A salicylic acid-cyclodextrin-amino acid ternary inclusion compound, a preparation method and application thereof

Abstract

The application discloses a salicylic acid-cyclodextrin-amino acid ternary inclusion compound and a preparation method thereof. The salicylic acid-cyclodextrin-amino acid ternary inclusion compound is formed by non-covalent bond interaction of salicylic acid, amino acid and cyclodextrin derivatives, wherein the cyclodextrin derivative is a cross-linked beta-cyclodextrin polymer, wherein the salicylic acid molecules are included in the cavity of the cross-linked beta-cyclodextrin polymer, and meanwhile, the guanidino group or carboxyl group of the amino acid side chain interacts with the hydroxyl group outside the cross-linked beta-cyclodextrin polymer or the exposed part of the salicylic acid molecules after inclusion. The application uses the cross-linked beta-cyclodextrin polymer and introduces arginine as a synergist to construct a salicylic acid-cross-linked beta-cyclodextrin polymer-arginine ternary inclusion compound, and through charge neutralization and hydrogen bond network synergistic effect, the inclusion efficiency is significantly improved, and the water solubility of salicylic acid is improved.

Description

Technical Field

[0001] This invention relates to the field of cosmetic / drug sustained-release technology, specifically to a salicylic acid-cyclodextrin-amino acid ternary inclusion complex and its preparation method. Background Technology

[0002] Salicylic acid (o-hydroxybenzoic acid) is an important fat-soluble organic acid widely used in the pharmaceutical, chemical, and cosmetic industries. As a pharmaceutical raw material, it is used to synthesize drugs such as aspirin and sodium salicylate, and in skin care products, it softens keratin and has antibacterial and acne-reducing effects. However, salicylic acid's slight water solubility presents challenges in its formulation development, especially in cosmetics where it often relies on alcohol for solubilization. The rapid evaporation of alcohol can cause localized precipitation of salicylic acid, leading to skin irritation and limiting its application in products for sensitive skin. This contradiction has spurred the need for novel solubilization technologies to balance efficacy and safety.

[0003] To address the aforementioned issues, complexation solubility enhancement technology utilizes specific interactions between host and guest molecules to achieve drug solubilization. Compared to solubilization methods, pH adjustment methods, and emulsion solubilization systems, this approach offers faster, more significant, and more predictable dissolution rates. Among numerous complexing agents, cyclodextrin (CD) is frequently used as a drug carrier due to its unique hydrophobic cavity structure, improving the solubility, stability, and bioavailability of poorly soluble drugs by forming inclusion complexes. Existing technology (CN106726690A) discloses a binary inclusion complex of cyclodextrin and salicylic acid, which can address the low solubility and poor stability of salicylic acid to some extent. However, the binary inclusion complex has limited effectiveness in reducing skin irritation from salicylic acid, and its transdermal absorption behavior still has room for optimization. Furthermore, hydrogen bonds form between the C2-OH and C3-OH groups in β-cyclodextrin, resulting in persistently low solubility. The reaction of the hydroxyl groups on the cross-linked β-cyclodextrin polymer with the cross-linking agent to form a polymer disrupts the ability of β-cyclodextrin to form hydrogen bonds within the molecule itself, thus eliminating some of the undesirable physicochemical properties of β-cyclodextrin to a certain extent. After a drug is encapsulated in a cross-linked β-cyclodextrin polymer, its solubility and dissolution rate increase significantly.

[0004] In recent years, the strategy of adding ternary auxiliary agents to enhance the drug-drug complexation efficiency has attracted much attention. Amino acids possess advantages such as low molecular weight, good water solubility, high safety (GRAS certified), and multiple interaction sites. Their charged functional groups (such as amino and carboxyl groups) can synergistically regulate the stability of drug-drug complexes through ionic bonds, hydrogen bonds, and hydrophobic interactions. However, the stability of amino acids in ternary systems remains uncertain, and this issue urgently needs to be addressed. Currently, although there are studies on salicylic acid-cyclodextrin inclusion complexes and cyclodextrin-amino acid interactions, there are no reports on the formation of stable, industrially producible ternary inclusion complexes by combining salicylic acid, β-cyclodextrin, and specific amino acids, nor on their application in reducing salicylic acid skin irritation and enhancing its skin drug delivery efficiency. Therefore, developing a novel salicylic acid-cyclodextrin-amino acid ternary inclusion complex and its preparation method is of great significance for improving the safety and efficacy of salicylic acid therapy and expanding its application in therapeutic and functional cosmetics. Summary of the Invention

