A hydroxypropyl-beta-cyclodextrin-based supramolecular inclusion compound, and a preparation method and application thereof

Abstract

The present application relates to the field of cosmetic technology, and particularly relates to a supramolecular inclusion complex based on hydroxypropyl-beta-cyclodextrin and a preparation method and application thereof, which comprises 20-60 parts of cyclodextrin derivatives, 5-30 parts of active components, 1-20 parts of co-inclusion components, 10-40 parts of cosolvents, 1-10 parts of stabilizers, and 0.5-5 parts of preservatives by weight, wherein the cyclodextrin derivatives comprise cyclodextrin derivative A and cyclodextrin derivative B, the cyclodextrin derivative A is hydroxypropyl-beta-cyclodextrin, the cyclodextrin derivative B is selected from one of gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin and hydroxypropylated cucurbituril derivative, and the mass ratio of the cyclodextrin derivative A to the cyclodextrin derivative B is 1:0.1-1:1. The present application introduces a second host molecule (cyclodextrin derivative B) and a co-inclusion component to construct a supramolecular system of double-host synergistic inclusion or co-crystallization and then re-inclusion, and systematically solves the core technical problems of solubility, stability, safety and transdermal efficiency of the poorly soluble active ingredients in the application of cosmetics.

Description

Technical Field

[0001] This invention relates to the field of cosmetic technology, and in particular to a supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin, its preparation method, and its application. Background Technology

[0002] In cosmetics, active ingredients such as salicylic acid, azelaic acid, and retinol often contain nonpolar groups such as benzene rings, long-chain alkanes, or polycyclic aromatic hydrocarbons. These groups are difficult to form effective hydrogen bonds with water molecules in aqueous systems, resulting in extremely low solubility. These molecules can spontaneously arrange themselves into ordered crystals through π-π stacking, hydrogen bonding, and van der Waals forces. When the concentration exceeds the thermodynamic solubility, the system enters a supersaturated state, and the molecules spontaneously aggregate to form crystal nuclei and grow into macroscopic crystals, causing turbidity, stratification, and precipitation in the formulation. Free-state active components have small molecular weights and are lipid-soluble, easily and rapidly partitioning into the stratum corneum lipid matrix, directly contacting epidermal cells, and causing a localized burst of high concentrations. Some acidic components (such as salicylic acid, pKa=2.97) have a pH far lower than normal skin values ​​(approximately 4.5~6.5) in their free acidic form, which may damage the skin barrier and activate pain receptors such as TRP channels, causing irritation. In addition, the brick-wall structure of the stratum corneum of the skin constitutes the main barrier to transdermal absorption, and the transdermal penetration efficiency is limited by molecular weight and oil-water partition coefficient; some active ingredients containing sensitive groups such as unsaturated bonds and phenolic hydroxyl groups are highly sensitive to light, heat and reactive oxygen species, have poor chemical stability, and are difficult to disperse evenly and stably in water-soluble cosmetic bases.

[0003] Cyclodextrin inclusion is a common technique for improving the above-mentioned problems. Hydroxypropyl-β-cyclodextrin (HP-β-CD) is obtained by hydroxypropylation modification of β-cyclodextrin. The molecule is hollow truncated pyramidal: the inner cavity is composed of hydrophobic regions formed by CH bonds and glycosidic oxygen atoms, and the outer edge is distributed with hydrophilic hydroxyl groups. Its water solubility is greater than 50g / 100mL, which is much better than 1.85g / 100mL of β-cyclodextrin. Moreover, it has good biocompatibility and is suitable for use in the cosmetics field.

[0004] However, existing single hydroxypropyl-β-cyclodextrin inclusion technology still has the following shortcomings: limited capacity for synergistic loading of multiple components; high process temperature for inclusion of heat-sensitive components, which easily leads to degradation of active ingredients; room for improvement in inclusion rate and drug loading; lack of systematic design for the long-term stability of inclusion compounds in formulations; and a single transdermal enhancement mechanism. Summary of the Invention

[0005] The purpose of this invention is to provide a supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin, its preparation method and application. By introducing a second host molecule (cyclodextrin derivative B) and co-inclusion components, a supramolecular system with dual host synergistic inclusion or co-crystallization followed by inclusion is constructed, systematically solving the core technical problems of solubility, stability, safety and transdermal efficiency of poorly soluble functional ingredients in cosmetic applications.

