A polyglutamic acid-amino acid synergistically stabilized salicylic acid intelligent sustained-release ternary compound, a preparation thereof, a preparation method thereof and an application thereof

Abstract

The application discloses a polyglutamic acid-amino acid synergistically stabilized salicylic acid intelligent sustained-release ternary compound, a preparation method and application thereof, a mass ratio of polyglutamic acid, salicylic acid and amino acid in the ternary compound is (2-10):1:(0.1-1.2); the polyglutamic acid has a molecular weight of 500,000-1,500,000 Dalton; the amino acid is an alkaline amino acid, which is composed of arginine, lysine and histidine, the three amino acids are sequentially anchored in the polyglutamic acid skeleton by the difference in the degree of protonation and the electrostatic binding strength, and high-concentration salicylic acid is effectively and stably wrapped by synergistically capturing the salicylic acid molecules, meanwhile, the salicylic acid release behavior is regulated by using the acidic environment of human skin, the initial burst release of the salicylic acid is effectively inhibited, the skin irritation is significantly reduced, and the ternary compound has good industrial amplification feasibility.

Description

Technical Field

[0001] This invention belongs to the field of cosmetic technology, specifically relating to a polyglutamic acid-amino acid synergistically stabilized salicylic acid intelligent sustained-release ternary complex, its formulation, preparation method, and application. Background Technology

[0002] Salicylic acid, also known as o-hydroxybenzoic acid, is a natural active ingredient derived from birch, holly leaves, and willow bark. Due to its unique lipid solubility and multiple pharmacological activities, it has wide applications in the pharmaceutical and cosmetic fields. In cosmetics, salicylic acid can exfoliate and renew the epidermis by disrupting desmosomes around keratinocytes and activating the regeneration of keratinocytes and fibroblasts. In addition, salicylic acid can also reduce inflammation and melanin deposition, achieving multiple skincare effects such as oil control, acne treatment, improvement of closed comedones, and whitening and fading of dark spots. It is a commonly used ingredient in cosmetics and skincare products.

[0003] In practical applications, salicylic acid suffers from poor water solubility, a tendency to cause irritation, and difficulty in precisely controlling its release behavior. On one hand, salicylic acid is a lipid-soluble organic acid with extremely low solubility in water at room temperature. On the other hand, its high lipid solubility and small molecular weight result in rapid penetration into the stratum corneum of the skin, easily leading to excessively high local drug concentrations and irritating reactions. Therefore, how to fully dissolve salicylic acid, control its release effect, reduce irritation, and prolong the duration of action of the active ingredient on the skin surface has been a key technical challenge that urgently needs to be addressed.

[0004] Chinese patent application CN120918962A discloses a salicylic acid-cyclodextrin-amino acid ternary inclusion complex, its preparation method, and its application. This complex combines salicylic acid, β-cyclodextrin, and a specific arginine to form a ternary inclusion complex. The core technology of this inclusion complex is the inclusion of salicylic acid within the cavity of the cyclodextrin polymer. However, the inclusion capacity of the salicylic acid is limited by the cavity size and inclusion capacity of the cyclodextrin. For products with high concentrations of salicylic acid, it is difficult to ensure the stability of the inclusion complex, leading to burst release and making it difficult to achieve a balance between the effective concentration and the safety threshold. Furthermore, the β-crosslinked cyclodextrin used is a semi-synthetic polymer modification product, posing certain safety risks as a skincare ingredient. Its crosslinked network structure is also too dense, making it difficult to achieve the expected effect in containing salicylic acid. In addition, the inclusion complex introduces arginine as a synergist, which further anchors the arginine on the network surface and in the gaps of cyclodextrin. Although this can improve the inclusion efficiency to some extent, it also blocks the diffusion channels of salicylic acid molecules and further tightens the encapsulation network, affecting the release rate of salicylic acid and thus affecting the efficacy of the product.

[0005] Therefore, how to effectively and stably encapsulate high-concentration salicylic acid and effectively control the release rate of salicylic acid remains an urgent problem to be solved. Summary of the Invention

[0006] To address the aforementioned problems and achieve the above objectives, this invention provides a polyglutamic acid-amino acid synergistically stabilized controlled-release salicylic acid composition. Through the synergistic effect of γ-polyglutamic acid of a specific molecular weight and basic amino acids, a stable controlled-release system is formed. The release behavior is regulated by the skin's own pH signal, eliminating the need for external control methods. This significantly improves the physicochemical stability of the composition and the controllability of salicylic acid release behavior while safely loading a high content of salicylic acid. The specific technical solution is as follows:

[0007] First, this invention provides a polyglutamic acid-amino acid synergistically stabilized salicylic acid intelligent sustained-release ternary complex. The mass ratio of polyglutamic acid, salicylic acid, and amino acids in this ternary complex is (2-10):1:(0.1-1.2). The molecular weight of the polyglutamic acid is 500,000 to 1,500,000 Daltons. The amino acids are basic amino acids, composed of arginine, lysine, and histidine. These three amino acids are orderly anchored in the polyglutamic acid backbone through differences in protonation degree and electrostatic binding strength, synergistically capturing and stabilizing salicylic acid molecules. At the same time, the acidic environment of human skin itself is used to regulate the release behavior of salicylic acid.

[0008] Preferably, in the aforementioned polyglutamic acid-amino acid synergistically stabilized salicylic acid smart sustained-release ternary complex, the mass ratio of arginine, lysine, and histidine in the basic amino acids is (0.4-0.6): (0.2-0.4): (0.1-0.2).

[0009] Secondly, the present invention provides a polyglutamic acid-amino acid synergistically stabilized salicylic acid smart sustained-release composition, the composition having a pH value of 6.0-7.0, and comprising the following components by weight:

[0010] The aforementioned ternary complex, 2.0–20.0 parts,

[0011] Thickener 0.1-0.6 parts,

[0012] 5-10 parts of moisturizer

[0013] Antibacterial and preservative agent 0.5-1.0 parts,

[0014] Soothing agent 0.1–2.0 parts,

[0015] pH buffer solution 0.5–5.0 parts,

[0016] The remainder is purified water.

