CN116602884A - Multi-effect anti-aging co-delivery nano composition suitable for microneedles and preparation method and application thereof - Google Patents
Multi-effect anti-aging co-delivery nano composition suitable for microneedles and preparation method and application thereof Download PDFInfo
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- CN116602884A CN116602884A CN202310700077.9A CN202310700077A CN116602884A CN 116602884 A CN116602884 A CN 116602884A CN 202310700077 A CN202310700077 A CN 202310700077A CN 116602884 A CN116602884 A CN 116602884A
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Classifications
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- A—HUMAN NECESSITIES
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- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
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Abstract
The invention belongs to the technical field of nano-compositions, and particularly relates to a multi-effect anti-aging co-delivery nano-composition suitable for microneedles, and a preparation method and application thereof. The invention provides a multi-effect anti-aging co-delivery nano composition suitable for microneedles, which comprises a composite active factor, an emulsifying agent, a co-emulsifying agent, a preservative and water, wherein the composite active factor comprises polydeoxyribonucleotide, acetyl hexapeptide-8, palmitoyl pentapeptide-4, dihydro oat alkaloid and ergothioneine. The combination and collocation of the composite active factors can realize excellent skin anti-aging effect through multi-path and multi-target synergism.
Description
Technical Field
The invention belongs to the technical field of nano-compositions, and particularly relates to a multi-effect anti-aging co-delivery nano-composition suitable for microneedles, and a preparation method and application thereof.
Background
With the increase of the average life of people and the aging of society, the modern consumers have gradually enhanced awareness of skin health management. Therefore, the deep search for the skin aging mechanism and the development of corresponding means for delaying skin aging have become one of the research hotspots in the medical and cosmetic industries. According to the product components, the common anti-aging products in the current market have single action mechanism and often have unsatisfactory anti-aging effect. Based on the main action way related to the skin aging process, different functional components which are natural in source, high in safety and excellent in action effect are selected for scientific collocation, and the development of novel, synergistic and efficient anti-aging products has important significance.
On the other hand, the application of the functional skin care product starts from the skin surface, the percutaneous absorption process is required to be completed, the functional skin care product finally enters into the deep epidermal tissues, and target cells at the target part are accumulated to an effective concentration so as to smoothly play a target role. For various functional components, the skin-specific physiological structure also limits the percutaneous delivery efficiency of Wei Jiti while protecting it from external injury. Therefore, reducing the resistance of the stratum corneum, increasing the skin permeability, enabling the anti-aging functional components to smoothly enter epidermis, dermis and subcutaneous tissues involved in the skin aging process, and playing the anti-aging role at a plurality of layers and targets is a key for solving the problem.
At present, the development of relatively mature microneedle technology can solve the transdermal problem of partial functional components, a certain number of microneedles are arranged on a carrier in an array mode, and can break through the skin stratum corneum disorder to form a recoverable instant microchannel, so that the functional components can be directly led in the penetration of epidermis or dermis without causing pain and skin injury. However, in the existing commercially available products with anti-aging effects, commonly used anti-aging effect components are single, and because of the complexity of different anti-aging effect components in terms of molecular size, solubility, stability and the like, mutual interference or reaction among different anti-aging components can not be realized, so that the complex application of various anti-aging effect components in the microneedle technology can not be realized.
Disclosure of Invention
The invention aims to provide a multi-effect anti-aging co-delivery nano composition suitable for microneedles, a preparation method and application thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a multi-effect anti-aging co-delivery nano composition suitable for microneedles, which comprises the following components in percentage by mass:
1-10% of composite active factors, 2-10% of emulsifying agents, 2-12% of auxiliary emulsifying agents, 0.1-0.5% of preservative and the balance of water;
the complex active factors include polydeoxyribonucleotide, acetyl hexapeptide-8, palmitoyl pentapeptide-4, dihydroavenanthramide and ergothioneine.
Preferably, based on 100% of the mass of the multi-effect anti-aging co-delivery nano composition suitable for microneedles, the composite active factors comprise the following components in percentage by mass: 0.1 to 2 percent of polydeoxyribonucleotide, 80.001 to 0.01 percent of acetyl hexapeptide, 40.001 to 0.1 percent of palmitoyl pentapeptide, 1 to 5 percent of dihydro oat alkaloid and 0.1 to 2 percent of ergothioneine.
Preferably, the particle size of the multi-effect anti-aging co-delivery nano composition suitable for the micro-needle is 10-500 nm.
Preferably, the emulsifier comprises one or more of lecithin and/or polyoxyethylated hydrogenated castor oil.
Preferably, the co-emulsifier comprises one or more of butanediol, hexanediol and propylene glycol.
Preferably, the preservative comprises p-hydroxyacetophenone.
The invention provides a preparation method of a multi-effect anti-aging co-delivery nano composition suitable for a microneedle, which comprises the following steps:
uniformly mixing the composite active factors, the emulsifying agent, the auxiliary emulsifying agent, the preservative and the water to obtain a mixture;
carrying out micronization treatment on the mixture to obtain micron-sized particles;
and carrying out nanocrystallization treatment on the micrometer-sized particles to obtain the anti-aging nanometer composition.
Preferably, the micronization treatment is shearing mixing, and the rotating speed of the shearing mixing is 4000-30000 rpm, and the time is 1-20 min.
Preferably, the nanocrystallization treatment is a high-pressure homogenization treatment or a high-pressure micro-jet treatment;
the pressure of the high-pressure homogenizing treatment is 300-1600 bar, the temperature is 20-70 ℃, and the cycle times are 1-10 times;
the pressure of the high-pressure micro-jet treatment is 3000-16000 psi, the temperature is 20-70 ℃, and the cycle times are 1-10.
The invention provides the application of the multi-effect anti-aging co-delivery nano composition suitable for the micro-needles or the multi-effect anti-aging co-delivery nano composition suitable for the micro-needles obtained by the preparation method of the technical scheme in the preparation of cosmetics for resisting skin aging.
