Ferulic acid-chitosan composite microspheres and application thereof in cosmetics

Abstract

This invention discloses a ferulic acid-chitosan composite microsphere with dual electrolyte and temperature responsiveness and its application in cosmetics. The composite microsphere comprises ferulic acid and / or ferulic acid salts and chitosan; wherein the ferulic acid and / or ferulic acid salts are bound to the amino groups of the chitosan. The composite microspheres have a uniform particle size (1-8 μm, PDI < 0.1) and carry a high positive charge (Zeta > +30 mV). The microspheres undergo a phase transition at approximately 41 °C and can trigger demulsification and release in NaCl solution. Simultaneously, the released ferulic acid exhibits the same antioxidant activity as its free state. This invention also provides a cosmetic composition comprising the microspheres and a stabilizer. This invention overcomes the problems of easy inactivation and low delivery efficiency of ferulic acid, creating a high-end active ingredient delivery platform integrating stable storage and intelligent release, particularly suitable for functional skincare products such as those for sensitive skin repair.

Description

Technical Field

[0001] This invention relates to the field of functional cosmetic ingredients and drug delivery systems, specifically to a smart responsive composite microsphere based on natural products, its preparation method, a stable composition containing the microsphere, and its application in high-end skin care products, particularly suitable for the repair, soothing, and antioxidant effects on sensitive skin. Background Technology

[0002] Ferulic acid is a natural phenolic acid widely found in plants, possessing excellent antioxidant, anti-inflammatory, and whitening properties. However, its inherent chemical properties are unstable; it is easily oxidized in aqueous solutions and degraded by light, leading to a rapid loss of activity. Furthermore, its transdermal absorption efficiency is limited, restricting its efficacy in cosmetics. Chitosan is a natural cationic polysaccharide with good biocompatibility, often used as a drug carrier and moisturizer, but its water solubility is poor at physiological pH levels.

[0003] Currently available ferulic acid-related products on the market mostly employ simple dissolution or physical mixing methods to add it to the formulation. For example, some serums directly use ferulic acid or its derivatives. These traditional methods have significant drawbacks: 1) they cannot protect ferulic acid from oxidation during shelf life and use, leading to product discoloration and inactivation; 2) they lack a controllable release mechanism, resulting in low bioavailability; and 3) the product form is monotonous, lacking a differentiated experience. In the current technology, there are no reports of a ferulic acid-chitosan composite delivery system that can simultaneously achieve "long-term stable storage" and "intelligently triggered release."

[0004] Therefore, developing a novel ferulic acid delivery platform that can comprehensively solve the above-mentioned industry problems has significant scientific value and broad market prospects. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the defects of existing ferulic acid preparations, such as poor stability, uncontrollable release, and low efficacy utilization, and to provide a ferulic acid-chitosan composite microsphere and its cosmetic composition with a well-defined structure, stable performance, environmental responsiveness, and the ability to enhance the efficacy of active ingredients.

[0006] In a first aspect, the present invention provides ferulic acid-chitosan composite microspheres, comprising ferulic acid and / or ferulic acid salts and chitosan; wherein the ferulic acid and / or ferulic acid salts are bonded to the amino groups of chitosan. The ferulic acid anions self-assemble with the protonated amino groups on the chitosan molecular chain through ionic and hydrogen bonding interactions.

[0007] In one optional embodiment, the ferulic acid-chitosan composite microspheres have the following precisely measurable physical parameters: the average hydrated particle size (Z-Average) of the ferulic acid-chitosan composite microspheres is 0.5 μm to 20.0 μm; the particle size polydispersity index (PDI) of the ferulic acid-chitosan composite microspheres is less than 0.1; and the Zeta potential of the ferulic acid-chitosan composite microspheres is greater than +30 mV. Preferably, the average hydrated particle size of the ferulic acid-chitosan composite microspheres is 3-5 μm; preferably, the particle size polydispersity index of the ferulic acid-chitosan composite microspheres is less than 0.05; and preferably, the Zeta potential of the ferulic acid-chitosan composite microspheres is +40 mV to +50 mV.