[0017] The aforementioned polyglutamic acid-amino acid synergistically stabilized salicylic acid intelligent sustained-release composition comprises, wherein the thickener is selected from one or more of sodium polyacrylate, methylcellulose, ethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, and xanthan gum; the humectant is selected from one or more of glycerin, butylene glycol, hexanediol, dipropylene glycol, and glyceryl polyether; the antibacterial and preservative agent is selected from one or more of methylparaben, phenoxyethanol, caprylyl glycol, pentylene glycol, hexanediol, and p-hydroxyacetophenone; the soothing agent is selected from one or more of bisabolol, ectoine, allantoin, dipotassium glycyrrhizate, panthenol, chamomile extract, and aloe extract; and the pH buffer is a disodium hydrogen phosphate and / or sodium dihydrogen phosphate buffer system.

[0018] The aforementioned polyglutamic acid-amino acid synergistically stabilized salicylic acid smart sustained-release composition, when applied topically, releases 50% to 70% of the salicylic acid within 6 to 8 hours and 90% to 95% within 12 hours.

[0019] Furthermore, this invention provides a method for preparing a polyglutamic acid-amino acid synergistically stabilized salicylic acid smart sustained-release composition, the composition containing the aforementioned ternary complex; the preparation method includes the following steps:

[0020] 1) Add salicylic acid to the humectant and stir thoroughly until the salicylic acid is completely dispersed to form an SA solution;

[0021] 2) Add polyglutamic acid to a portion of purified water and stir until completely dissolved to form an aqueous PGA solution;

[0022] 3) Add the amino acids to the PGA aqueous solution prepared in step 2), and sonicate at 40-60°C until completely dissolved to form a PGA-amino acid complex solution; the amino acids are basic amino acids, composed of arginine, lysine and histidine;

[0023] 4) Under stirring conditions at 40-60℃, add the SA solution prepared in step 1) to the PGA-amino acid complex solution formed in step 3). After the addition is complete, continue stirring for 20-40 minutes to obtain a uniformly mixed ternary complex solution.

[0024] 5) Disperse the thickener in the remaining purified water, fully hydrate to form a transparent gel, and then mix it with the ternary composite solution from step 4) to obtain a ternary composite gel solution;

[0025] 6) Add the soothing agent, thickener, preservative and pH buffer to the mixture obtained in step 5) in sequence, and continue to stir and mix evenly at 40-60°C to obtain the target composition.

[0026] As a preferred technical solution, in the preparation method of the aforementioned polyglutamic acid-amino acid synergistically stabilized salicylic acid intelligent sustained-release composition, in step 3), the order in which the basic amino acids are added to the PGA solution is as follows: arginine, lysine and histidine are added to the PGA aqueous solution in sequence, ultrasonically vibrated until completely dissolved, and then another component is added to obtain a clear and transparent solution; the ultrasonic vibration conditions are: frequency 20-40kHz, power 100-300W.

[0027] As a preferred technical solution, in the aforementioned method for preparing the polyglutamic acid-amino acid synergistically stabilized salicylic acid intelligent sustained-release composition, in step 4), the SA solution is added to the PGA-amino acid composite solution at a rate of 2-5 mL / min, and the stirring speed is 200-400 rpm.

[0028] As a preferred technical solution, in the preparation method of the aforementioned polyglutamic acid-amino acid synergistically stabilized salicylic acid intelligent sustained-release composition, in step 5), the process of mixing the thickener with the ternary composite solution after forming a transparent gel is as follows: the ternary composite solution is slowly added to the thickener gel at a rate of 20-50 mL / min in a thin stream, and the addition process is completed in 1-3 minutes; the stirring speed after addition is controlled at 100-300 rpm.

[0029] In addition, the present invention also provides the application of the aforementioned composition containing a salicylic acid intelligent sustained-release ternary complex synergistically stabilized by polyglutamic acid and amino acids in the preparation of cosmetics with the effects of acne removal, oil control, exfoliation, and improvement of closed comedones.

[0030] The beneficial effects of this invention are:

[0031] 1) The polyglutamic acid-amino acid synergistically stable salicylic acid intelligent sustained-release ternary complex provided by this invention forms a three-dimensional anionic network rich in carboxyl groups in the aqueous phase through γ-polyglutamic acid with a specific molecular weight (500,000 to 1,500,000 Daltons); arginine, lysine and histidine, with their protonated side chains as cationic anchors, form multiple ionic bonds with the carboxyl groups of polyglutamic acid through electrostatic attraction; salicylic acid molecules, in the form of carboxyl anions, are captured by the cationic anchors of amino acids to form a polyglutamic acid-amino acid-salicylic acid tertiary electrostatic assembly complex, which fundamentally avoids the problem of salicylic acid crystallization due to decreased inclusion rate. At the same time, the intelligent sustained-release effect is achieved by utilizing the acidic environment of the skin to regulate the release through the functional differences in charge characteristics, pH responsiveness and space filling of the three amino acids.

[0032] 3) This invention limits the amino acids to arginine, lysine, and histidine. These three amino acids are sequentially and orderly anchored in the polyglutamic acid backbone through differences in their protonation degree and electrostatic binding strength, synergistically capturing salicylic acid molecules to achieve effective and stable encapsulation of high-concentration salicylic acid. Simultaneously, the acidic environment of human skin is utilized to regulate the release behavior of salicylic acid. The guanidino group of arginine is almost completely protonated within the pH range of 6–7, exhibiting the highest positive charge density, providing the strongest electrostatic driving force as the main anchor point for salicylic acid. Similarly, the ε-amino group of lysine remains fully protonated within the pH range of 6–7, providing an additional anchoring site for salicylic acid molecules and regulating space filling. When the imidazole group of histidine is in the pH range of 6-7, some of it exists in the form of neutral imidazole, which makes the network of the composition moderately loose during storage (pH 6.0-6.5) to facilitate the stable dispersion of salicylic acid without aggregation and crystallization. When the local pH drops to about 5.0 after contact with the skin, the protonation fraction of histidine increases, the positive charge density increases significantly, and the electrostatic fixation effect on salicylic acid is enhanced. At the same time, the protonation degree of polyglutamic acid carboxyl group increases, the electrostatic repulsion between molecular chains weakens, the three-dimensional network shrinks moderately, and the diffusion channels narrow. The superposition of the dual effects makes the release rate of salicylic acid decrease rather than increase after the pH decreases, realizing the intelligent sustained-release effect of regulating the release by utilizing the acidic environment of the skin itself.