[0006] To achieve the above objectives, the present invention provides a supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin, comprising, by weight, 20-60 parts of cyclodextrin derivative, 5-30 parts of active component, 1-20 parts of co-inclusion component, 10-40 parts of cosolvent, 1-10 parts of stabilizer, and 0.5-5 parts of preservative. The cyclodextrin derivative includes cyclodextrin derivative A and cyclodextrin derivative B, wherein cyclodextrin derivative A is hydroxypropyl-β-cyclodextrin, and cyclodextrin derivative B is selected from γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and hydroxypropylated cucurbituril derivative. The mass ratio of cyclodextrin derivative A to cyclodextrin derivative B is 1:0.1 to 1:1.

[0007] Preferably, the active ingredient includes one or more of salicylic acid, phenylethyl resorcinol, azelaic acid, 4-butylresorcinol, retinol, adenosine, glycyrrhizin, nicotinamide, and ferulic acid.

[0008] Preferably, the co-inclusion component is selected from one or more of ferulic acid and nicotinamide.

[0009] Preferably, the co-solvent includes one or more of 1,3-butanediol, anhydrous ethanol, and propylene glycol.

[0010] Preferably, the stabilizer includes one or more of glycerol and propylene glycol.

[0011] Preferably, the preservative includes one or more of p-hydroxyacetophenone and hexanediol.

[0012] This invention also provides a method for preparing the above-mentioned supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin, comprising the following steps: S1. Add cyclodextrin derivative A and cyclodextrin derivative B to purified water, stir to dissolve, and obtain a mixed cyclodextrin aqueous solution; S2. Mix the active component and the co-inclusion component, add a cosolvent, and grind or stir to form a eutectic by hydrogen bonding and π-π stacking of the active component and the co-inclusion component; add the obtained eutectic to the mixed cyclodextrin aqueous solution in S1 and carry out inclusion under stirring conditions; after inclusion is completed, add stabilizer and preservative, mix well, and freeze-dry, spray-dry or vacuum-dry to obtain supramolecular inclusion powder.

[0013] Preferably, in S1, the total mass ratio of cyclodextrin derivative A and cyclodextrin derivative B to purified water is 1:2 to 1:5; and the stirring and dissolving temperature is 25 to 50°C.

[0014] Preferably, in S2, when the active component is one or more of salicylic acid, phenylethyl resorcinol, azelaic acid, 4-butylresorcinol, glycyrrhizin, nicotinamide, and ferulic acid, the inclusion temperature is 40~60℃ and the inclusion time is 0.5~4h. When the active component is one or more of retinol and adenosine, the inclusion temperature is 25~40℃, and ultrasonic-assisted inclusion is used for 0.5~2h. The pre-freezing temperature for freeze drying is -45 to -75℃, the pre-freezing time is 2 to 5 hours, and the freeze drying time is 24 to 36 hours.

[0015] The present invention also provides the application of the above-mentioned supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin for the preparation of cosmetics; the dosage form of the cosmetic is essence water, lotion, cream, gel, mask, shampoo or hair growth liquid; the pH of the cosmetic is 4.5~6.5.

[0016] Therefore, the present invention employs the above-mentioned supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin, its preparation method, and its application, which has the following beneficial effects: (1) This invention uses hydroxypropyl-β-cyclodextrin (HP-β-CD) as the first host molecule and introduces γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, or hydroxypropylated cucurbituril derivatives as the second host molecule (cyclodextrin derivative B) to construct a dual-host synergistic inclusion system. HP-β-CD provides high water solubility and initial inclusion, while the second host deeply locks in the active component through stronger host-guest interactions (such as the flexible cavity of γ-CD, the electrostatic interaction of SBE-β-CD, and the strong recognition ability of hydroxypropylated cucurbituril derivatives), forming a dual-host cavity or lock-and-key structure. The synergistic effect of the two significantly improves the inclusion rate and drug loading, and enhances the synergistic loading capacity for multiple components.

[0017] (2) The present invention introduces co-inclusion components (ferulic acid and nicotinamide), which are co-crystallized and then encapsulated. The two active components first form a co-crystallization through hydrogen bonding and π-π stacking, and then are encapsulated by cyclodextrin. The formation of the co-crystallization reduces the steric hindrance of the single component in the cyclodextrin cavity and improves the encapsulation efficiency. At the same time, the co-crystallized components achieve multi-component synergistic loading and synergistic effect through non-covalent bond synergistic effect.