[0008] In one optional embodiment, the ferulic acid-chitosan composite microspheres are electrolyte responsive, and the ferulic acid-chitosan composite microspheres dissociate and release ferulic acid in the microstructure containing sodium chloride; the ferulic acid-chitosan composite microspheres are temperature responsive, and their phase transition temperature is between 39°C and 43°C.

[0009] In one optional embodiment, the molar ratio of ferulic acid to the amino group in chitosan is (0.5-2):1; preferably, the molar ratio is 1:1; the degree of deacetylation of the chitosan is greater than or equal to 85%; and the molecular weight is 50-200 kDa. After electrolyte-triggered release, the ferulic acid-chitosan composite microspheres exhibit the same in vitro antioxidant activity of ferulic acid as a standard of the same concentration of free ferulic acid.

[0010] Secondly, the present invention also provides a method for preparing ferulic acid-chitosan composite microspheres, comprising the following steps: heating and dissolving chitosan and ferulic acid in a solvent to obtain a transparent solution of ferulic acid-chitosan complex, and then cooling to obtain ferulic acid-chitosan composite microspheres; wherein the chitosan and ferulic acid are dissolved in a solvent at 85-95°C; the cooling temperature is 20-30°C; and the solvent is water.

[0011] Thirdly, the present invention provides a smart responsive cosmetic composition comprising the ferulic acid-chitosan composite microspheres as described in claim 1 and a cosmetically acceptable carrier. The cosmetically acceptable carrier includes polydimethylsiloxane, etc., providing a smooth, refreshing feel and reducing stickiness; alkyl-modified cellulose, etc., used to adjust the viscosity and texture of the product and increase stability; fatty alcohols, etc., as a base oil phase, providing a moisturizing, smooth feel.

[0012] This composition possesses the following dual smart response characteristics:

[0013] 1. Temperature responsiveness: Through rheological temperature scanning tests, within the temperature range of 39℃-43℃, the ratio of storage modulus (G') to loss modulus (G'') changes from greater than 1 to less than 1, showing a reversible transition from liquid behavior to solid-gel-like behavior.

[0014] 2. Electrolyte responsiveness: When the electrolyte concentration in the environment reaches a certain threshold, the stable structure of the composite microspheres is disrupted, and the active ingredient ferulic acid is rapidly released. Preferably, the electrolyte is sodium chloride, and the critical condition for initiating complete demulsification is that the molar ratio of NaCl to ferulic acid is greater than 2.5.

[0015] In an alternative embodiment, the above-described smart responsive cosmetic composition further comprises 0.05wt%-0.2wt% of a metal ion chelating agent and 0.1wt%-1.0wt% of an antioxidant.

[0016] In one optional embodiment, the metal ion chelating agent is selected from one or more of disodium ethylenediaminetetraacetate, phytic acid, citric acid and its salts, or sodium gluconate; optionally, the metal ion chelating agent is disodium ethylenediaminetetraacetate. The antioxidant is one or more of tocopherol and its derivatives, ascorbic acid and its derivatives, tea polyphenols, resveratrol, or coenzyme Q10; optionally, the antioxidant is D-α-tocopherol acetate.

[0017] In one alternative embodiment, the composition is at least one of a serum, lotion, cream, or gel formulation. The pH value of the above cosmetic composition is 6.5-7.5.

[0018] Fourthly, the present invention provides the use of the above-mentioned ferulic acid-chitosan composite microspheres or smart responsive cosmetic compositions in the preparation of skin care cosmetics, particularly in the preparation of cosmetics for skin barrier repair, soothing and anti-inflammatory, antioxidant and moisturizing purposes. The cosmetics are also used for the care of sensitive skin.

[0019] The technical solution of this invention has the following advantages: (1) The product of this invention has a precise structure and excellent stability. Through a controllable ion complexation process, composite microspheres with extremely narrow distribution (PDI<0.1) and high surface positive charge (Zeta>+30mV) were obtained for the first time. The high Zeta potential ensures strong electrostatic repulsion between particles, giving the dispersion excellent long-term physical stability (anti-aggregation, anti-sedimentation), and solving the problem of storage stability of ferulic acid in the formulation.