[0033] 4) The preparation method of this invention adopts a step-by-step construction and step-by-step assembly process: first, polyglutamic acid is dissolved to form an anionic polymer backbone, and then added step by step in the order of arginine → lysine → histidine. The differences in the protonation degree and electrostatic binding strength of the three amino acids are used to achieve ordered anchoring. After the network is constructed, salicylic acid is added so that it can be captured by cationic anchors. This process strategy of building the network first and then loading the drug ensures the integrity of the network structure and the uniformity of anchoring. Moreover, the process of this invention is carried out at 40-60℃ in an aqueous phase, without the need for organic solvents and pH adjusters. It can be completed in one step of self-assembly, and the process is simple, green and environmentally friendly, and easy to scale up industrially.

[0034] 5) When the composition of the present invention is applied transdermally, the release of salicylic acid is 50% to 70% within 6 to 8 hours and 90% to 95% within 12 hours, effectively inhibiting the initial burst release and significantly reducing skin irritation. At the same time, polyglutamic acid and amino acids themselves have multiple skin care effects such as moisturizing, repairing, and strengthening the skin barrier, realizing the functional reuse of the carrier material. It comprehensively solves the defects of existing technologies such as storage crystallization, initial burst release, single carrier function, and narrow pH window, and has outstanding practical and economic value. Attached Figure Description

[0035] Figure 1 These are comparative photographs of the stability test results of the product and the control standard of this invention.

[0036] Figure 2These are comparative photographs of the irritation tests of the product and control substances of this invention. Detailed Implementation

[0037] To stably encapsulate salicylic acid and ensure its long-lasting, uniform, and stable dispersion in the composition, while effectively controlling the release rate of salicylic acid and reducing its irritation to the skin, this invention provides a polyglutamic acid-amino acid synergistically stabilized intelligent sustained-release ternary complex, its formulation, preparation method, and application. Through the synergistic effect of polyglutamic acid with a specific molecular weight and basic amino acids, a stable sustained-release system is formed. The release behavior is regulated by the skin's own pH signal without the need for external control measures. Under the premise of safely loading a high content of salicylic acid, the physicochemical stability of the composition and the controllability of salicylic acid release behavior are significantly improved.

[0038] Specifically, in the polyglutamic acid-amino acid synergistically stabilized salicylic acid smart sustained-release ternary complex provided by the present invention, the mass ratio of polyglutamic acid (PGA), salicylic acid (SA) and amino acids is (2-10):1:(0.1-1.2); the molecular weight of the polyglutamic acid is 500,000 to 1,500,000 Daltons; the amino acids are basic amino acids, which are composed of arginine (Arg), lysine (Lys) and histidine (His); preferably, the mass ratio of arginine, lysine and histidine is (0.4-0.6):(0.2-0.4):(0.1-0.2).

[0039] In this invention, polyglutamic acid serves as the backbone, constructing a complete three-dimensional network structure and providing sufficient sites to stably load high concentrations of salicylic acid. Experiments show that when the molecular weight of polyglutamic acid is below 500,000 Da, the molecular chains are too short to form a sufficiently dense three-dimensional network, resulting in poor physical encapsulation of salicylic acid and significantly reduced stability of the composition during long-term storage. When the molecular weight of polyglutamic acid is above 1,500,000 Da, although the composition has acceptable stability during long-term storage, its viscosity is too high, leading to poor skin comfort and hindering the intelligent controlled release of salicylic acid. Therefore, this invention limits the molecular weight of polyglutamic acid to 500,000–1,500,000 Daltons, balancing the integrity of the network structure with the fluidity of the formulation, ensuring both the diffusion barrier of salicylic acid and facilitating formulation processing and user experience. Building upon this foundation, the present invention introduces three basic amino acids—arginine, lysine, and histidine—into an aqueous phase rich in carboxyl groups (—COO⁻) formed by polyglutamic acid. These three basic amino acids, with their protonated side chains (guanidinyl, ε-amino, and imidazole groups) as cation anchors, form multiple ionic bonds with the carboxyl groups of polyglutamic acid through electrostatic attraction, distributing themselves within the anionic network of polyglutamic acid. Simultaneously, the amino acid cations can also act as trapping anchors, binding with the carboxyl anions of salicylic acid molecules and trapping and anchoring them within the polyglutamic acid network, forming a tertiary electrostatically assembled complex of "polyglutamic acid-amino acid-salicylic acid." This fundamentally avoids the problems of decreased inclusion rate and salicylic acid crystallization associated with cyclodextrin inclusion complexes during long-term storage. Furthermore, the three-dimensional network of polyglutamic acid provides a physical diffusion barrier for salicylic acid, allowing the complex to remain clear and transparent for extended periods under high pH storage conditions, preventing salicylic acid precipitation, crystallization, and degradation. This ensures the composition maintains a uniform, transparent, and stable state during room temperature storage.