[0005] This invention addresses the problems of low drug loading efficiency and insufficient water solubility of salicylic acid in existing traditional cyclodextrin encapsulation techniques. It provides a salicylic acid-cyclodextrin-amino acid ternary inclusion complex and its preparation method. This invention uses a cross-linked β-cyclodextrin polymer and introduces arginine as a synergist to construct a salicylic acid-cross-linked β-cyclodextrin polymer-arginine ternary inclusion complex. Through charge neutralization and the synergistic effect of hydrogen bonding networks, the inclusion efficiency is significantly improved.

[0006] This invention is achieved through the following technical solutions:

[0007] The first objective of this invention is to provide a salicylic acid-cyclodextrin-amino acid ternary inclusion complex, which is formed by the non-covalent interaction of salicylic acid, amino acids and cyclodextrin derivatives, wherein the cyclodextrin derivative is a cross-linked β-cyclodextrin polymer, wherein salicylic acid molecules are included in the cavity of the cross-linked β-cyclodextrin polymer, and simultaneously interact with the hydroxyl groups on the outside of the cross-linked β-cyclodextrin polymer or the exposed portion of the included salicylic acid molecules through the guanidinium or carboxyl groups of the amino acid side chains.

[0008] The ternary inclusion complex proposed in this invention exhibits a conformational invariance of molecular docking throughout the simulated trajectory. Arginine binds to the broad edge of the cross-linked β-cyclodextrin polymer, establishing several hydrogen bond contacts with the hydroxyl groups located in this region. This ternary inclusion complex demonstrates the lowest total interaction energy among all simulated complexes.

[0009] Preferably, the method for preparing the crosslinked β-cyclodextrin polymer includes the following steps:

[0010] S1. Add deionized water to a mixing container, add citric acid, β-cyclodextrin and sodium dihydrogen phosphate and mix. Stir evenly at room temperature to obtain a suspension. Then, pre-treat the suspension by freezing and freeze-dry it in a freeze dryer.

[0011] S2. Transfer the obtained freeze-dried material to a reaction vessel at a temperature of 140℃-180℃ for polymerization reaction for 1-3 hours;

[0012] S3. The cross-linked material obtained from the polymerization reaction is washed with water and alcohol, and then dried to obtain the final cross-linked β-cyclodextrin polymer.

[0013] Further preferred, in step S1, 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.

[0014] Further preferred, the freezing temperature for freezing the suspension in step S1 is -18°C.

[0015] Further optimization is made to the following conditions for the polymerization reaction in step S2: reaction temperature of 160℃ and reaction time of 2h.

[0016] Further optimization, the specific steps of water washing, alcohol washing and drying in step S3 are as follows: the cross-linked material after reaction is washed with water and then with alcohol (ethanol or propanol) in sequence, and finally the purified powder is placed in a petri dish and dried in an electric oven at 50°C for 2 hours.

[0017] Preferably, the salicylic acid-cyclodextrin-amino acid ternary inclusion complex is composed of 25%–35% cyclodextrin derivative, 30%–40% salicylic acid, and 30%–40% amino acids by mass fraction.

[0018] Further preferably, the salicylic acid-cyclodextrin-amino acid ternary inclusion complex is composed of 30% cyclodextrin derivative, 30%–40% salicylic acid, and 30%–40% amino acids by mass fraction.

[0019] Preferably, the amino acid is a natural α-amino acid.

[0020] Further preferred, the amino acid is arginine.

[0021] A second objective of this invention is to provide a method for preparing the salicylic acid-cyclodextrin-amino acid ternary inclusion complex, comprising the following steps:

[0022] (1) Dissolve the cross-linked β-cyclodextrin polymer in water to obtain a β-cyclodextrin solution;

[0023] (2) Add salicylic acid to the β-cyclodextrin solution in step (1) and stir or sonicate for a certain time to form a salicylic acid-cyclodextrin binary inclusion complex solution;

[0024] (3) Dissolve arginine in water to obtain an arginine solution with a mass fraction of 2%-4%;

[0025] (4) Add the arginine solution obtained in step (3) to the salicylic acid-cyclodextrin binary inclusion complex solution obtained in step (2), mix evenly, and perform inclusion to obtain a mixed solution;

[0026] (5) The mixed solution obtained in step (4) is dried to obtain a ternary inclusion solid.