The invention provides a multi-effect anti-aging co-delivery nano composition suitable for microneedles, which comprises the following components in percentage by mass: 1-10% of composite active factors, 2-10% of emulsifying agents, 2-12% of auxiliary emulsifying agents, 0.1-0.5% of preservative and the balance of water; the complex active factors include polydeoxyribonucleotide, acetyl hexapeptide-8, palmitoyl pentapeptide-4, dihydroavenanthramide and ergothioneine. Wherein polydeoxyribonucleotide can induce the regeneration of skin tissue and cells damaged under the actions of physical and chemical stimulus, ultraviolet rays and the like, supplement the elastic fiber structure reduced by aging and enable the skin to recover the healthy elasticity; the dihydro oat alkaloid is derived from active ingredients of oat, can block the generation process of cell inflammation, reduce the generation of inflammatory immune response and skin neurodermatitis response, and can exert multiple effects of antihistamine, antioxidation, anti-irritation, anti-inflammation, erythema improvement and the like; the ergothioneine has strong antioxidation effect because of the amino acid derivative, can remove active oxygen free radicals, and protect mitochondria from oxidative damage, thereby realizing the effect of delaying cell aging; acetyl hexapeptide-8 is neurotransmitter inhibiting peptide, and participates in competing SNAP-25 at the site of the foam fusion complex, so that muscles cannot effectively accept neurotransmitter, muscle contraction is weakened, muscles are relaxed, and wrinkles are prevented from forming; palmitoyl pentapeptide-4 acts on dermal fibroblasts, can stimulate and promote synthesis of skin elastin, fibronectin, glycosaminoglycan and collagen to supplement extracellular matrix, and can improve the appearance of skin aging, smooth wrinkles and enhance skin firmness and glossiness. The invention combines and matches the active factors such as polydeoxyribonucleotide, acetyl hexapeptide-8, palmitoyl pentapeptide-4, dihydro oat alkaloid, ergothioneine and the like, and can realize excellent skin anti-aging effect through multi-path and multi-target synergism.
Meanwhile, due to the structural characteristics of the nano particles, the product can be suitable for a microneedle introduction technology, the efficient permeation of the functional components through the stratum corneum is promoted, the multi-effect anti-aging nano composition has good skin permeability and detention performance, the functional components are effectively promoted to diffuse further after permeating through the stratum corneum, reach all acting target positions, are enriched in high concentration, are retained for a long time, are slowly released and controlled, are finally ingested by tissue cells, the bioavailability and the overall skin anti-aging effect of the composition are improved, and the acting time is prolonged.
The invention provides a preparation method of a multi-effect anti-aging co-delivery nano composition suitable for microneedles, which comprises the following steps: mixing the composite active factors, the emulsifier, the auxiliary emulsifier, the preservative and water to obtain a mixture; carrying out micronization treatment on the mixture to obtain micron-sized particles; and carrying out nanocrystallization treatment on the micrometer-sized particles to obtain the anti-aging nanometer composition. According to the preparation method, through the combination of the micronization treatment and the nanocrystallization treatment, a plurality of scientifically matched anti-aging functional components are wrapped by adopting the emulsifying agent, the auxiliary emulsifying agent and the water, so that the multi-effect anti-aging nano composition with the nano particle size is obtained, the water dispersibility is good, the solubility of part of water-insoluble functional components and the irritation of part of functional components are improved, and the functional components can reach enough concentration in a product so as to smoothly exert corresponding functional effects.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions of the prior art, the drawings that are needed in the embodiments will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 shows the results of cell safety evaluation in test example 2;
FIG. 2 shows the results of the test example 3;
FIG. 3 is a graph showing cumulative permeation and skin hold-up measurements for the free composition, co-delivered nano-composition, and microneedle delivery set of test example 5;
FIG. 4 is a graph showing the results of the skin permeation behavior observed by the laser confocal microscope of test example 6;
FIG. 5 shows the results of test example 7;
FIG. 6 shows the results of the test example 8 cell antioxidant effect study;
FIG. 7 shows the results of the test example 9 cell anti-aging effect test;
FIG. 8 shows the results of the cell anti-aging factor study of test example 10.
Detailed Description
The invention provides a multi-effect anti-aging co-delivery nano composition suitable for microneedles, which comprises the following components in percentage by mass:
1-10% of composite active factors, 2-10% of emulsifying agents, 2-12% of auxiliary emulsifying agents, 0.1-0.5% of preservative and the balance of water;
the complex active factors include Polydeoxyribonucleotide (PDRN), acetyl hexapeptide-8, palmitoyl pentapeptide-4, dihydroavenanthramide and ergothioneine.
In the present invention, the preparation materials are commercially available as known to those skilled in the art unless otherwise specified.
The multi-effect anti-aging co-delivery nano composition suitable for the micro needle comprises 1-10% of composite active factors, preferably 2-7% by mass. In the invention, the mass percentage of the composite active factors cannot be too high or too low; when the content of the composite active factor component is too low, the whole anti-aging effect is not obvious; when the content of the composite active factor component is increased, the action effect is improved to a certain extent, but when the content of the effective component exceeds 10%, the particle size of the anti-aging nano composition is obviously increased, and the long-term stability of the product is not facilitated.
In the present invention, the complex active factor includes polydeoxyribonucleotide, acetyl hexapeptide-8, palmitoyl pentapeptide-4, dihydroavenanthramide and ergothioneine, and preferably includes: 0.1 to 2 percent of polydeoxyribonucleotide, 80.001 to 0.01 percent of acetyl hexapeptide, 40.001 to 0.1 percent of palmitoyl pentapeptide, 1 to 5 percent of dihydro oat alkaloid and 0.1 to 2 percent of ergothioneine.
The multi-effect anti-aging co-delivery nano composition suitable for the micro needle comprises 0.1-2% of polydeoxyribonucleotide, preferably 1-2% by mass. In the invention, polydeoxyribonucleotide is used as a repair reconstruction factor, which can induce the regeneration of skin tissues and cells damaged under the actions of physical and chemical stimulus, ultraviolet rays and the like, supplement the elastic fiber structure reduced due to aging and recover the healthy elasticity of the skin. The mechanism of action includes selective stimulation of receptors, shortening the time of transition of cells to proliferative phase; promoting secretion of a cell growth factor to stimulate cell growth; fast generation of capillaries, providing nutrition and oxygen, and simultaneously providing nucleotide raw materials for tissue regeneration.