[0040] The pH value of the composition formulation suitable for the ternary complex of the present invention is 6.0 to 7.0. This is based on the functional differences of the three amino acids in charge characteristics, pH responsiveness, space filling, and synergistic design to achieve a smart sustained-release effect. Arginine's guanidino group is nearly 100% protonated in the pH range of 6–7, making it the amino acid with the highest positive charge density and strongest electrostatic binding force among the three. As the main anchoring site, it provides the strongest electrostatic driving force, preferentially forming stable ionic bonds with the carboxyl group of polyglutamic acid to capture salicylic acid. Lysine's ε-amino group also remains fully protonated in this pH range, providing additional ionic anchoring sites for salicylic acid loading and regulating the space filling of the network. Histidine's imidazole group has a protonation fraction of 50%–76% in the pH range of 6.0–6.5, of which about 24%–50% of histidine exists in the form of neutral imidazole and does not participate in electrostatic anchoring. At this time, salicylic acid mainly exists in the form of negatively charged carboxyl group. The electrostatic anchoring force provided by arginine and lysine is sufficient to maintain structural stability during storage, and the network as a whole is in a moderately loose state, which is conducive to the molecular movement of salicylic acid during storage and prevents aggregation and crystallization.

[0041] Upon contact with the skin, the local pH of the product decreases (the pH of human skin surface is typically between 4.5 and 5.5). At this point, the histidine protonation fraction rises to approximately 91%, significantly increasing the positive charge density and enhancing the electrostatic fixation effect on salicylic acid. Simultaneously, with the decrease in pH, the carboxylation degree of polyglutamic acid increases, the electrostatic repulsion between molecular chains weakens, and the three-dimensional network moderately contracts from an extended state, narrowing the physical diffusion channels. The combined effect of these two factors results in a lower release rate of salicylic acid at pH 5.0 compared to the diffusion rate at pH 6.0–6.5. This negatively correlated release mechanism achieves an intelligent sustained-release effect by utilizing the skin's own acidic environment to regulate release behavior, avoiding the problems of stinging, redness, and other irritation caused by a sudden large release of high-concentration salicylic acid upon skin contact. Furthermore, this design addresses the limitation of salicylic acid to low pH values ​​in formulation systems, facilitating the expansion of compatibility between salicylic acid and other active ingredients.

[0042] The present invention provides a composition containing the aforementioned polyglutamic acid-amino acid synergistically stabilized salicylic acid intelligent sustained-release ternary complex, which comprises the following components by weight: 2.0-20.0 parts of the aforementioned ternary complex, 0.1-0.6 parts of thickener, 5-10 parts of humectant, 0.5-1.0 parts of antibacterial preservative, 0.1-2.0 parts of soothing agent, 0.5-5.0 parts of pH buffer, and the balance being purified water. The thickener is selected from one or more of sodium polyacrylate, methylcellulose, ethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, and xanthan gum; the moisturizer is selected from one or more of glycerin, butylene glycol, hexanediol, dipropylene glycol, and glyceryl polyether; the antibacterial preservative is selected from one or more of methylparaben, phenoxyethanol, caprylyl glycol, pentylene glycol, hexanediol, and p-hydroxyacetophenone; the soothing agent is selected from one or more of bisabolol, ectoine, allantoin, dipotassium glycyrrhizate, panthenol, chamomile extract, and aloe extract; and the pH buffer is a disodium hydrogen phosphate and / or sodium dihydrogen phosphate buffer system. Experiments show that when this composition is applied to the surface of fresh pigskin at 32°C (simulating human skin use), the release of salicylic acid is 50%–70% after 6–8 hours and 90%–95% after 12 hours, ensuring a stable release rate and maintaining the product at an effective concentration for an extended period, thus guaranteeing its acne-removing and exfoliating effects.

[0043] The preparation method of the above composition employs a stepwise construction and step-by-step assembly process. First, polyglutamic acid is dissolved to form an anionic polymer backbone solution. Then, it is added stepwise in a specific order: arginine → lysine → histidine. Orderly anchoring is achieved by utilizing the differences in the protonation degree and electrostatic binding strength of the three amino acids. Specifically, the method includes the following steps:

[0044] 1) Add salicylic acid to the humectant and stir thoroughly until the salicylic acid is completely dispersed to form an SA solution;

[0045] 2) Add polyglutamic acid to a portion of purified water and stir until completely dissolved to form an aqueous PGA solution;

[0046] 3) At 40–60°C, amino acids are added to the PGA aqueous solution prepared in step 2), and ultrasonically vibrated until completely dissolved to form a PGA-amino acid composite solution; the order in which the basic amino acids are added to the PGA solution is as follows: arginine, lysine, and histidine are added to the PGA aqueous solution in sequence, ultrasonically vibrated until completely dissolved, and then another component is added to obtain a clear and transparent solution; the ultrasonic vibration conditions are: frequency 20–40 kHz, power 100–300 W;

[0047] 4) At 40–60°C, under stirring conditions, add the SA solution prepared in step 1) to the PGA-amino acid composite solution formed in step 3). After the addition is complete, continue stirring for 20–40 min to obtain a uniformly mixed ternary composite solution. The rate at which the SA solution is added to the PGA-amino acid composite solution is 2–5 mL / min, and the stirring speed is 200–400 rpm.

[0048] 5) Disperse the thickener in the remaining purified water and fully hydrate it to form a transparent gel. Then mix it with the ternary composite solution from step 4) to obtain a ternary composite gel solution. The mixing process is as follows: slowly add the ternary composite solution to the thickener gel in a thin stream at a rate of 20-50 mL / min. The addition process should be completed in 1-3 minutes. After addition, the stirring speed should be controlled at 100-300 rpm and stirred until the mixture is uniform.

[0049] 6) Add the soothing agent, thickener, preservative and pH buffer to the mixture obtained in step 5) in sequence, and continue to stir until homogeneous to obtain the target composition.