[0027] This invention prepares a supramolecular structure encapsulating salicylic acid through biomimetic-driven self-assembly, molecular simulation algorithm optimization, and low-temperature spray drying process, namely the salicylic acid-cyclodextrin-amino acid ternary inclusion complex proposed in this invention.

[0028] Preferably, in step (1), the mass ratio of cross-linked β-cyclodextrin polymer to water is 1:5 to 10; in step (4), the temperature of the inclusion process is 25℃ to 70℃, and the time is 5 to 1440 min.

[0029] Preferably, the mass fraction of arginine in the arginine solution in step (3) is 3%.

[0030] Further preferably, the inclusion temperature is 30℃~60℃. Even more preferably, the inclusion temperature is 40℃. In this invention, during the inclusion process, the hydrophobic portion of salicylic acid enters and occupies the hydrophobic cavity of the cross-linked β-cyclodextrin polymer, causing water molecules with high enthalpy values ​​originally in the cavity to be released, forming an inclusion complex.

[0031] Preferably, the drying in step (5) is specifically freeze spray drying, with an inlet air temperature of 40-50°C, an outlet air temperature of 25-35°C, and a spray drying pressure of 0.7-1.25 MPa.

[0032] Further optimized, the inlet air temperature is 45℃, the outlet air temperature is 28℃, and the spray drying pressure is 1~1.2MPa. The solution is broken down by the spray drying atomization pressure, ultimately yielding a white powdery ternary inclusion complex.

[0033] Preferably, the ternary inclusion complex is a freeze-dried powder or a spray-dried powder.

[0034] A third objective of this invention is to provide the application of the aforementioned salicylic acid-cyclodextrin-amino acid ternary inclusion complex in cosmetics or drug sustained release.

[0035] Compared with the prior art, the beneficial effects of the present invention are:

[0036] (1) This invention innovatively uses cross-linked β-cyclodextrin polymer and introduces arginine as a synergist to construct a salicylic acid-cross-linked β-cyclodextrin polymer-arginine ternary inclusion complex. Through charge neutralization and the synergistic effect of hydrogen bond network, the inclusion efficiency is significantly improved and the water solubility of salicylic acid is enhanced.

[0037] (2) Compared with the binary inclusion complex of β-cyclodextrin, the ternary inclusion complex proposed in this invention has a safety factor that is two levels higher, an encapsulation rate that is 120% higher, a stability that is 120% higher, and an antibacterial effect that is 75% higher; compared with salicylic acid and cross-linked β-cyclodextrin polymers without added amino acids, the ternary inclusion complex proposed in this invention has a safety factor that is one level higher, an encapsulation rate that is 28% higher, a stability that is 22% higher, and an antibacterial effect that is 25% higher; compared with the ternary inclusion complex formed using β-cyclodextrin, the ternary inclusion complex proposed in this invention has an encapsulation rate that is 50% higher, a stability that is 50% higher, and an antibacterial effect that is 40% higher.

[0038] (3) The arginine used in this invention has a guanidine group that can interact with negatively charged groups in the stratum corneum of the skin, temporarily disturbing the ordered structure of the stratum corneum. The ternary inclusion complex can utilize this property to increase the retention and penetration of salicylic acid in the stratum corneum of the skin, thereby improving local bioavailability. At the same time, arginine itself has potential effects such as moisturizing and promoting wound healing, which can produce a synergistic effect with the therapeutic effect of salicylic acid, providing more comprehensive skin benefits. Attached Figure Description

[0039] Figure 1 The absorbance standard curve for cyclodextrin-encapsulated salicylic acid.

[0040] Figure 2 The structure and nuclear magnetic resonance signal markers of salicylic acid.