The multi-effect anti-aging co-delivery nano composition suitable for the micro needle comprises 0.001-0.01% of acetyl hexapeptide-8, preferably 0.005-0.01% by mass. In the invention, acetyl hexapeptide-8 is taken as a signal anti-wrinkle factor to participate in competing with SNAP-25 at the site of the foam fusion complex, so that muscles cannot effectively accept neurotransmitters, muscle contraction is weakened, muscles are relaxed, and wrinkles are prevented from forming.
The multi-effect anti-aging co-delivery nano composition suitable for the micro needle comprises 0.001-0.1% of palmitoyl pentapeptide-4, preferably 0.005-0.01% by mass percent. In the invention, palmitoyl pentapeptide-4 acts as a regenerative wrinkle-relaxing factor on dermal fibroblasts, can stimulate and promote synthesis of skin elastin, fibronectin, glycosaminoglycan and collagen to supplement extracellular matrix, and can improve the appearance of skin aging, smooth wrinkles and enhance skin firmness and glossiness from deep level.
The multi-effect anti-aging co-delivery nano composition suitable for the microneedles comprises 1-5% of dihydro oat alkaloid, preferably 2-5% by mass. In the invention, the dihydro oat alkaloid is derived from an active ingredient of oat (Avena Sativa), is taken as an anti-allergic anti-inflammatory factor, and has the functions of inhibiting the degradation of keratinized cell nuclear factor NF-kappa B-alpha related to inflammation, and preventing the phosphorylation of p65 protein subunit on the cell nuclear factor NF-kappa B, thereby blocking the occurrence process of cell inflammation; reduces inflammation immune reaction and skin neurodermatitis reaction, and has antihistamine, antioxidant, anti-irritation, antiinflammatory, and erythema improving effects.
The multi-effect anti-aging co-delivery nano composition suitable for the micro needle comprises 0.1-2% of ergothioneine, and preferably 1-2% of ergothioneine. In the invention, ergothioneine is taken as a photoprotection factor, has strong antioxidation, can remove active oxygen free radicals, and protects mitochondria from oxidative damage, thereby realizing the effect of delaying cell aging. As a super antioxidant, it is the only antioxidant capable of repairing mitochondria with a definite mechanism. It has also been shown to inhibit the activation and production of inflammatory cytokines by UVB irradiation, while having fibroblast protective effects.
According to the skin aging development process and mechanism, polydeoxyribonucleotide, acetyl hexapeptide-8, palmitoyl pentapeptide-4, dihydro oat alkaloid and ergothioneine active factors are combined and matched, so that the multi-way multi-target effect is realized from the multi-action ways of stimulating collagen and elastic fiber formation, promoting extracellular matrix construction, resisting oxidative inflammation stimulation, protecting ultraviolet injury and regulating skin neurotransmitter, and the excellent skin anti-aging effect is realized.
The multi-effect anti-aging co-delivery nano composition suitable for the micro needle comprises 2-10% of emulsifying agent, preferably 2-8% by mass. In the present invention, the emulsifier preferably comprises lecithin and/or polyoxyethylene hydrogenated castor oil, more preferably lecithin and polyoxyethylene hydrogenated castor oil, and the mass ratio of the lecithin to the polyoxyethylene hydrogenated castor oil is preferably 1 (1-3), more preferably 1:1.
The multi-effect anti-aging co-delivery nano composition suitable for the micro needle comprises 5-12% of co-emulsifier, preferably 5-10% by mass. In the present invention, the co-emulsifier preferably includes one or more of butanediol, hexanediol, and propylene glycol, more preferably butanediol, 1, 2-hexanediol, and 1, 3-propanediol. In the present invention, the mass ratio of the butanediol, 1, 2-hexanediol and 1, 3-propanediol is preferably (1 to 3): (2.5-5): (2.5 to 5), more preferably 1:2.5:2.5. The invention combines butanediol, 1, 2-hexanediol and 1, 3-propanediol, which is beneficial to the dispersion of the composition and improves the solubility of the composite active factors.
In the invention, when the types and the contents of the emulsifying agent and the auxiliary emulsifying agent in the multi-effect anti-aging co-delivery nano composition suitable for the micro needle are in the above preferred ranges, the prepared anti-aging nano composition has smaller particle size, uniform size distribution and high stability.
The multi-effect anti-aging co-delivery nano composition suitable for the microneedles comprises 0.1-0.5% of preservative, and the preservative preferably comprises p-hydroxyacetophenone.
The multi-effect anti-aging co-delivery nano composition suitable for the microneedles comprises the balance of water in percentage by mass, wherein the water is preferably distilled water or purified water.
In the invention, the particle size of the multi-effect anti-aging co-delivery nano composition suitable for the microneedles is preferably 10-500 nm, more preferably 10-200 nm, and the stability of the multi-effect anti-aging co-delivery nano composition in the particle size range is higher.
The invention provides a preparation method of a multi-effect anti-aging co-delivery nano composition suitable for a microneedle, which comprises the following steps:
mixing the composite active factors, the emulsifier, the auxiliary emulsifier, the preservative and water to obtain a mixture;
carrying out micronization treatment on the mixture to obtain micron-sized particles;
and carrying out nanocrystallization treatment on the micrometer-sized particles to obtain the multi-effect anti-aging co-delivery nano composition suitable for the microneedles.
The invention mixes the composite active factors, the emulsifying agent, the auxiliary emulsifying agent, the preservative and the water to obtain the mixture.
In the present invention, the mixing temperature is preferably 30 to 50 ℃, more preferably 45 ℃; the mixing preferably comprises the steps of:
(1) Heating and mixing polydeoxyribonucleotide, part of auxiliary emulsifier and part of water for the first time to obtain phase A, wherein the part of auxiliary emulsifier is preferably butanediol; the temperature of the first mixing is preferably 45 ℃; the heating is preferably water bath heating;
(2) Heating and mixing acetyl hexapeptide-8, palmitoyl pentapeptide-4, the other part of auxiliary emulsifier and the other part of water for the second time to obtain a phase B; the further portion of the co-emulsifier is preferably propylene glycol; the temperature of the second mixing is preferably 45 ℃; the heating is preferably water bath heating;
(3) Heating the dihydro oat alkaloid, the emulsifier, the residual auxiliary emulsifier and the residual water for third mixing to obtain a C phase; the residual co-emulsifier is preferably hexanediol; the temperature of the third mixing is preferably 45 ℃; the heating is preferably water bath heating;
(4) Heating ergothioneine and a preservative for fourth mixing to obtain a D phase; the temperature of the fourth mixing is preferably 45 ℃; the heating is preferably water bath heating;
(5) And carrying out fifth mixing on the B phase and the C phase to obtain a mixed phase, namely a phase A and a D phase. The temperature of the fifth mixing is preferably 45 ℃, the fifth mixing is preferably performed under stirring, and the stirring rotation speed is preferably 500rpm.