[0020] (2) This invention employs a dual intelligent response mechanism to provide a precise and controllable release effect. The temperature response (approximately 41°C) delivers a unique "melt-on-skin" sensory experience and triggers release through a preliminary phase change; the electrolyte response simulates the sweat environment on the skin surface, enabling precise and rapid release of active ingredients under biological conditions, ensuring efficient delivery when needed. This dual response mechanism adds a differentiated technological narrative to the product.

[0021] (3) The composite microspheres provided by the present invention effectively protect ferulic acid from oxidation and inactivation by encapsulating it. The ferulic acid released after being triggered by NaCl has similar antioxidant activity to the monomer (as determined by DPPH method). At the same time, it significantly improves the water solubility of ferulic acid. The content of ferulic acid in the composite microspheres can reach 28 mg / mL, while unmodified ferulic acid is difficult to dissolve in water and has a solubility of less than 1 mg / mL.

[0022] (4) The product of this invention has a clear target application and great market potential. This technology is particularly suitable for the sensitive skin repair and post-workout soothing markets that have extremely high requirements for the gentleness, stability and immediate effect of the product, and has the potential to create a high-end star product. Attached Figure Description

[0023] 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.

[0024] Figure 1 Scanning electron microscope (SEM) image of the ferulic acid-chitosan composite microspheres prepared in Example 1 of this invention; Figure 2 Particle size distribution diagram of the ferulic acid-chitosan composite microspheres prepared in Example 1 of this invention; Figure 3 The rheological temperature scanning curve of the suspension in Example 1 of this invention shows the changes of storage modulus (G') and loss modulus (G'') with temperature, and the arrow indicates the phase transition temperature point (approximately 41.2°C). Figure 4 Effect curves of different concentrations of sodium chloride on the permeability of composite microsphere suspension; Figure 5 : Electrolyte responsiveness demonstration diagram of the composition of the present invention. (A) Initial opalescent suspension; (B) Clear solution after adding 0.9% NaCl solution and mixing. Detailed Implementation

[0025] The following embodiments are provided to better understand the present invention, but the following embodiments do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the scope of protection of the present invention.

[0026] Unless otherwise specified, all experimental steps or conditions in the examples were performed according to conventional experimental procedures and conditions in the art. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0027] Example 1 This embodiment discloses the preparation of ferulic acid-chitosan composite microspheres.

[0028] Weigh 1.44 g of chitosan with a degree of deacetylation of 95% and a viscosity-average molecular weight of approximately 150 kDa, and 1.56 g of ferulic acid in an equal molar amount. Add the mixture to 97 mL of deionized water. Stir the mixture at 90 °C for approximately 30 minutes. Rapidly centrifuge to remove a small amount of insoluble matter to obtain a ferulic acid-chitosan complex solution with a concentration of approximately 5.5%. Freeze-dry the solution to obtain ferulic acid-chitosan composite microspheres. Label this as sample S1.

[0029] Systematic characterization of sample S1: 1. Microstructure: A small amount of S1 sample was freeze-dried and sputter-coated with gold to obtain microspheres, which were then observed using a field emission scanning electron microscope (FE-SEM). For example... Figure 1 As shown, the product consists of smooth, regularly shaped spherical or near-spherical particles.

[0030] 2. Colloidal properties: Measured using a dynamic light scattering (DLS) instrument at 25°C. For example... Figure 2 As shown, its Z-average particle size is 3.83 μm and its polydispersity index (PDI) is 0.038, demonstrating the high homogeneity of the system. The Zeta potential is +43.6 ± 1.8 mV, indicating that the particle surface carries a strong positive charge, which is the fundamental reason for its excellent colloidal stability.