[0050] This invention utilizes the principle that arginine provides the strongest electrostatic driving force to preferentially occupy strong binding sites in the network, lysine supplements medium-strength anchoring sites, and histamine finally embeds itself in the network gaps to act as a pH response probe. After the PGA-amino acid composite network is constructed, a salicylic acid solution pre-dispersed in a humectant is slowly added, allowing salicylic acid molecules to be captured by the cationic anchoring sites in the already formed three-dimensional network. This stepwise self-assembly strategy of building the network first and then loading the drug ensures the integrity of the polyglutamic acid-amino acid network structure and the uniformity of salicylic acid anchoring, avoiding the interference of complex issues such as component ratios and pH control in existing technologies. Moreover, the entire preparation process is completed under mild conditions of 40-60℃, using only water as a solvent, without the participation of organic solvents, the addition of external pH adjusters, or post-processing steps such as spray drying and freeze drying. A stable ternary composite can be obtained through a one-step aqueous self-assembly, which is simple to operate, mild in conditions, environmentally friendly, and has good feasibility for industrial scale-up.

[0051] The composition of this invention can be used to prepare cosmetics with effects such as acne removal, oil control, exfoliation, and improvement of closed comedones, such as toners, serums, facial masks, acne patches, foaming cleansing mousses, or scalp care serums. In application, each product needs to consider the water solubility and pH sensitivity of the composition itself according to the dosage form, and select the type and amount of thickener, preservative, and pH buffer to ensure that the three-dimensional network structure of the ternary complex is not damaged.

[0052] In summary, the composition provided by this invention not only achieves stable and sustained release behavior, effectively suppressing the initial burst release phenomenon commonly found in existing cyclodextrin inclusion complexes, but also significantly reduces skin irritation. Simultaneously, polyglutamic acid and amino acids themselves possess multiple skincare benefits, including moisturizing, repairing, and strengthening the skin barrier, enabling the reuse of the carrier material's functions. Furthermore, its preparation process is simple and easily scaled up, requiring no external pH adjusters or organic solvents throughout the process. This overcomes the technical shortcomings of existing cyclodextrin inclusion complexes, such as storage crystallization, initial burst release irritation, single carrier function, and narrow pH window. It is an innovative salicylic acid skincare composition that combines high stability, low irritation, intelligent sustained release, and green safety, possessing significant practical and economic value.

[0053] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below in conjunction with embodiments. All pharmaceuticals involved in the embodiments are commercially available, and those without a specified purity are industrial or reagent grade.

[0054] The specific implementation method is as follows:

[0055] Example 1

[0056] This embodiment describes the preparation of a composition containing a salicylic acid smart sustained-release ternary complex synergistically stabilized by polyglutamic acid and amino acids. The mass ratio of polyglutamic acid, salicylic acid, and amino acids in this composition is 5:1:0.5. The specific formulation is shown in Table 1.

[0057] Table 1:

[0058]

[0059] The specific preparation process is as follows:

[0060] 1) Weigh each component raw material according to the weight parts listed in Table 1; at room temperature, add salicylic acid to the humectant and stir at 300 rpm until the salicylic acid is completely dispersed to obtain SA solution;

[0061] 2) Divide the purified water into two equal parts. At room temperature, add polyglutamic acid to one part of the purified water and stir at 300 rpm until the polyglutamic acid is completely dissolved to form a PGA aqueous solution.

[0062] 3) At 50℃, arginine, lysine and histidine were added to PGA aqueous solution in sequence and ultrasonically vibrated at 30kHz and 200W until completely dissolved. Then another component was added to obtain a clear and transparent PGA-amino acid complex solution.

[0063] 4) Keep the temperature at 50℃ and stir at 300 rpm. Add the SA solution prepared in step 1) to the PGA-amino acid complex solution formed in step 3) at a rate of 2 mL / min. After the addition is complete, continue stirring for 30 min to obtain a uniformly mixed ternary complex solution.

[0064] 5) Disperse the thickener in another portion of purified water and fully hydrate to form a transparent gel. Then, slowly add the ternary composite solution obtained in step 4) to the thickener gel in a thin stream at a rate of 25 mL / min. The addition process lasts for about 2 minutes, and the stirring speed is controlled at 200 rpm. After the addition is completed, continue stirring for 15 minutes to obtain the ternary composite gel solution.

[0065] 6) Add the soothing agent, preservative and pH buffer to the ternary complex gel obtained in step 5) in sequence, and continue to stir at 200 rpm until homogeneous. A clear and transparent composition containing a salicylic acid smart sustained-release ternary complex with polyglutamic acid-amino acid synergistic stability is obtained. Its pH value is 6.7, and it is referred to as composition 1.

[0066] Example 2

[0067] The only difference between this composition and Example 1 is that the molecular weight of polyglutamic acid in the formulation is 500,000 Daltons. The preparation method and process parameters are the same as in Example 1. The prepared composition has a pH of 6.7 and is designated as Composition 2.

[0068] Example 3

[0069] The only difference between this composition and Example 1 is that the molecular weight of polyglutamic acid in the formulation is 1.5 million Daltons. The preparation method and process parameters are the same as in Example 1. The prepared composition has a pH of 6.6 and is designated as Composition 3.

[0070] Comparative Example 1

[0071] The difference between this composition and Example 1 is that the polyglutamic acid in the formulation has a molecular weight of 300,000 Daltons. The preparation method of this composition is the same as that of Example 1. The prepared composition has a pH of 6.6 and is designated as control 1.

[0072] Comparative Example 2

[0073] The difference between this composition and Example 1 is that the polyglutamic acid in the formulation has a molecular weight of 1.8 million Daltons. The preparation method of this composition is the same as that of Example 1. The prepared composition has a pH of 6.6 and is designated as control 2.

[0074] Comparative Example 3

[0075] The difference between this composition and Example 1 is that the polyglutamic acid in the formulation is replaced with cross-linked β-cyclodextrin. The preparation method of cross-linked β-cyclodextrin is as follows, referring to patent application CN120918962A: Deionized water is added to a flat-bottomed glass container, citric acid and sodium dihydrogen phosphate of β-cyclodextrin are added and stirred for 5 minutes to mix evenly. The mass ratio of citric acid, β-cyclodextrin and sodium dihydrogen phosphate is 1:1:0.6, and the mass ratio of β-cyclodextrin and deionized water is 1:3. The mixture is stirred evenly at room temperature to obtain a suspension. The suspension is then frozen at -18°C and lyophilized overnight. The lyophilized material is then transferred to a reaction vessel at 160°C for polymerization reaction for 2 hours. Finally, the cross-linked material obtained after the reaction is washed 4 times with deionized water and 4 times with alcohol, and then dried in an electric oven at 50°C for 2 hours to obtain the final cross-linked β-cyclodextrin polymer for later use.