After the mixture is obtained, the mixture is subjected to micronization treatment to obtain the micron-sized fraction.
In the present invention, the micronization treatment is preferably shear mixing. The rotational speed of the shear mixing is preferably 4000 to 30000rpm, more preferably 10000 to 30000rpm, and the time is preferably 1 to 20 minutes, more preferably 5 to 15 minutes.
After obtaining the micro-scale fraction, the invention carries out nanocrystallization treatment on the micro-scale fraction to obtain the multi-effect anti-aging co-delivery nano composition suitable for the micro-needle. In the present invention, the nanocrystallization treatment is preferably a high-pressure homogenization treatment or a high-pressure microfluidization treatment; the pressure of the high-pressure homogenizing treatment is preferably 300-1600 bar, more preferably 500-1500 bar, the temperature is preferably 20-70 ℃, more preferably 40-60 ℃, and the cycle time is preferably 1-10 times, more preferably 2-6 times; the pressure of the high pressure microfluidic treatment is preferably 3000 to 16000psi, more preferably 5000 to 15000psi, the temperature is preferably 20 to 70 ℃, more preferably 40 to 60 ℃, and the number of cycles is preferably 1 to 10, more preferably 2 to 6.
According to the invention, a plurality of scientifically matched functional components are packaged and delivered by adopting an emulsifier and an auxiliary emulsifier through a method of combining micron treatment and nanocrystallization treatment, and the multi-effect anti-aging nano composition obtained through packaging nanocrystallization has good water dispersibility based on a nano carrier structure and characteristics, so that the solubility of part of water-insoluble functional components and the irritation of part of functional components are improved, and each functional component can reach enough concentration in a product to smoothly exert corresponding functional effects. Thanks to the structural characteristics of the nano carrier, the product can be suitable for a microneedle introduction technology, the efficient permeation of the functional components through the stratum corneum is promoted, the multi-effect anti-aging nano composition has good skin permeability and detention performance, the functional components are effectively promoted to further diffuse after permeating through the stratum corneum, reach various action target positions, are enriched in high concentration and are retained for a long time, slow release and controlled release, and finally are ingested by tissue cells, so that the bioavailability and the overall skin anti-aging effect of the composition are improved, and the action time is prolonged.
The invention provides the application of the multi-effect anti-aging co-delivery nano composition suitable for the micro-needles or the multi-effect anti-aging co-delivery nano composition suitable for the micro-needles obtained by the preparation method of the technical scheme in the preparation of cosmetics for resisting skin aging. The multi-effect anti-aging co-delivery nano composition suitable for the microneedles can be used for preparing cosmetics with the effects of resisting aging, removing wrinkles, repairing, whitening and the like. The cosmetic forms include, but are not limited to, lotions, creams, lotions, essences, and gels. The multi-effect anti-aging co-delivery nano composition suitable for the microneedles is easy to dissolve in water and can be used in combination with a microneedle introduction technology.
In the invention, the skin aging resistant cosmetic preferably comprises the multi-effect aging resistant co-delivery nano composition and the blank essence which are suitable for the microneedles and are prepared by the technical scheme. The mass percentage of the anti-aging nano composition added into the cosmetic is preferably 0.1-30%.
In the invention, the blank essence preferably comprises the following components in percentage by mass: glycerin 1-3%, carbomer 0.1-0.3%, xanthan gum 0.1-0.2%, phenoxyethanol 0.1-0.5% and water in balance ； More preferably glycerol 2%, carbomer 0.3%, xanthan gum 0.1%, phenoxyethanol 0.5% and the balance water.
In the invention, the anti-aging nanometer composition can be used in combination with a microneedle introduction technology, the microneedle is a novel physical permeation promotion technology, hundreds of microneedles with the height of 10-2000 mu m and the width of 10-50 mu m are arranged on a base, and the length, the size and the shape of the microneedles can be accurately regulated and controlled and individually designed according to requirements. The microneedles can be directed through the stratum corneum without touching the pain nerve, forming immediate delivery channels on the skin surface to allow the efficacy product to reach the designated depth of the skin, and be placed directly on the epidermis or upper dermis. The channel can be automatically restored within 20-30 minutes after the microneedle is acted on. The microneedle technology can play a role in safely and effectively promoting transdermal penetration of the functional components, and provides a new research thought for improving the functional effects of cosmetics. The invention wraps the components with different anti-aging mechanisms in the nano-carrier, and after encapsulation, the structural integrity and biological activity of the components are still maintained, and meanwhile, the light and heat stability of the functional components are improved, the solubility and water dispersibility of indissolvable active components are improved, and the irritation of part of active components is reduced. The characteristics and advantages of the nano carrier are benefited, a foundation is provided for the combination of the multi-effect anti-aging nano composition and the microneedle introduction technology, and the effect components can quickly penetrate through the stratum corneum of the skin to reach the target site. In addition, the nano carrier has small particle size and large specific surface area, shows slow and controlled release characteristics and high bioadhesion in percutaneous delivery, can effectively promote the permeation and diffusion of high-content functional components at the action target part, and has the effects of detention, prolonging the action time, improving the bioavailability and enhancing the integral skin anti-aging effect.