[0031] 3. Thermal Behavior Analysis: Temperature scanning tests were performed using a rotational rheometer (frequency 1Hz, strain 1%, heating rate 1℃ / min). Results are as follows: Figure 3 As shown, when the temperature rises to 41.2 ± 0.3 °C, the storage modulus (G') begins to be less than the loss modulus (G''), indicating that a significant phase transition from sol to gel has occurred in the system. This temperature point is defined as the phase transition temperature (T). gel ).

[0032] Example 2 This embodiment discloses the preparation of ferulic acid-chitosan composite microspheres.

[0033] Weigh 1.44 g of chitosan with a degree of deacetylation of 85% and a viscosity-average molecular weight of approximately 50 kDa, and 1.56 g of ferulic acid in equal molar amounts. Add the mixture to 97 mL of deionized water. Stir the mixture at 85 °C for approximately 30 minutes. Rapidly centrifuge to remove a small amount of insoluble matter to obtain a ferulic acid-chitosan complex solution. Freeze-dry the solution to obtain ferulic acid-chitosan composite microspheres. Label this as sample S2.

[0034] Example 3 This embodiment discloses the preparation of ferulic acid-chitosan composite microspheres.

[0035] Weigh 1.44 g of chitosan with a degree of deacetylation of 90% and a viscosity-average molecular weight of approximately 200 kDa, and 1.56 g of ferulic acid in an equal molar amount. Add the mixture to 97 mL of deionized water. Stir the mixture at 95 °C for approximately 30 minutes. Rapidly centrifuge to remove a small amount of insoluble matter to obtain a ferulic acid-chitosan complex solution. Freeze-dry the solution to obtain ferulic acid-chitosan composite microspheres. Label this as sample S3.

[0036] Example 4 This embodiment discloses the preparation of a smart responsive cosmetic composition comprising the above-mentioned ferulic acid-chitosan composite microspheres.

[0037] The S1 sample was mixed with 0.1 wt% of a metal ion chelating agent and 0.5 wt% of an antioxidant to obtain a smart responsive cosmetic composition. This smart responsive cosmetic composition can be a lotion. In specific applications, the pH of the composition is controlled at 7 to ensure its gentleness and stability on the skin.

[0038] Example 5 This embodiment discloses the preparation of a smart responsive cosmetic composition comprising the above-mentioned ferulic acid-chitosan composite microspheres.

[0039] The microsphere S1 sample was mixed with 0.05 wt% of a metal ion chelating agent and 1 wt% of an antioxidant to obtain a smart responsive cosmetic composition. This smart responsive cosmetic composition can be a lotion. In specific applications, the pH of the composition is controlled at 6.5 to ensure its gentleness and stability on the skin.

[0040] Example 6 This embodiment discloses the preparation of a smart responsive cosmetic composition comprising the above-mentioned ferulic acid-chitosan composite microspheres.

[0041] The microsphere S1 sample was mixed with 0.2 wt% of a metal ion chelating agent and 0.1 wt% of an antioxidant to obtain a smart responsive cosmetic composition. This smart responsive cosmetic composition can be a lotion. In specific applications, the pH of the composition is controlled at 7.5 to ensure its gentleness and stability on the skin.

[0042] Experimental Example 1: Determination of critical concentration for electrolyte-responsive demulsification and verification of activity synergy This embodiment aims to quantitatively study the response characteristics of composite microspheres to electrolytes and verify their synergistic effect.

[0043] 1.1 Determination of critical demulsification concentration: Prepare a 2M sodium chloride stock solution and mix it with sample S1 and deionized water to prepare a series of mixed solutions containing different concentrations of sodium chloride (0, 0.05, 0.1, 0.2, 0.4, 0.6M) and the same concentration of ferulic acid (0.08M). Vortex for 10 seconds and let stand for 5 minutes. Measure the transmittance at 800nm ​​using a UV-Vis spectrophotometer. Plot a graph with NaCl concentration on the x-axis and transmittance on the y-axis. The results are shown below. Figure 4 As shown. When the NaCl concentration is below 0.2 M, the transmittance is close to 0; when the concentration reaches or exceeds 0.2 M, the transmittance increases sharply, and the system visually changes from opalescent to clear. Figure 5 Therefore, the critical condition for initiating complete demulsification of the composite microspheres of this invention is that the molar ratio of sodium chloride to ferulic acid is greater than 2.5.