[0076] The preparation method of this composition is as follows:

[0077] 1) At room temperature, add salicylic acid to the humectant and stir at 300 rpm until the salicylic acid is completely dispersed to obtain an SA solution;

[0078] 2) Dissolve the cross-linked β-cyclodextrin polymer in purified water at a mass ratio of 1:6 to obtain a cross-linked β-cyclodextrin solution;

[0079] 3) Add the SA solution obtained in step 1) to the β-cyclodextrin solution in step 2), stir well to form a salicylic acid-cyclodextrin binary mixture solution;

[0080] 4) Dissolve arginine, lysine, and histidine in purified water to obtain an amino acid solution;

[0081] 5) Add the amino acid solution obtained in step 4) to the salicylic acid-cyclodextrin binary mixture solution obtained in step 3), mix well, and stir at 40°C for 4 hours to obtain a salicylic acid-cyclodextrin-amino acid ternary mixture solution.

[0082] 6) Disperse the thickener in purified water and fully hydrate to form a transparent gel. Then, slowly add the salicylic acid-cyclodextrin-amino acid ternary mixture solution obtained in step 5) into the thickener gel in a thin stream at a rate of 25 mL / min. The addition process lasts for about 2 minutes, and the stirring speed is controlled at 200 rpm. After the addition is completed, continue stirring for 15 minutes to obtain the mixture.

[0083] 7) Add the soothing agent, preservative, and pH buffer to the mixture obtained in step 6) in sequence, and continue stirring at 200 rpm until homogeneous. The prepared composition has a pH of 6.7 and is designated as control 3.

[0084] Comparative Example 4

[0085] The difference between this composition and Example 1 is that the amino acids in the formulation are arginine and lysine, and it does not contain histidine. The preparation method of this composition is the same as in Example 1, except that in step 3), arginine is completely dissolved in the PGA aqueous solution before adding lysine; the remaining steps are identical. The prepared composition has a pH of 6.7 and is designated as control 4.

[0086] Comparative Example 5

[0087] The difference between this composition and Example 1 is that the amino acids in the formulation are arginine and histidine, and it does not contain lysine. The preparation method of this composition differs from Example 1 in that step 3) involves completely dissolving arginine in a PGA aqueous solution before adding histidine; the remaining steps are the same. The prepared composition has a pH of 6.6 and is designated as control 5.

[0088] Comparative Example 6

[0089] The difference between this composition and Example 1 is that the amino acids in the formulation are lysine and histidine, and arginine is not present. The preparation method of this composition differs from Example 1 in that step 3) involves completely dissolving lysine in a PGA aqueous solution before adding histidine; the remaining steps are the same. The prepared composition has a pH of 6.4 and is designated as control 6.

[0090] Comparative Example 7

[0091] The difference between this composition and Example 1 is that the amino acid in the formulation is only arginine, excluding lysine and histidine. The preparation method of this composition is the same as in Example 1, except that in step 3), arginine is added to the PGA aqueous solution and completely dissolved; the remaining steps are identical. The prepared composition has a pH of 6.6 and is designated as control 7.

[0092] Comparative Example 8

[0093] The difference between this composition and Example 1 is that the amino acid in the formulation is only lysine, excluding arginine and histidine. The preparation method of this composition is the same as in Example 1, except that in step 3), lysine is added to the PGA aqueous solution and completely dissolved; the remaining steps are identical. The prepared composition has a pH of 6.4 and is designated as control 8.

[0094] Comparative Example 9

[0095] The difference between this composition and Example 1 is that the amino acid in the formulation is only histidine, excluding arginine and lysine. The preparation method of this composition is the same as in Example 1, except that in step 3), histidine is added to the PGA aqueous solution and completely dissolved; the remaining steps are identical. The prepared composition has a pH of 6.3 and is designated as control 9.

[0096] Comparative Example 10

[0097] The composition is identical to the formulation of Example 1. The preparation method of this composition differs from Example 1 except that the order of addition in step 4) is reversed; the PGA-amino acid complex solution formed in step 3) is added to the SA solution prepared in step 1) at a rate of 2 mL / min. The remaining steps are the same. The prepared composition has a pH of 6.7 and is designated as control 10.

[0098] Example of effect

[0099] This embodiment examines the stability, in vitro acne-reducing efficacy, irritation, and sustained-release effect of the compositions prepared in Examples 1-3 and Comparative Examples 1-10. Details are as follows:

[0100] 1) Stability Test: The prepared compositions 1-3 of the present invention and comparative compositions 1-10 (numbered 1-13 respectively) were placed at 4°C, room temperature, and 40°C for 6 months respectively, and the appearance and pH value of each composition were observed and tested periodically. The test results are shown in Table 2 and... Figure 1 As shown.

[0101] Table 2: Results of stability studies for each composition

[0102]

[0103] From Table 2 and Figure 1 The results show that compositions 1-3 have good stability. After being placed at 4℃, room temperature and 40℃ for 6 months, the appearance and pH value of the samples did not change significantly.

[0104] The comparison results between composition 1 and controls 1 and 2 show that when the molecular weight of polyglutamic acid is below 500,000 Da, the molecular chain is too short to form a sufficiently dense three-dimensional network, resulting in a weak physical encapsulation effect on salicylic acid. This leads to a significant decrease in composition stability during long-term storage. While the composition's stability is acceptable during long-term storage when the molecular weight of polyglutamic acid is above 1,500,000 Da, its viscosity is too high, resulting in poor skin comfort and hindering the intelligent controlled release of salicylic acid. Therefore, this invention limits the molecular weight of polyglutamic acid to between 500,000 and 1,500,000 Daltons.