For further explanation of the present invention, an anti-aging nano-composition, a preparation method and application thereof, provided by the present invention, are described in detail below with reference to the accompanying drawings and examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Mixing 1% of PDRN, 1% of butanediol and 30% of water according to mass percentage, and heating and dissolving in a water bath at 45 ℃ to obtain a phase A;
mixing 0.005% of acetyl hexapeptide-8, 0.005% of palmitoyl pentapeptide-4, 2.5% of 1, 3-propanediol and 23.99% of water, and heating and dissolving in water bath at 45 ℃ to obtain phase B;
mixing 2.5% of dihydro oat alkaloid, 2.5% of lecithin, 2.5% of PEG-40 hydrogenated castor oil, 2.5% of 1, 2-hexanediol and 30% of water, and heating in water bath at 45 ℃ to dissolve to obtain phase C;
mixing 1% ergothioneine extract with 0.5% p-hydroxyacetophenone, and heating in 45deg.C water bath to dissolve to obtain phase D;
mixing the phase B and the phase C under the stirring condition of 45 ℃ and 500rpm, sequentially adding A, D phases, uniformly mixing, and carrying out high-speed shearing treatment for 8min at the rotating speed of 10000rpm to obtain micro-sized particles;
and (3) carrying out high-pressure homogenization treatment on the micro-sized fraction at the temperature of 45 ℃ and the pressure of 700bar, circulating for 2 times, and cooling to room temperature to obtain the multi-effect anti-aging co-delivery nano composition.
Example 2
The formulation was the same as in example 1, except that after the micron-sized fraction was obtained according to the procedure of example 1, high-pressure micro-jet treatment was performed at a pressure of 8000psi and a temperature of 45℃and circulated 3 times, and cooled to room temperature, to obtain a multi-effect anti-aging co-delivery nanocomposite.
Examples 3 to 15
The formulations are shown in Table 1, and the preparation method is the same as in example 1, except that some components and contents in the formulations are slightly changed.
Comparative examples 1 to 15
The formulation is shown in Table 2, and the preparation method is the same as that of example 1, except that part of the components and contents in the formulation are changed greatly.
Comparative example 16
All the functional components and 2% dimethyl sulfoxide in the formula of the example 1 are added into the balance of purified water, and ultrasonic dissolution is carried out at 45 ℃ to obtain the free multi-effect anti-aging composition.
Comparative example 17
The preparation method is the same as in example 1, except that the functional component in the formulation is only 2.5% of the dihydro oat alkaloid, and the single-package nano-carrier containing 2.5% of the dihydro oat alkaloid is obtained.
Comparative example 18
The preparation method is the same as in example 1, except that the effective components in the formula are 1% PDRN, 1% ergothioneine, 0.005% acetyl hexapeptide-8 and 0.005% palmitoyl pentapeptide-4, and the nano composition containing 1% PDRN, 1% ergothioneine, 0.005% acetyl hexapeptide-8 and 0.005% palmitoyl pentapeptide-4 is obtained.
TABLE 1 kinds and mass% of raw materials used in examples
TABLE 2 kinds and mass% of raw materials used in each comparative example
Application example 1
Preparation of efficacy test sample essence
2.0% of glycerol, 0.3% of carbomer, 0.1% of xanthan gum, 0.5% of phenoxyethanol and 97.2% of purified water are stirred and dissolved at room temperature to obtain blank essence. And each set of test samples was prepared as follows.
Table 3 test essence composition
| Control group 1 | Blank essence |
| Control group 2 | Blank essence +20% sample from comparative example 16 |
| Sample group | Blank essence +20% nanocarriers from example 1 |
| Microneedle group | Blank essence +20% nanocarriers from example 1 |
Test example 1 stability test
The multi-effect anti-aging co-delivery nano composition prepared in examples 1-15 and comparative examples 1-10 was placed in a closed container, and placed at normal temperature and 45 ℃ for 3 months respectively, and subjected to freeze thawing experiments, appearance of the samples before and after storage was checked, particle size of the nano composition before and after storage was tested, and stability of the nano composition was comprehensively evaluated.
Freeze thawing experiment: the sample was placed in a closed container, placed at-20 ℃ for 48 hours, then placed at 45 ℃ for 48 hours, and cycled twice to observe the change of the sample.
The particle size of the nano composition is detected by a Zetasizer Nano-ZS90 laser particle sizer, a proper amount of the nano composition is taken, and diluted by ultrapure water for 50 times, so that the average light intensity of the sample solution is 200-300, the particle size measuring angle of the laser particle sizer is 90 degrees, and the testing temperature is 25 ℃.
TABLE 4 stability results of anti-aging nanocomposites
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As can be seen from the data in Table 4, the anti-aging nano-compositions (examples 1-15) prepared under the conditions of the efficacy, the emulsifier, the co-emulsifier and the corresponding content according to the invention have uniform appearance and no layering and precipitation phenomena. On the other hand, the nano composition was not formed (comparative examples 2, 4, 5 to 9), or the stability was very poor, and the phenomenon such as delamination and precipitation was liable to occur (comparative examples 1, 3, 10). The particle size of the obtained multi-effect nano composition is lower under the conditions of preferable functional substances, emulsifying agents and auxiliary emulsifying agents, and the particle size of the nano composition prepared under non-preferable conditions is relatively larger, but the particle size is kept in the range of 10-500 nm. After being inspected for 3 months at room temperature and 45 ℃ and freeze thawing experiments, the multi-effect anti-aging co-delivery nano composition of each embodiment is still stable, and meets the practical application requirements.
Test example 2 cell safety evaluation
The testing method comprises the following steps: HSF cells (human skin fibroblasts) and HaCaT cells (human keratinocytes) were individually seeded in 96-well plates at 5% CO using the CCK-8 assay 2 After 24h incubation at 37℃100. Mu.L of complete DMEM medium (50, 100, 200, 400 and 800. Mu.g/mL of PDRN) containing the multi-effect anti-aging nano-composition described in example 1 and the free anti-aging composition described in comparative example 16 was added to 96-well plates of 2 cells, respectively, and after further incubation for 24h, cell viability was measured by CCK-8 method, and the control group was 100. Mu.L of complete DMEM medium alone.
As shown in (A) of FIG. 1, the concentration is 50-400. Mu.g/mL, and the HaCaT cell activity of the free composition and the co-delivery nano-composition is above 80%, and the free composition and the co-delivery nano-composition have no cytotoxicity. As shown in (B) of FIG. 1, in the range of 50-800. Mu.g/mL, the HSF cell activities of the free composition and the co-delivery nano-composition are both above 80%, and the above results show that the multi-effect anti-aging co-delivery nano-composition has safety.