[0041] Figure 3 The images show the 1H NMR spectra of the inclusion complex obtained in Example 1, where: (a) represents the 1H NMR spectrum of salicylic acid; (b) represents the 1H NMR spectrum of the cross-linked β-cyclodextrin polymer obtained in Example 1; (c) represents the 1H NMR spectrum of the binary complex salicylic acid-β-cyclodextrin derivative in Example 1; and (d) represents the ternary inclusion complex obtained in Example 1. 1 H nuclear magnetic resonance spectrum. Detailed Implementation

[0042] The present invention will be further described in detail below with reference to the embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions in the art or as recommended by the manufacturer; the raw materials and reagents used, unless otherwise specified, are considered to be commercially available materials and reagents that can be obtained through conventional markets and other commercial channels.

[0043] In this invention, the method for preparing crosslinked β-cyclodextrin polymers includes the following steps:

[0044] S1. Add deionized water to a flat-bottomed glass container, add citric acid, β-cyclodextrin, and sodium dihydrogen phosphate and mix. 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. Stir evenly at room temperature to obtain a suspension. Then, pre-treat the suspension by freezing and freeze-dry it in a freeze dryer.

[0045] S2. Transfer the obtained freeze-dried material to a reaction vessel at a temperature of 140-180℃ for polymerization reaction for 1-3 hours;

[0046] S3. After the reaction, the cross-linked material is washed with deionized water more than 3 times, washed with alcohol more than 3 times, and then dried to obtain the final cross-linked β-cyclodextrin polymer.

[0047] In the preferred embodiment described below, in step S1, the suspension is frozen at -18°C and subjected to overnight freeze-drying.

[0048] In the preferred embodiment described below, the polymerization reaction conditions in step S2 are: a reaction temperature of 160°C and a reaction time of 2 hours.

[0049] In the preferred embodiment described below, the alcohol in step S3 is ethanol or propanol, and the specific drying conditions are: drying in an electric oven at 50°C for 2 hours.

[0050] The preparation method of salicylic acid-cyclodextrin-amino acid ternary inclusion complex includes the following steps:

[0051] (1) Dissolve the cross-linked β-cyclodextrin polymer in water to obtain a β-cyclodextrin solution;

[0052] (2) Add salicylic acid to the β-cyclodextrin solution in step (1), stir or sonicate to form a salicylic acid-cyclodextrin binary inclusion complex solution;

[0053] (3) Dissolve arginine in water to obtain an arginine solution with a mass fraction of 2%-4%;

[0054] (4) Add the arginine solution obtained in step (3) to the salicylic acid-cyclodextrin binary inclusion complex solution obtained in step (2), mix evenly, and perform inclusion to obtain a mixed solution;

[0055] (5) The mixed solution obtained in step (4) is dried to obtain a ternary inclusion solid.

[0056] In this invention, the salicylic acid-cyclodextrin-amino acid ternary inclusion complex comprises, by mass fraction, 25% to 35% of cross-linked β-cyclodextrin polymer, 30% to 40% of salicylic acid, and 30% to 40% of arginine.

[0057] In the preferred embodiment described below, the mass ratio of the cross-linked β-cyclodextrin polymer to water in step (1) is 1:5 to 10.

[0058] In the preferred embodiment described below, the mass fraction of arginine in the arginine solution in step (3) is 3%.

[0059] In the following preferred embodiments, the temperature for the inclusion process in step (4) is 25°C to 70°C, and the time is 5 to 1440 min. More preferably, the temperature for the inclusion process is 40°C, and the time is 240 min.

[0060] In the following preferred embodiments, the drying in step (5) is specifically freeze spray drying, with an inlet air temperature of 40°C to 50°C, an outlet air temperature of 25°C to 35°C, and a spray drying pressure of 0.7 to 1.25 MPa. More preferably, the inlet air temperature is 45°C, the outlet air temperature is 28°C, and the spray drying pressure is 1 to 1.2 MPa.

[0061] The solution is broken down by spray drying under atomization pressure, ultimately yielding a white powdery ternary inclusion complex. This invention does not have a specific time limit for freeze-spray drying; drying to constant weight is sufficient.

[0062] Example 1

[0063] The preparation method of crosslinked β-cyclodextrin polymer includes the following steps:

[0064] S1. Add deionized water to a flat-bottomed glass container, add citric acid and sodium dihydrogen phosphate of β-cyclodextrin, and stir 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. Stir evenly at room temperature to obtain a suspension, and then freeze the suspension at -18°C and freeze-dry overnight.

[0065] S2. Transfer the obtained freeze-dried material to a reaction vessel at 160°C for polymerization reaction for 2 hours.