[0105] The comparison results between composition 1 and control 3 show that the composition without polyglutamic acid has poor stability and significant salicylic acid precipitation.

[0106] The comparison results between composition 1 and controls 4-9 show that the stability of the composition is relatively poor when the components of the ternary complex are incomplete, especially the combinations of controls 7-9 which lack two amino acid components. The experimental results fully demonstrate the synergistic effect of each component in the ternary complex. The absence of any component will lead to a weakening of the electrostatic effect inside the polyglutamic acid-amino acid-salicylic acid tertiary electrostatic assembly complex, thereby causing a decrease in the stability of the composition.

[0107] The comparison results between composition 1 and control 10 show that control 10, with the addition order changed, has poor stability. It is speculated that the reason may be that changing the addition order is not conducive to the formation of the three-dimensional network structure of the ternary complex.

[0108] 2) Irritation Test: A closed patch test was used. A Finnish-made (square) patch applicator from Baiyiyida was used. Using a relative quantitative pipette, 0.020–0.025 g of each of the compositions 1-3 and controls 1-10 were transferred into the patch applicator. The patch applicator containing the test substance was then evenly applied to the flexor surface of the subject's forearm. After 24 hours, the patch applicator was removed, and after a 30-minute wait, the results were recorded according to the skin reaction grading standards in the *Cosmetic Hygiene Standard* and the *Cosmetic Safety Technical Standard*. The scoring criteria are shown in Table 3, and the test results are shown in Table 4. Figure 2 .

[0109] Table 3: Skin Reaction Grading Standards

[0110]

[0111] Table 4: Skin irritation test scores for each composition and the control group

[0112]

[0113] From Table 4 and Figure 2 The results show that no adverse reactions were observed in humans with compositions 1-3, demonstrating that under the action of the three-dimensional network structure formed by polyglutamic acid-amino acid-salicylic acid, the release rate of salicylic acid is inhibited when the composition is applied to human skin, and it will not be released rapidly and in large quantities on the skin surface, thus avoiding the irritating effect of high concentrations of salicylic acid on the skin.

[0114] The comparison results of control 1, control 2 and composition 1 show that the control with added low molecular weight polyglutamic acid has a slight irritant effect, which proves that the low molecular weight polyglutamic acid has a poor encapsulation effect on salicylic acid and the electrostatic interaction in the three-dimensional network structure is unstable. Control 2 with added ultra-high molecular weight polyglutamic acid is not irritating, but the sample itself is too sticky and has a poor skin feel when used.

[0115] The comparison results between control 3 and composition 1 show that control 3, which uses β-cyclodextrin instead of polyglutamic acid, is significantly more irritating. This indicates that the sustained-release effect of salicylic acid in the composition is insufficient, and a large amount of salicylic acid is released in a short period of time, resulting in skin irritation.

[0116] The comparison between composition 1 and controls 4-9 shows that when the amino acid components in the ternary complex are incomplete, all controls produced varying degrees of skin irritation, especially compositions 7-9, which lack two amino acids, exhibiting a more pronounced irritation. This demonstrates that when the amino acid components in the ternary complex are incomplete, the electrostatic interaction between salicylic acid and amino acids / polyglutamic acid is weakened. Upon contact with the skin, the salicylic acid is released too quickly, leading to an excessively high local concentration of salicylic acid and thus causing irritation.

[0117] The comparison results between composition 1 and control 10 show that control 10, with the changed order of feeding, has a slight irritant effect, proving that the order of feeding in the preparation method is also one of the key factors to ensure the network structure of the ternary composite and the electrostatic interaction between them.

[0118] 4) Salicylic acid sustained-release effect test: The Franz diffusion cell method was used. The receiving cell was filled with pH 7.4 phosphate buffer and a rotor was placed inside. Fresh piglet abdominal skin with the stratum corneum facing upwards was clamped on the support of the Franz diffusion cell. Composition 1-3 and control 1-10 were added to the supply cell and evenly applied to the pig skin surface. The temperature was set at 32℃ to simulate the use of the composition on human skin. At different time points, the pig skin was removed and the stratum corneum was carefully washed with buffer solution. The samples were then combined with the samples from the receiving and supply cells, and the free salicylic acid content in the samples was detected. The release amount of the composition at different time points was calculated based on the detection results. The results are shown in Table 5.

[0119] Table 5: Results of sustained-release tests for each composition

[0120]

[0121] As shown in Table 5, the release of salicylic acid from compositions 1-3 was 50%-70% at 6-8 hours and 92%-93% at 12 hours, indicating that it has a good and stable release rate, which can maintain the product at an effective concentration for a long time and ensure the efficacy of acne removal and exfoliation.

[0122] Control compound 1 (polyglutamic acid 500,000 Daltons) released more than 50% of its content in 2 hours, and the release of salicylic acid was 75% to 86% in 6 to 8 hours. Its sustained-release effect was significantly worse than that of all compositions 1-3, which further proves that the three-dimensional network structure formed by low molecular weight polyglutamic acid has a smaller encapsulation and binding effect on salicylic acid.

[0123] Although control compound 2 (polyglutamic acid 1.5 million Daltons) has a sustained-release effect, the three-dimensional network structure formed by high molecular weight polyglutamic acid has an excessively strong encapsulating and binding effect on salicylic acid, resulting in a significantly slower salicylic acid release rate than compositions 1-3. Moreover, the release amount at 12 hours is only 85%, which is too low. This low release amount will lead to a lower actual salicylic acid concentration in the product, affecting the product's effectiveness.

[0124] The control compound 3, which replaced polyglutamic acid with β-cyclodextrin, achieved 88% salicylic acid release in 2 hours, with virtually no sustained-release effect.