Test example 3 evaluation of allantoic irritation of chick embryo
The multi-effect anti-aging nano-composition described in examples 1-15 was diluted 10-fold with physiological saline, 0.2mL of the sample was sucked and dropped on the surface of chorioallantoic membrane, vascular changes were observed for 5min and the initial time of the chorioallantoic membrane vessels to develop congestion, hemorrhage and coagulation was recorded, and the stimulation score IS was calculated. .
IS＝[(301-secH)×5+(301-secL)×7+(301-secC)×9]/300
Wherein secH is the initial time of table congestion, s; secL is the initial time of superficial bleeding, s; secC is the initial time of surface coagulation, s.
The stimulation was classified according to the mean size, with 0-0.9, 1.0-4.9, 5.0-8.9, and 9-21.0 being classified as no stimulation, mild stimulation, moderate stimulation, severe stimulation, respectively.
The final results of examples 1-15 of the present invention are similar, and the results of the stimulation evaluation of the multi-effect anti-aging co-delivered nano-composition of example 1 are shown in FIG. 2. After the 10-fold diluted nano composition is contacted with chick embryo allantoic membrane for 300 seconds, capillary vessels have no bleeding, no vascular thawing and no coagulation phenomenon, and the reaction integral is 0.7, which shows that the 10-fold diluted multi-effect anti-aging co-delivery nano composition has better safety and no irritation.
Test example 4 Patch test
45 subjects were selected for the experiment and the response of the subjects was recorded. The filter paper sheets of 10% of the multi-effect anti-aging nano-composition described in examples 1-15 are placed in a plaque tester, and normal holes are blank controls. The sample and the blank are attached to the forearm curved side of the subject, the sample and the blank are uniformly attached to the skin by lightly pressing the palm, the time lasts for 24 hours, the interval is 30 minutes after the spot tester is removed, and the skin reaction is observed after the indentation disappears. The skin reaction was observed after removing the plaque tester for 24 hours and 48 hours.
The results showed that none of the 45 subjects had erythema, edematous erythema, significant redness, infiltration or pimple, pimple or bleb, etc., indicating that the multi-effect anti-aging nano-composition in this test was non-irritating to human skin.
Test example 5 cumulative penetration and skin hold-up measurement
The transdermal experiments of the isolated pigskin were performed using the vertical Franz diffusion cell method. Taking 0.5g of 5% multi-effect anti-aging nano-composition essence of the sample group in application example 1 and 0.5g of 5% free multi-effect anti-aging composition essence of the control group 2 respectively in a supply chamber, simultaneously continuously injecting 0.5g of application example 1 essence into the vertical surface of a microneedle, and analyzing and calculating the accumulated permeation quantity of specific medicines in unit area at different time by using PBS (pH 7.4) as a receiving solution through HPLC. After 24 hours, the skin homogenate supernatant was analyzed by HPLC to calculate the skin storage per unit area of the specific functional ingredient. The cumulative skin permeation of the functional components at different sampling times was calculated according to the following formula.
Where Qn is the cumulative drug permeation quantity, cn is the drug concentration measured at the nth time, ci is the drug concentration measured at the ith point, V0 is the volume of the diffusion cell, i.e., the quantity of release medium added, and Vi is the quantity of each sample. Cumulative permeation per unit area q=qn/S, where S is the area of the diffusion cell 2.27cm 2 。
As can be seen from FIG. 3, the 24-hour cumulative skin permeation rate per unit area of the free composition, co-delivered nano-composition and the dihydroavenanthramide in the microneedle delivery set was 8.65 μg/cm, respectively 2 、29.42μg/cm 2 And 82.37. Mu.g/cm 2 The skin storage amounts were 24.36. Mu.g/cm, respectively 2 、75.26μg/cm 2 And 95.34. Mu.g/cm 2 . Compared with the free group, the accumulated permeation quantity of the dihydro-avenanthramide per unit area of the skin in the co-delivery group and the microneedle group is respectively increased by 240.1 percent and 852.3 percent, and the accumulated skin storage quantity of the dihydro-avenanthramide is respectively increased by 208.9 percent and 291.4 percent. The nanometer carrier coating of the active component can effectively promote the transdermal absorption of the active component and the storage quantity in the skin, improve the bioavailability of the skin and is more beneficial to the transdermal absorption after the treatment of the microneedle.
Test example 6 laser confocal microscopy for skin penetration behavior
The test experimental device is the same as the transdermal experimental device, 5% of multi-effect anti-aging co-delivery nano composition essence of a sample group in application example 1 marked by Rhodamine B (RhoB) and 5% of free anti-aging composition essence of a control group 2 are taken in a supply room, meanwhile, the essence of application example 1 is continuously injected into the vertical surface of a microneedle, PBS is taken as a receiving solution, the PBS is stirred and diffused at 37 ℃, residual samples on the skin are gently wiped off after 2 hours and 4 hours, the skin in a target area is taken down, the skin is rinsed again, and residual moisture is wiped after thorough cleaning. The samples were frozen and the sections were observed by laser confocal microscopy.
As can be seen from fig. 4, the fluorescence penetration depth of the skin increases with time. The results show that the fluorescence intensity of the RhoB marked multi-effect anti-aging co-delivery nano-composition essence in the skin is obviously stronger than that of the free form in the same time, and the multi-effect anti-aging co-delivery nano-composition essence can enter the active epidermis and dermis layers. And after the skin is delivered by the microneedle, the fluorescence intensity and penetration depth of the skin are further enhanced and reach the deep dermis, which indicates that the microneedle combined with the nano carrier can promote the entrapped components to permeate the skin rapidly, thereby exerting better anti-aging effect.
Test example 7 study of proliferation-promoting Effect of cells
HaCaT and HSF cells were seeded in 96-well plates at 100. Mu.L per well in 5% CO 2 Culturing at 37 ℃ for 24 hours. 100. Mu.L of DMEM complete medium (100, 200 and 400. Mu.g/mL) containing the multi-effect anti-aging nano-composition of example 1 and the free multi-effect anti-aging composition of comparative example 16 was added to each well, and 100. Mu.L of DMEM complete medium was added to the control group, and the cell proliferation rate was measured by the CCK-8 method after culturing was continued for 48 hours.