[0066] S3. After the reaction, the cross-linked material is washed with deionized water more than 3 times, then washed with alcohol more than 3 times, and then dried in an electric oven at 50°C for 2 hours to obtain the final cross-linked β-cyclodextrin polymer.

[0067] The salicylic acid-cyclodextrin-amino acid ternary inclusion complex comprises, by mass fraction, 30% cross-linked β-cyclodextrin polymer, 40% salicylic acid, and 30% arginine.

[0068] The preparation method of salicylic acid-cyclodextrin-amino acid ternary inclusion complex includes the following steps:

[0069] (1) Dissolve the cross-linked β-cyclodextrin polymer in water at a mass ratio of 1:6 to obtain a β-cyclodextrin solution;

[0070] (2) Add salicylic acid to the β-cyclodextrin solution in step (1) and stir until homogeneous to form a salicylic acid-cyclodextrin binary inclusion complex solution;

[0071] (3) Dissolve arginine in water to obtain an arginine solution with a mass fraction of 3%;

[0072] (4) Add the arginine solution obtained in step (3) to the salicylic acid-cyclodextrin binary inclusion complex solution obtained in step (2), mix evenly, and stir at 40°C for 4 hours to obtain a mixed solution;

[0073] (5) The mixed solution obtained in step (4) is spray-dried at low temperature to constant weight. The low temperature spray drying conditions are: inlet air temperature 45℃, outlet air temperature 28℃, and atomization pressure 1MPa to obtain a ternary inclusion solid.

[0074] Example 2

[0075] Same as Example 1, except that: the salicylic acid-cyclodextrin-amino acid ternary inclusion complex comprises, by mass fraction, 30% cross-linked β-cyclodextrin polymer, 30% salicylic acid and 40% arginine.

[0076] Comparative Example 1

[0077] Same as Example 2, except that no cross-linked β-cyclodextrin polymer and arginine were added. Salicylic acid was stirred at 40°C for 4 hours, and the resulting reaction solution was then spray-dried at low temperature to constant weight. The low-temperature spray-drying conditions were: inlet air temperature 45°C, outlet air temperature 28°C, and atomization pressure 1 MPa.

[0078] Comparative Example 2

[0079] Same as Example 2, except that arginine is not added, and the mass ratio of cross-linked β-cyclodextrin polymer to salicylic acid is 1:1.

[0080] The preparation method of the above inclusion complex includes the following steps:

[0081] (1) Dissolve the cross-linked β-cyclodextrin polymer in water at a mass ratio of 1:6 to obtain a β-cyclodextrin solution;

[0082] (2) Add salicylic acid to the β-cyclodextrin solution in step (1) and stir until homogeneous to form a salicylic acid-cyclodextrin binary inclusion complex solution;

[0083] (3) Stir the salicylic acid-cyclodextrin binary inclusion complex solution at 40°C for 4 hours to obtain a mixed solution;

[0084] (4) The mixed solution obtained in step (3) is spray-dried at low temperature to constant weight. The low temperature spray drying conditions are: inlet air temperature 45℃, outlet air temperature 28℃, and atomization pressure 1MPa to obtain the inclusion solid.

[0085] Comparative Example 3

[0086] Similar to Example 2, except that no cross-linked β-cyclodextrin polymer was added. Salicylic acid and arginine in a mass ratio of 3:4 were mixed with water and stirred. The mixture was then stirred at 40°C for 4 hours. The resulting reaction solution was spray-dried at low temperature to constant weight. The low-temperature spray-drying conditions were: inlet air temperature 45°C, outlet air temperature 28°C, and atomization pressure 1 MPa. This yielded a salicylic acid inclusion complex based on cross-linked β-cyclodextrin polymer.

[0087] Comparative Example 4

[0088] Same as Example 2, except that: the salicylic acid-cyclodextrin-amino acid ternary inclusion complex, by mass fraction, includes 30% β-cyclodextrin, 30% salicylic acid and 40% arginine.

[0089] Comparative Example 5

[0090] Same as Example 2, except that: the amino acid is lysine, and the salicylic acid-cyclodextrin-amino acid ternary inclusion complex comprises, by mass fraction, 30% β-cyclodextrin polymer, 30% salicylic acid and 40% lysine.