[0018] (3) The present invention uses low temperature ultrasonic assisted encapsulation at 25~40℃ for heat-sensitive active components (retinol, adenosine, etc.) to avoid high temperature degradation; spray drying or vacuum drying is used instead of freeze drying to shorten drying time, reduce energy consumption and improve production efficiency.

[0019] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0020] Figure 1This is a schematic diagram of the inclusion ratio of Embodiments 1-3 and Comparative Example 1 of the present invention.

[0021] Figure 2 This is a schematic diagram of the content retention rate of Examples 1-3 and Comparative Example 1 of the present invention. Detailed Implementation

[0022] This invention provides a supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin, comprising, by weight, 20-60 parts of cyclodextrin derivative, 5-30 parts of active component, 1-20 parts of co-inclusion component, 10-40 parts of cosolvent, 1-10 parts of stabilizer, and 0.5-5 parts of preservative. The cyclodextrin derivative includes cyclodextrin derivative A and cyclodextrin derivative B. Cyclodextrin derivative A is hydroxypropyl-β-cyclodextrin, and cyclodextrin derivative B is selected from γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and hydroxypropylated cucurbituril derivative. The mass ratio of cyclodextrin derivative A to cyclodextrin derivative B is 1:0.1 to 1:1.

[0023] In the supramolecular inclusion complex of this invention, the active component, as a guest molecule, is molecularly encapsulated within the hydrophobic cavity of the first host molecule. Hydroxypropyl-β-cyclodextrin is obtained by hydroxypropylation modification of β-cyclodextrin, and the molecule is hollow truncated pyramidal in shape: the inner cavity is composed of hydrophobic regions formed by CH bonds and glycosidic oxygen atoms, while the outer edge is distributed with hydrophilic hydroxyl groups. Its water solubility is greater than 50 g / 100 mL, far superior to the 1.85 g / 100 mL of β-cyclodextrin, and it exhibits good biocompatibility, making it suitable for use in the cosmetics field. The inclusion process relies on non-covalent forces such as van der Waals forces, hydrophobic interactions, hydrogen bonds, electrostatic interactions, and π-π stacking between the host and guest molecules. When the hydrophobic active component is mixed with hydroxypropyl-β-cyclodextrin in an aqueous solution, the hydrophobic region of the active component, repelled by the hydrogen bond network of water molecules, tends to enter the hydrophobic cavity of the hydroxypropyl-β-cyclodextrin to reduce the system's free energy. The introduction of a second host molecule enables dual-host synergistic inclusion: γ-cyclodextrin has a flexible cavity and high solubility, excellent toxicological properties, and can form complementary inclusion with hydroxypropyl-β-cyclodextrin; sulfobutyl ether-β-cyclodextrin is negatively charged and suitable for cationic or neutral active components, but should be carefully selected for anionic active components containing carboxyl or phenolic hydroxyl groups; hydroxypropylated cucurbituril derivatives have high water solubility and retain strong host-guest recognition ability.

[0024] Preferably, the active ingredient includes one or more of salicylic acid, phenylethyl resorcinol, azelaic acid, 4-butylresorcinol, retinol, adenosine, glycyrrhizin, nicotinamide, and ferulic acid. The active ingredient of the present invention contains one or more hydrophobic regions in its molecular structure and its molecular size matches the cavity of the cyclodextrin, allowing it to be uniformly dispersed in an aqueous matrix at the molecular level after inclusion.

[0025] Preferably, the co-inclusion component is selected from one or more of ferulic acid and nicotinamide. The eutectic component and the active component form a eutectic through hydrogen bonding and π-π stacking before being encapsulated by cyclodextrin, which reduces the steric hindrance of the single component in the cyclodextrin cavity and improves the inclusion rate.

[0026] Preferably, the co-solvent includes one or more of 1,3-butanediol, anhydrous ethanol, and propylene glycol. The co-solvent of this invention is used to dissolve the active component and the co-inclusion component, promote eutectic formation, and ensure that the eutectic is uniformly dispersed in the cyclodextrin aqueous solution, thereby improving inclusion efficiency. Among these, 1,3-butanediol has less competition for cyclodextrin inclusion sites compared to other polyols, which is beneficial for improving the inclusion rate.

[0027] Preferably, the stabilizer includes one or more of glycerol and propylene glycol. The stabilizer of the present invention protects the low-temperature stability of the active component by lowering the freezing point of the solution, inhibiting ice crystal formation, and simultaneously helps maintain the long-term stability of the inclusion complex in the formulation.