As shown in (A) of FIG. 5, the concentration of the multi-effect anti-aging nano-composition was 200 and 400. Mu.g/mL, as compared with the control group, which had an effect of promoting proliferation of HaCaT cells (P <0.01 or P < 0.05). Compared with the free composition, the multi-effect anti-aging nano composition has the effect of promoting proliferation of HaCaT cells (P < 0.01) at 400 mug/mL. As shown in FIG. 5 (B), the concentration of the multi-effect anti-aging nano-composition was 400. Mu.g/mL, which has an effect of promoting proliferation of HSF cells (P <0.01 or P < 0.05) compared to the control group and the free composition at the same concentration. The data prove that the multi-effect anti-aging nano-composition can effectively resist skin aging by promoting the proliferation and renewal of HaCaT and HSF cells, and the cell proliferation promoting effect of the anti-aging nano-composition obtained by the nano-carrier technology is further improved. Wherein, the legend of "100 μg/mL" in FIG. 5 corresponds to the bar graph filled with "black dots", the legend of "200 μg/mL" corresponds to the bar graph filled with "squares", and the legend of "400 μg/mL" corresponds to the bar graph filled with "twills" (the same in the following figures).
Test example 8 cell antioxidant Effect study
HSF cells were seeded in 24-well plates at 500. Mu.L per well in 5% CO 2 Culturing at 37 ℃ for 24 hours. Is divided into a control group,Model group, administration group, control group added with DMEM complete medium only, model group added with 0.8mmol/L H 2 O 2 DMEM complete medium containing 0.8mmol/L H was added to each of the drug administration groups 2 O 2 And example 1 DMEM complete medium of multi-effect anti-aging co-delivered nanocomposites, DMEM complete medium of different concentrations of comparative example 16 free multi-effect anti-aging composition (concentrations 100, 200 and 400 μg/mL) were co-cultivated for 24h. Cell activity was determined with CCK8 and cell supernatants were assayed for SOD activity, GSH content, and MDA content with the kit.
As shown in FIG. 6 (A), model group HSF cells were cultured at 0.8mmol/L H 2 O 2 The cell survival rate after injury is reduced to 40.95 percent, and the cell injury effect is obvious, which indicates H 2 O 2 Oxidative damage HaCaT cell model establishment was successful. Compared with the model group, the anti-aging co-delivery nano composition can obviously improve the cell activity (P) of oxidative damage when the concentration is 200 and 400 mu g/mL<0.01). Compared with the free anti-aging composition, the anti-aging co-delivery nano composition can remarkably improve the cell activity (P) of oxidative damage when the concentration is 200 and 400 mu g/mL <0.05 or P<0.01)。
As shown in FIG. 6 (B), model group HSF cells were cultured at 0.8mmol/L H 2 O 2 The SOD activity after injury is 19.54U/mg prot, which is obviously reduced compared with the control group. Compared with the model group, the anti-aging co-delivery nano composition can obviously improve SOD activity (P)<0.01). Compared with free anti-aging composition, the anti-aging co-delivery nano-composition can significantly improve the SOD activity (P) of cells with oxidative damage<0.05 or P<0.01)。
As shown in FIG. 6 (C), model group HSF cells were cultured at 0.8mmol/L H 2 O 2 GSH content after injury is 7.37mg/Lt, which is obviously reduced compared with the control group. Compared with the model group, the GSH content of the free anti-aging composition group and the anti-aging co-delivery nano composition group is obviously increased (P<0.05 or P<0.01). Compared with the free anti-aging composition, the anti-aging co-delivery nano composition can obviously improve the GSH content (P) of cells damaged by oxidation when the concentration of the anti-aging co-delivery nano composition is 400 mu g/mL<0.01)。
As shown in FIG. 6 (D), model group HSF cells were cultured at 0.8mmol/L H 2 O 2 MDA content increases after injuryThe addition rate is 10.98nmol/mL, and the addition rate is obviously increased compared with the control group. Compared with the model group, when the concentration of the anti-aging co-delivery nano composition is 200 and 400 mu g/mL, the MDA content (P) can be obviously reduced<0.01)。
The experimental results show that the anti-aging co-delivery nano composition can improve SOD activity and GSH content, and can effectively reduce cell oxidative damage. Compared with the free anti-aging composition with the same dosage, the anti-aging co-delivery nano composition has more excellent skin oxidation resistance.
Test example 9 cell anti-aging Effect detection
HSF cells were seeded in 24-well plates at 500. Mu.L per well in 5% CO 2 Culturing at 37 ℃ for 24 hours. The experiments were divided into a blank group, a model group, and a sample group (example 1, comparative example 16, comparative example 17, comparative example 18). Adding complete culture solution into blank control group, adding 10mg/mL D-galactose into model group to induce and construct aging model, adding culture solution diluted solution of the compositions prepared in example 1, comparative example 16, comparative example 17 and comparative example 18 which are diluted 1000 times, pretreating for 5 hr, adding 10mg/mL D-galactose, placing into CO 2 Incubator (37 ℃,5% CO) 2 ) Each group of cells was washed 3 times with 0.01mol/LPBS, 1mL of beta-galactosidase staining fixative was added to each well, fixed for 15min at room temperature, washed 3 times with pbs, 1mL of beta-galactosidase staining working solution was added, incubated overnight at 37 ℃, and staining results were observed under a microscope. Each group was randomly selected from 3 fields, the number of positive cells in 100 cells was counted, and the positive cell rate was calculated, and the results are shown in fig. 7.
As shown in FIG. 7, after HSF cells were molded with 10mg/mL of D-galactose, the positive cell rate was significantly increased compared to the blank control group. The positive cell rates of comparative example 16, comparative example 18 and example 1 were all significantly reduced (P < 0.01) compared to the model group, while the positive cell rate of comparative example 17 was not significantly changed (P > 0.05). The positive cell rate was significantly reduced for example 1 (P < 0.01) compared to comparative example 16, and for example 1 (P < 0.01) compared to comparative example 18. The results showed that the single package nanocarrier with only the dihydroavenanthramide (comparative example 17) had no anti-aging effect, the positive cell rate of the nanocomposite with the addition of the polydeoxyribonucleotide, the acetyl hexapeptide-8, the palmitoyl pentapeptide-4 and the ergothioneine 4 raw materials (comparative example 18) was 41%, the positive cell rate of the nanocomposite with the addition of the polydeoxyribonucleotide, the acetyl hexapeptide-8, the palmitoyl pentapeptide-4, the ergothioneine and the dihydroavenanthramide 5 raw materials (example 1) was 17%, and the positive cell rate of example 1 was reduced by 141% compared to comparative example 18. The positive cell rate of the free composition (comparative example 16) to which 5 raw materials were added was 45%, and the positive cell rate of example 1 was reduced by 165% as compared with comparative example 16. The compound of the dihydro oat alkaloid and the polydeoxyribonucleotide, the acetyl hexapeptide-8, the palmitoyl pentapeptide-4 and the ergothioneine raw materials can promote the effect of the anti-aging effect components to be improved, and the anti-aging effect of the packaged nano composition is greatly enhanced compared with that of the free components.