[0091] Example 3

[0092] Same as Example 1, except that:

[0093] In the preparation method of cross-linked β-cyclodextrin polymer, the polymerization reaction conditions are: polymerization reaction is carried out at 140℃ for 3 hours.

[0094] The salicylic acid-cyclodextrin-amino acid ternary inclusion complex comprises, by mass fraction, 25% cross-linked β-cyclodextrin polymer, 40% salicylic acid, and 35% arginine.

[0095] In the preparation method of salicylic acid-cyclodextrin-amino acid ternary inclusion complex, the mass ratio of cross-linked β-cyclodextrin polymer to water is 1:5, the mass fraction of arginine in the arginine solution is 2%, and the inclusion conditions are: stirring at 70℃ for 5 min; the low-temperature spray drying conditions are: inlet air temperature 40℃, outlet air temperature 25℃, and atomization pressure 0.7MPa.

[0096] Example 4

[0097] Same as Example 1, except that:

[0098] In the preparation method of crosslinked β-cyclodextrin polymer, the polymerization reaction conditions are: polymerization reaction is carried out at 180℃ for 1 hour.

[0099] The salicylic acid-cyclodextrin-amino acid ternary inclusion complex comprises, by mass fraction, 35% cross-linked β-cyclodextrin polymer, 30% salicylic acid, and 35% arginine.

[0100] In the preparation method of salicylic acid-cyclodextrin-amino acid ternary inclusion complex, the mass ratio of cross-linked β-cyclodextrin polymer to water is 1:10, the mass fraction of arginine in the arginine solution is 4%, and the inclusion conditions are: stirring at 25℃ for 24 hours, and low-temperature spray drying conditions are: inlet air temperature 50℃, outlet air temperature 35℃, and atomization pressure 1.25MPa.

[0101] The substances obtained in Examples 1-4 and Comparative Examples 1-5 were tested as follows:

[0102] Test Example 1: Encapsulation Rate Determination

[0103] Encapsulation efficiency is an important indicator for evaluating supramolecular products. Salicylic acid is soluble in ethanol, but supramolecular salicylic acid encapsulated by dextrin is insoluble in ethanol. The encapsulation efficiency can be calculated by determining the concentration of salicylic acid using its absorbance.

[0104] Experimental Methods: Preparation of Standard Curve: Dissolve 10 mg of salicylic acid in 100 mL of ethanol to prepare a 0.1 g / L salicylic acid ethanol standard solution. Dilute the 0.1 g / L salicylic acid solution to concentrations of 1, 2, 5, 10, and 20 mg / L, respectively. Measure the absorbance of each solution using a UV spectrophotometer, with the maximum absorption wavelength set to 300 nm. Record the absorbance values ​​as shown in Table 1. Plot a standard curve using linear fitting. Figure 1 .

[0105] Table 1: Absorbance of Standard Solutions

[0106] Salicylic acid ethanol solution (mg / L) 1 2 5 10 20 absorbance 0.027 0.054 0.116 0.233 0.499

[0107] The substances obtained in Examples 1-4 and Comparative Examples 1-5 were determined as follows: 0.1 g of the test sample was weighed into 50 mL of ethanol and sonicated for 10 min to obtain a supramolecular salicylic acid-ethanol mixture. The supramolecular salicylic acid-ethanol mixture was transferred to a constant temperature shaker and shaken at 35°C and 150 r / min for 8 h. The supramolecular salicylic acid-ethanol mixture was removed, filtered through a filter membrane, and the filtrate was collected. The filtrate was diluted 100 times, and its absorbance A was measured. The concentration ρ of salicylic acid in the filtrate was calculated according to the standard curve. The concentration and encapsulation efficiency of salicylic acid were calculated using the following formula: Concentration ρ (mg / L) = (A + 0.0031) / 0.0249. The calculation results are shown in Table 2.