[0044] 1.2 Validation of enhanced antioxidant activity: The S1 solution, completely demulsified with 0.9% NaCl and clarified by centrifugation, was used as the "experimental release solution." A standard solution of free ferulic acid of precisely equal concentration was prepared using 0.9% NaCl solution as the "control group." Both solutions were diluted to the same ferulic acid test concentration (0.05, 0.1, 0.2, 0.4, 0.6 mg / mL), and the DPPH free radical scavenging method was used for determination. Each experiment was performed in triplicate.

[0045] Results: At concentrations of 0.05, 0.1, 0.2, 0.4, and 0.6 mg / mL, the DPPH clearance rates in the experimental group were 14.23±1.26, 19.82±1.04, 31.56±1.59, 47.84±1.82, and 54.42±1.05, respectively, while the DPPH clearance rates in the control group were 11.96±0.56, 18.83±1.25, 31.40±1.87, 48.23±0.85, and 56.09±1.22, respectively.

[0046] Conclusion: Comparison revealed that the in vitro antioxidant activity of ferulic acid after electrolyte-triggered release from the composite microspheres prepared in this invention was essentially the same as that of its free form. Therefore, it can be confirmed that the composite microspheres and the demulsification process do not affect the antioxidant activity of ferulic acid.

[0047] Comparative Example 1: Physical Mixture Control To highlight the key aspects of the "controllable ion complexation" process of this invention, this comparative example is provided.

[0048] Weigh out equal amounts of chitosan and ferulic acid as in Example 1. Prepare a 1% acetic acid solution from the chitosan. Add the ferulic acid powder directly to the stirred chitosan-acetic acid solution. Immediately, a large amount of white flocculent precipitate is observed to form, and the system rapidly separates into layers, failing to form a uniform dispersion. After standing for 30 minutes, take the upper turbid liquid for DLS testing. The signal is extremely unstable, and no effective particle size distribution data can be obtained, indicating that it is a polydisperse coarse aggregate. Its zeta potential measurement value is only +8.5 mV.

[0049] This result contrasts sharply with Example 1, demonstrating that simple physical mixing is simply insufficient to obtain the functional microspheres with specific microstructure and stability defined in this invention.

[0050] This comparison conclusively demonstrates that only microspheres with high Zeta potential (>+30mV) obtained through the specific process of this invention simultaneously possess excellent colloidal stability, temperature responsiveness, and electrolyte responsiveness. This parameter range is a key technical feature for achieving the beneficial effects of this invention, rather than an arbitrary choice.

[0051] Experimental Example: Preliminary Verification of Product Safety and Efficacy 1. Safety Basis: The core active ingredient of this invention—the ferulic acid-chitosan ionic complex—has undergone in vitro cytotoxicity evaluation using the standard MTT assay. The evaluation results showed that, within the tested concentration range, the complex did not exhibit cytotoxicity against mouse embryonic fibroblasts, and cell viability remained above 85%, providing preliminary scientific evidence for its safety for topical application.

[0052] 2. Preliminary efficacy verification: In vitro antioxidant: As shown in Example 2.2, this product has a strong DPPH free radical scavenging ability.

[0053] 3. Formulation compatibility: Sample S1 was added at a ratio of 5% to various common basic cosmetic cream bases. After testing, its microscopic particle size remained stable with PDI, and no demulsification or precipitation occurred, proving that it has good compatibility with the actual formulation system.

[0054] Product Application Example: Using the composite microsphere suspension prepared in Example 1 of this invention as the active ingredient, various dosage forms of cosmetics, such as serums, lotions, creams, and gels, can be easily prepared according to conventional cosmetic preparation processes in the art (e.g., mixing, emulsifying, and homogenizing with suitable moisturizers, emollients, emulsifiers, thickeners, and preservatives). The long-term stability of the product can be further optimized by adding 0.05%-0.2% EDTA-2Na and 0.1%-1.0% vitamin E, etc., as stabilizers. The products thus prepared all inherit the dual-response characteristics and synergistic activity advantages of the microspheres of this invention.