[0125] In the ternary complexes, controls 4-9, which lacked complete amino acid components, exhibited rapid salicylic acid release. Combinations 7-9, lacking two amino acids, showed a release rate of 66%–73% within 2 hours, potentially causing skin irritation. This further demonstrates that the amino acid composition in the ternary complex plays a crucial role in the intelligent release of salicylic acid within the system.

[0126] The control compound 10, with a changed feeding order, released 49% of its salicylic acid in 2 hours, and its sustained-release effect was significantly worse than that of compositions 1-3, proving that changing the feeding order can also lead to a worse sustained-release effect of salicylic acid in the composition.

[0127] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered exemplary and not restrictive in all respects. Furthermore, it should be understood that although this specification describes embodiments, it does not encompass only one technical solution. This descriptive method is merely for clarity, and those skilled in the art should consider the specification as a whole. The technical solutions in the embodiments can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A polyglutamic acid-amino acid synergistically stabilized salicylic acid smart sustained-release ternary complex, characterized in that: The mass ratio of polyglutamic acid, salicylic acid, and amino acids in this ternary complex is (2-10):1:(0.1-1.2). The polyglutamic acid has a molecular weight of 500,000 to 1,500,000 Daltons; The amino acids are basic amino acids, consisting of arginine, lysine, and histidine. These three amino acids are sequentially and orderly anchored in the polyglutamic acid backbone through differences in protonation degree and electrostatic binding strength, synergistically capturing and stabilizing salicylic acid molecules, while utilizing the acidic environment of human skin to regulate the release behavior of salicylic acid.

2. The polyglutamic acid-amino acid synergistically stabilized salicylic acid smart sustained-release ternary complex according to claim 1, characterized in that: The mass ratio of arginine, lysine, and histidine in the basic amino acids is (0.4-0.6): (0.2-0.4): (0.1-0.2).

3. A polyglutamic acid-amino acid synergistically stabilized salicylic acid smart sustained-release composition, characterized in that: The composition has a pH of 6.0 to 7.0 and consists of the following components in parts by weight. composition: 2.0 to 20.0 parts of the ternary composite according to claim 1 or 2, Thickener 0.1-0.6 parts, 5-10 parts of moisturizer Antibacterial and preservative agent 0.5-1.0 parts, Soothing agent 0.1–2.0 parts, pH buffer solution 0.5–5.0 parts, The remainder is purified water.

4. The polyglutamic acid-amino acid synergistically stabilized salicylic acid smart sustained-release composition according to claim 3, characterized in that: The thickener is selected from one or more of sodium polyacrylate, methylcellulose, ethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, and xanthan gum; The moisturizer is selected from one or more of glycerin, butylene glycol, hexanediol, dipropylene glycol, and glycerol polyether; The antibacterial and preservative agent is selected from one or more of methylparaben, phenoxyethanol, octyl glycol, pentylene glycol, hexanediol, and p-hydroxyacetophenone; The soothing agent is selected from one or more of the following: bisabolol, ectoine, allantoin, dipotassium glycyrrhizate, panthenol, chamomile extract, and aloe extract. The pH buffer solution is a sodium dihydrogen phosphate and / or sodium dihydrogen phosphate buffer system.

5. The polyglutamic acid-amino acid synergistically stabilized salicylic acid smart sustained-release composition according to claim 3 or 4, characterized in that: When this composition is applied topically, the release of salicylic acid is 50%–70% after 6–8 hours and 90%–95% after 12 hours.

6. A method for preparing a polyglutamic acid-amino acid synergistically stabilized salicylic acid smart sustained-release composition, characterized in that: The composition contains the ternary complex according to claim 1 or 2; the preparation method includes the following steps: 1) Add salicylic acid to the humectant and stir thoroughly until the salicylic acid is completely dispersed to form an SA solution; 2) Add polyglutamic acid to a portion of purified water and stir until completely dissolved to form an aqueous PGA solution; 3) Add the amino acids to the PGA aqueous solution prepared in step 2), and sonicate at 40-60°C until completely dissolved to form a PGA-amino acid complex solution; the amino acids are basic amino acids, composed of arginine, lysine and histidine; 4) Under stirring conditions at 40-60℃, add the SA solution prepared in step 1) to the PGA-amino acid complex solution formed in step 3). After the addition is complete, continue stirring for 20-40 minutes to obtain a uniformly mixed ternary complex solution. 5) Disperse the thickener in the remaining purified water, fully hydrate to form a transparent gel, and then mix it with the ternary composite solution from step 4) to obtain a ternary composite gel solution; 6) Add the soothing agent, thickener, preservative and pH buffer to the mixture obtained in step 5) in sequence, and continue to stir and mix evenly at 40-60°C to obtain the target composition.

7. The method for preparing the polyglutamic acid-amino acid synergistically stabilized salicylic acid smart sustained-release composition according to claim 6, characterized in that: In step 3), the order in which the basic amino acids are added to the PGA solution is as follows: arginine, lysine and histidine are added to the PGA aqueous solution in sequence, ultrasonically vibrated until completely dissolved, and then another component is added to obtain a clear and transparent solution; the ultrasonic vibration conditions are: frequency 20-40kHz, power 100-300W.

8. The method for preparing the polyglutamic acid-amino acid synergistically stabilized salicylic acid smart sustained-release composition according to claim 7, characterized in that: In step 4), the SA solution is added to the PGA-amino acid complex solution at a rate of 2-5 mL / min, and the stirring speed is 200-400 rpm.

9. The method for preparing the polyglutamic acid-amino acid synergistically stabilized salicylic acid smart sustained-release composition according to claim 8, characterized in that: In step 5), the process of mixing the thickener with the ternary composite solution after the thickener forms a transparent gel is as follows: the ternary composite solution is slowly added to the thickener gel in a thin stream at a rate of 20-50 mL / min, and the addition process is completed in 1-3 minutes; the stirring speed after addition is controlled at 100-300 rpm.

10. The use of the composition according to any one of claims 3-5 in the preparation of cosmetics having the effects of acne removal, oil control, exfoliation, and improvement of closed comedones.

Images