[0108]

[0109] Table 2: Encapsulation rates of Examples 1-4 and Comparative Examples 1-5

[0110] Test sample Encapsulation rate Example 1 87.1％ Example 2 90.6％ Example 3 84.2％ Example 4 92.3％ Comparative Example 1 0％ Comparative Example 2 67.7％ Comparative Example 3 0％ Comparative Example 4 70.8％ Comparative Example 5 78％

[0111] Test Example 2: Water Solubility Test

[0112] To determine the water solubility of the substances obtained in Examples 1-4 and Comparative Examples 1-5, 1.0 g of each sample was weighed, placed in a 100 mL volumetric flask, dissolved in water by sonication, and diluted to the mark with water at 25℃±0.5℃. The solution was filtered through a filter membrane, and 1 mL of the filtrate was accurately pipetted into a 50 mL volumetric flask. The absorbance was then diluted to the mark with water, and the absorbance was measured at the characteristic absorption peak wavelength of 290 nm. The content of salicylic acid in the solution was calculated according to the standard curve, as shown in Table 3.

[0113] Table 3 Solubility of Examples 1-4 and Comparative Examples 1-5

[0114] Test sample Solubility (mg / mL) Example 1 67.4 Example 2 69.5 Example 3 68.7 Example 4 70.1 Comparative Example 1 1.07 Comparative Example 2 41.5 Comparative Example 3 1.65 Comparative Example 4 37.3 Comparative Example 5 57.4

[0115] Test Example 3: Nuclear Magnetic Resonance Spectroscopy Experiment

[0116] All nuclear magnetic resonance (NMR) spectra were acquired on a Bruker Avance II-400 NMR spectrometer equipped with a broadband reverse probe (BBY) and a variable temperature unit (VTU) in heavy water (D₂O) at 298 K. Spectra were recorded using Topspin 2.0 software.

[0117] Figure 3 The corresponding spectra of salicylic acid, cross-linked β-cyclodextrin polymer, binary inclusion complex of salicylic acid and cross-linked β-cyclodextrin polymer, and ternary inclusion complex of salicylic acid: cross-linked β-cyclodextrin polymer: arginine (Example 1) are shown, as well as the spectra after complexation. Proton numbering is shown below. Figure 2 The proton NMR spectrum is shown below. Figure 3 .

[0118] according to Figure 3 Figures a, b, and c show that the protons located within the hydrophobic cavity of the cross-linked β-cyclodextrin polymer exhibit different chemical shifts, thus confirming the formation of the inclusion complex. Figure d shows that the corresponding proton H of salicylic acid changes with or without arginine. A H B H C H D The different chemical shifts (shifts to lower fields) indicate that the formation of the binary complex is altered in the presence of the third component.

[0119] Test Example 4: Stability Test of Supramolecular Encapsulated Salicylic Acid

[0120] The salicylic acid or salicylic acid inclusion complexes obtained in Examples 1-4 and Comparative Examples 1-5 were placed in an environment of 45°C. As shown in Table 4, Examples 1-4 showed good stability.

[0121] Table 4: Stability of Examples 1-4 and Comparative Examples 1-5

[0122]

[0123] Test Example 5: Irritation Test of Supramolecular Encapsulated Salicylic Acid:

[0124] Qualified spot test materials were selected. The substances obtained in Examples 1-4 and Comparative Examples 1-5 were prepared into 1% salicylic acid solutions and placed in the spot test apparatus. The control well was a blank control (without any substance). The spot test apparatus containing the test substance was applied to the flexor side of the subject's forearm with non-irritating adhesive tape, and the palm was used to gently press it to ensure even application to the skin for 24 hours. After removing the spot test apparatus, the skin reaction was observed after a 30-minute interval until the pressure mark disappeared. This experiment was conducted on 30 volunteers. The reaction results were recorded according to the skin reaction grading criteria in Table 5.

[0125] Table 5: Grading Criteria for Adverse Skin Reactions in Patch Testing

[0126] Adverse skin reactions grade No response 0 Light red spots 1 Erythema, infiltration, papules 2 Erythema, edema, papules, vesicles 3 Erythema, fluid, bullae 4

[0127] In the patch test, as shown in Table 6, Examples 1-4 showed no adverse skin reactions, and their irritation was significantly reduced compared to Comparative Examples 1-4. Therefore, this study improved the stimulating effect of salicylic acid on the microvessels and nerves distributed in the deep layers of the skin, enabling salicylic acid to better exert its excellent exfoliating and pore-cleaning abilities.