Test example 10 cell anti-aging factor study
HSF cells were seeded in 24-well plates at 500. Mu.L per well in 5% CO 2 Culturing at 37 ℃ for 24 hours. Control group was supplemented with DMEM complete medium alone, model group was 20J/cm 2 The cells were subjected to pretreatment for 1 hour with the DMEM complete medium containing the multi-effect anti-aging co-delivery nanocomposites of example 1 and the DMEM complete medium (concentrations 100, 200 and 400. Mu.g/mL) of the free multi-effect anti-aging composition of comparative example 16 at different concentrations, followed by 20J/cm 2 Is placed in CO 2 Incubation was performed in an incubator for 24h, and supernatants were assayed for type I collagen (ColI), type III collagen (ColIII) and Hyaluronic Acid (HA) content using an Elisa kit.
As shown in FIG. 8, HSF was purified by 20J/cm 2 After UVA irradiation, the cell secretes ColI, colIII and HA amount is obviously reduced. As shown in FIG. 8A, free anti-aging compositions and anti-aging co-delivered nanocomposites significantly increased ColI secretion (P<0.05 or P<0.01). Compared with the free anti-aging composition, the anti-aging co-delivery nano composition can obviously improve the Col I secretion (P) when the concentration is 200 and 400 mu g/mL<0.05 or P<0.01). As shown in FIG. 8 (B), the anti-aging co-delivery nano-combinations compared to the model set When the concentration of the compound is 100, 200 and 400 mug/mL, the secretion amount (P) of Col III can be obviously improved<0.01). Compared with the free anti-aging composition, the anti-aging co-delivery nano-composition can significantly improve the secretion amount (P<0.05 or P<0.01). As shown in fig. 8C, the free ingredient concentration and anti-aging co-delivered nanocomposites significantly increased HA content (P<0.05 or P<0.01). Compared with the free anti-aging composition, the concentration of the anti-aging co-delivery nano composition is 200 and 400 mu g/mL, and the HA secretion (P) can be obviously improved<0.01). The experimental result shows that the anti-aging co-delivery nano-composition can effectively resist the reduction of collagen and hyaluronic acid caused by UVA irradiation, has obvious skin aging resisting effect, and has better skin aging resisting effect compared with the free anti-aging composition with the same dose.
Although the foregoing embodiments have been described in some, but not all, embodiments of the invention, it should be understood that other embodiments may be devised in accordance with the present embodiments without departing from the spirit and scope of the invention.
Claims (10)
1. The multi-effect anti-aging co-delivery nano composition suitable for the microneedles is characterized by comprising the following components in percentage by mass:
1-10% of composite active factors, 2-10% of emulsifying agents, 2-12% of auxiliary emulsifying agents, 0.1-0.5% of preservative and the balance of water;
the complex active factors include polydeoxyribonucleotide, acetyl hexapeptide-8, palmitoyl pentapeptide-4, dihydroavenanthramide and ergothioneine.
2. The multi-effect anti-aging co-delivery nanocomposite suitable for use in microneedles according to claim 1, wherein the complex active factors comprise, based on 100% mass of the multi-effect anti-aging co-delivery nanocomposite suitable for use in microneedles: 0.1 to 2 percent of polydeoxyribonucleotide, 80.001 to 0.01 percent of acetyl hexapeptide, 40.001 to 0.1 percent of palmitoyl pentapeptide, 1 to 5 percent of dihydro oat alkaloid and 0.1 to 2 percent of ergothioneine.
3. The multi-effect anti-aging co-delivery nanocomposite for microneedles according to claim 1, wherein the particle size of the multi-effect anti-aging co-delivery nanocomposite for microneedles is 10 to 500nm.
4. The multi-effect anti-aging co-delivery nanocomposite suitable for use in microneedles according to claim 1, wherein the emulsifying agent comprises lecithin and/or polyoxyethylene hydrogenated castor oil.
5. The multi-effect anti-aging co-delivery nanocomposite suitable for use in microneedles according to claim 1 or 4, wherein the co-emulsifier comprises one or more of butylene glycol, hexylene glycol, and propylene glycol.
6. The multi-effect anti-aging co-delivery nanocomposite suitable for use in microneedles according to claim 1, wherein the preservative comprises p-hydroxyacetophenone.
7. A method for preparing a multi-effect anti-aging co-delivery nanocomposite suitable for microneedles according to any one of claims 1 to 6, comprising the steps of:
mixing the composite active factors, the emulsifier, the auxiliary emulsifier, the preservative and water to obtain a mixture;
carrying out micronization treatment on the mixture to obtain micron-sized particles;
and carrying out nanocrystallization treatment on the micrometer-sized particles to obtain the multi-effect anti-aging co-delivery nano composition suitable for the microneedles.
8. The method according to claim 7, wherein the micronization is shear mixing at 4000 to 30000rpm for 1 to 20min.
9. The method according to claim 7, wherein the nanocrystallization treatment is a high-pressure homogenization treatment or a high-pressure microjet treatment;
the pressure of the high-pressure homogenizing treatment is 300-1600 bar, the temperature is 20-70 ℃, and the cycle times are 1-10 times;
the pressure of the high-pressure micro-jet treatment is 3000-16000 psi, the temperature is 20-70 ℃, and the cycle times are 1-10.
10. Use of the multi-effect anti-aging co-delivery nanocomposite suitable for microneedles according to any one of claims 1 to 6 or the multi-effect anti-aging co-delivery nanocomposite suitable for microneedles obtained by the preparation method according to any one of claims 7 to 9 in the preparation of cosmetics for preventing skin aging.
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