, kava, glycyrrhetinic acid, and glycyrrhetinic acid ester; And / or, the fat-soluble antioxidant is selected from at least one of ascorbate tetraisopalmitate, guaiacol, tocopherol, tocopheryl acetate, lipoic acid, butylated hydroxyanisole, butylated hydroxytoluene, tea polyphenols, sarsaparilla acid, quercetin, tinraquinone, and ascorbate palmitate. And / or, the lipid hybrid layer further includes a lyophilization protectant and / or a water-soluble stabilizer; And / or, the freeze-drying protectant includes at least one of trehalose, sucrose, mannitol, sorbitol, maltitol, inositol, and glycine; And / or, the water-soluble stabilizer includes at least one of chelating agents, water-soluble antioxidants, pH buffers, preservatives, and co-emulsifiers; And / or, the preservative includes at least one of 1,2-pentanediol, 1,2-hexanediol, octanoyl hydroxamic acid, and sorbic acid.

5. The lipid hybrid nanoparticles according to any one of claims 1 to 3, characterized in that, Based on parts by weight, the polymer nanoparticles are mainly composed of 0.1 to 40 parts of biodegradable polymer material, 0.1 to 30 parts of anti-aging active ingredient, and 2 to 10 parts of emulsifier; And / or, by weight, the lipid hybrid layer is mainly composed of 1 to 10 parts of phospholipids and 0.01 to 1 part of fibroblast-targeting ligands.

6. The lipid hybrid nanoparticles according to claim 4, characterized in that, The polymer nanoparticles further include 0.05-10 parts by weight of a hydrophobic anti-sensitivity agent and / or 0.5-10 parts by weight of a lipid-soluble antioxidant. And / or, by weight, the lipid hybrid layer further includes 10-60 parts of a lyophilization protectant and / or 0.1-15 parts of a water-soluble stabilizer.

7. A method for preparing lipid hybrid nanoparticles according to any one of claims 1 to 6, characterized in that, Includes the following steps: A. Add biodegradable polymer materials and anti-aging active ingredients to the first organic solvent and mix evenly to obtain a transparent oil phase; add emulsifier to water and mix evenly to obtain a transparent aqueous phase; B. The aqueous phase and oil phase are mixed evenly, and after emulsification and high-pressure homogenization, an emulsion is obtained; then the solvent in the emulsion is removed, and after concentration, washing and drying, polymer nanoparticles are obtained. C. Add phospholipids and fibroblast-targeting ligands to the second organic solution and mix thoroughly to obtain a lipid mixture; D. The polymer nanoparticles are dispersed in the lipid mixture to form a homogeneous liquid to obtain an intermediate; then the intermediate is injected into rapidly stirred water and stirred evenly to obtain an aqueous solution of the intermediate; then the solvent in the aqueous solution of the intermediate is removed to obtain a lipid hybrid nanoparticle suspension; finally, the lipid hybrid nanoparticles are freeze-dried to obtain lipid hybrid nanoparticles.

8. The preparation method according to claim 7, characterized in that, The first organic solvent includes at least one of methanol, ethanol, ethyl acetate, isopropanol, n-heptane, and cyclohexane; And / or, the second organic solution includes ethanol; And / or, in step B, the solvent in the emulsion is removed by stirring at 0~45°C and combined with nitrogen blowing to evaporate the solvent; And / or, in step D, the solvent in the intermediate aqueous solution is removed by stirring at 0~45°C and combined with nitrogen blowing to evaporate the solvent.

9. The preparation method according to claim 7, characterized in that, In step D, during the preparation of the intermediate aqueous solution, the amount of water used is 10 to 20 times the volume of the intermediate; And / or, the pressure of the high-pressure homogenization process is 10,000 to 15,000 psi; And / or, the high-pressure homogenization process is performed 1 to 3 times.

10. The use of the lipid hybrid nanoparticles according to any one of claims 1 to 6 in the preparation of cosmetics.

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