[0128] Table 6: Irritation of Examples 1-4 and Comparative Examples 1-5

[0129] Test sample Adverse reaction grade Example 1 0 Example 2 0 Example 3 0 Example 4 0 Comparative Example 1 3 Comparative Example 2 0 Comparative Example 3 3 Comparative Example 4 1 Comparative Example 5 0

[0130] Test Example 6: Test on the Inhibition of Acne by Supramolecular Encapsulated Salicylic Acid

[0131] Take the substances obtained in Examples 1-4 and Comparative Examples 1-5 respectively to prepare salicylic acid solutions with a concentration of 1%, and then... 5 The proliferation of Propionibacterium acnes was evaluated on CFU / mL Propionibacterium acnes culture medium after 48 hours of treatment in Examples 1-4 and Comparative Examples 1-5.

[0132] Table 7: Acne Inhibition Tests of Examples 1-4 and Comparative Examples 1-5

[0133] Test sample Inhibition rate of Propionibacterium acnes proliferation (compared to blank control) Example 1 76％ Example 2 73％ Example 3 77％ Example 4 75％ Comparative Example 1 72％ Comparative Example 2 63％ Comparative Example 3 68％ Comparative Example 4 55％ Comparative Example 5 66％

[0134] As can be seen from Table 7, the ternary inclusion complex proposed in this invention can effectively inhibit the proliferation of Propionibacterium acnes.

[0135] The above description of the embodiments is only for the purpose of helping to understand the technical solution and core idea of ​​the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principle of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A salicylic acid-cyclodextrin-amino acid ternary inclusion complex, characterized in that, The cross-linked β-cyclodextrin polymer is formed by non-covalent interactions of salicylic acid, amino acids, and cyclodextrin derivatives. By mass fraction, it comprises 25%–35% cyclodextrin derivative, 30%–40% salicylic acid, and 30%–40% amino acids. The cyclodextrin derivative is a cross-linked β-cyclodextrin polymer, and the amino acid is arginine. The salicylic acid molecules are encapsulated within the cavity of the cross-linked β-cyclodextrin polymer, and interact with the hydroxyl groups on the exterior of the cross-linked β-cyclodextrin polymer or the exposed portion of the encapsulated salicylic acid molecules through the guanidinium or carboxyl groups of the amino acid side chains. The preparation method of the cross-linked β-cyclodextrin polymer includes the following steps: S1. Add deionized water to a mixing container, add citric acid, β-cyclodextrin and sodium dihydrogen phosphate and mix. Stir evenly at room temperature to obtain a suspension. Then, pre-treat the suspension by freezing and freeze-dry it in a freeze dryer. S2. Transfer the obtained freeze-dried material to a reaction vessel at a temperature of 140℃-180℃ for polymerization reaction for 1-3 h; S3. The cross-linked material obtained from the polymerization reaction is washed with water and alcohol, and then dried to obtain the final cross-linked β-cyclodextrin polymer.

2. The method for preparing the salicylic acid-cyclodextrin-amino acid ternary inclusion complex according to claim 1, characterized in that, Includes the following steps: (1) Dissolve the cross-linked β-cyclodextrin polymer in water to obtain a β-cyclodextrin solution; (2) Add salicylic acid to the β-cyclodextrin solution in step (1), stir or sonicate to form a salicylic acid-cyclodextrin binary inclusion complex solution; (3) Dissolve arginine in water to obtain an arginine solution with a mass fraction of 2%-4%; (4) Add the arginine solution obtained in step (3) to the salicylic acid-cyclodextrin binary inclusion complex solution obtained in step (2), mix evenly, and perform inclusion to obtain a mixed solution; (5) The mixed solution obtained in step (4) is dried to obtain a ternary inclusion solid.

3. The preparation method according to claim 2, characterized in that, In step (1), the mass ratio of cross-linked β-cyclodextrin polymer to water is 1:5~10; in step (4), the temperature of the inclusion process is 25℃~70℃ and the time is 5~1440 min.

4. The preparation method according to claim 2 or 3, characterized in that, The drying process described in step (5) is specifically freeze spray drying, with an inlet air temperature of 40℃~50℃, an outlet air temperature of 25℃~35℃, and a spray drying pressure of 0.7~1.25 MPa.

5. The preparation method according to claim 4, characterized in that, The ternary inclusion complex mentioned in step (5) is a lyophilized powder or a spray-dried powder.

6. The use of the salicylic acid-cyclodextrin-amino acid ternary inclusion complex according to claim 1 in the preparation of cosmetics or sustained-release drugs.

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