[0055] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A ferulic acid-chitosan composite microsphere, characterized in that, include: Ferulic acid and / or ferulic acid salts and chitosan; wherein the ferulic acid and / or ferulic acid salts are bound to the amino groups of chitosan.

2. The ferulic acid-chitosan composite microspheres according to claim 1, characterized in that, The average hydrated particle size of the ferulic acid-chitosan composite microspheres is 0.5-20 micrometers; The ferulic acid-chitosan composite microspheres have a polydispersity index of less than 0.

1. The zeta potential of the ferulic acid-chitosan composite microspheres is greater than +30mV; The molar ratio of ferulic acid to amino groups in chitosan is (0.5-2):1; The degree of deacetylation of the chitosan is greater than or equal to 85%; The molecular weight of the chitosan is selected from 50-200 kDa; Optionally, the molar ratio of ferulic acid to the amino group in chitosan is 1:1; The average hydrated particle size of the ferulic acid-chitosan composite microspheres is 3-5 micrometers. The ferulic acid-chitosan composite microspheres have a polydispersity index of less than 0.

05. The zeta potential of the ferulic acid-chitosan composite microspheres is +40mV to +50mV.

3. The ferulic acid-chitosan composite microspheres according to claim 1, characterized in that, The ferulic acid-chitosan composite microspheres are electrolyte responsive; the microstructure of the ferulic acid-chitosan composite microspheres dissociates and releases ferulic acid in an environment containing sodium chloride; The ferulic acid-chitosan composite microspheres are temperature responsive, and the phase transition temperature of the ferulic acid-chitosan composite microspheres is 39℃-43℃.

4. A method for preparing ferulic acid-chitosan composite microspheres according to any one of claims 1-3, characterized in that, The process includes the following steps: dissolving chitosan and ferulic acid in a solvent to obtain a transparent solution of ferulic acid-chitosan complex, and then cooling it to obtain ferulic acid-chitosan composite microspheres; The solvent is water, the dissolution temperature is 85-95℃, and the cooling temperature is 20-30℃.

5. A smart responsive cosmetic composition, characterized in that, The invention comprises ferulic acid-chitosan composite microspheres as described in any one of claims 1-3 and a cosmetically acceptable carrier.

6. The smart responsive cosmetic composition according to claim 5, characterized in that, The smart responsive cosmetic composition is electrolyte responsive, and the microstructure of the ferulic acid-chitosan composite microspheres dissociates and releases ferulic acid in an environment containing sodium chloride. The smart responsive cosmetic composition is temperature responsive, and the phase transition temperature of the smart responsive cosmetic composition is 39℃-43℃.

7. The smart responsive cosmetic composition according to claim 5, characterized in that, The composition further comprises 0.05wt%-0.2wt% of a metal ion chelating agent and 0.1wt%-1.0wt% of an antioxidant.

8. The smart responsive cosmetic composition according to claim 7, characterized in that, The metal ion chelating agent is selected from one or more of disodium ethylenediaminetetraacetate, phytic acid, citric acid and its salts or sodium gluconate; Optionally, the metal ion chelating agent is disodium ethylenediaminetetraacetate; The antioxidant is one or more of tocopherol and its derivatives, ascorbic acid and its derivatives, tea polyphenols, resveratrol, or coenzyme Q10. Optionally, the antioxidant is D-α-tocopherol acetate.

9. The smart responsive cosmetic composition according to claim 5, characterized in that, The composition is at least one of an essence, lotion, cream, or gel formulation; The pH value of the composition is 6.5-7.

5.

10. The use of the smart responsive cosmetic composition according to any one of claims 5-9 in cosmetics for caring for the skin, repairing the skin barrier, soothing skin inflammation, or resisting skin oxidation.

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