[0028] Preferably, the preservative includes one or more of p-hydroxyacetophenone and hexanediol. The preservative of the present invention does not affect the stability of the supramolecular inclusion complex system while providing preservation, and it has good compatibility with cyclodextrin inclusion systems.

[0029] This invention also provides a method for preparing the above-mentioned supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin, comprising the following steps: S1. Add cyclodextrin derivative A and cyclodextrin derivative B to purified water, stir to dissolve, and obtain a mixed cyclodextrin aqueous solution; S2. Mix the active component and the co-inclusion component, add a cosolvent, and grind or stir to form a eutectic by hydrogen bonding and π-π stacking of the active component and the co-inclusion component; add the obtained eutectic to the mixed cyclodextrin aqueous solution in S1 and carry out inclusion under stirring conditions; after inclusion is completed, add stabilizer and preservative, mix well, and freeze-dry, spray-dry or vacuum-dry to obtain supramolecular inclusion powder.

[0030] This invention first forms a eutectic by combining the active component and the co-inclusion component through hydrogen bonding and π-π stacking, pre-assembling the two components at the molecular level and reducing the steric hindrance of a single component in the cyclodextrin cavity. Then, the eutectic is added to a mixed cyclodextrin aqueous solution for inclusion, allowing the eutectic to enter the cyclodextrin cavity entirely or partially, achieving synergistic loading of multiple components. This significantly improves the inclusion rate and drug loading capacity.

[0031] Preferably, in S1, the total mass ratio of cyclodextrin derivative A and cyclodextrin derivative B to purified water is 1:2 to 1:5; the stirring and dissolving temperature is 25 to 50°C. This mass ratio and temperature range are conducive to the complete dissolution of cyclodextrin, forming a homogeneous mixed cyclodextrin aqueous solution, providing a good medium environment for subsequent inclusion.

[0032] Preferably, in S2, when the active component is one or more of salicylic acid, phenylethyl resorcinol, azelaic acid, 4-butylresorcinol, glycyrrhizin, nicotinamide, and ferulic acid, the inclusion temperature is 40~60℃ and the inclusion time is 0.5~4h. When the active component is one or more of retinol and adenosine, the inclusion temperature is 25~40℃, and ultrasonic-assisted inclusion is used for 0.5~2h. The pre-freezing temperature for freeze drying is -45 to -75℃, the pre-freezing time is 2 to 5 hours, and the freeze drying time is 24 to 36 hours.

[0033] The present invention also provides the application of the above-mentioned supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin for the preparation of cosmetics; the dosage form of the cosmetic is essence water, lotion, cream, gel, mask, shampoo or hair growth liquid; the pH of the cosmetic is 4.5~6.5.

[0034] Mechanism of the invention: (1) HP-β-CD, as the first host molecule, provides high water solubility and initial inclusion, and its hydrophobic cavity can accommodate the hydrophobic region of the active component. The second host molecule (cyclodextrin derivative B) locks the active component deeply through stronger host-guest interactions: γ-CD has a flexible cavity that can accommodate guest molecules of different sizes; SBE-β-CD binds to cationic or neutral active components through electrostatic interactions; and the hydroxypropylated cucurbituril derivative forms strong hydrogen bonds and hydrophobic interactions with the active component through carbonyl ports. The two work together to form a dual-host cavity or lock-and-key structure, which significantly improves the inclusion rate.

[0035] (2) The active component and the co-inclusion component first form a eutectic through hydrogen bonding and π-π stacking. The formation of the eutectic reduces the steric hindrance of the single component in the cyclodextrin cavity, enabling the cyclodextrin to be included more efficiently. The eutectic components achieve synergistic loading and synergistic effect of multiple components through non-covalent bond synergistic interaction.

[0036] (3) After contact with the skin, the inclusion complex gradually releases its active components through water evaporation, sebum action, and temperature changes, effectively avoiding skin irritation caused by the sudden release of free active components at high local concentrations. In terms of skin permeability, the inclusion complex dissociates on the surface of the stratum corneum, and the released free active components are distributed into the lipids of the stratum corneum; cyclodextrin maintains the concentration gradient in the aqueous phase by solubilizing, thereby improving the transdermal permeation efficiency.

[0037] The present invention will be further described below with reference to the accompanying drawings and embodiments. Unless otherwise defined, the technical or scientific terms used in this invention should be understood in their ordinary sense by those skilled in the art. The features mentioned above or in the specific examples mentioned in this invention can be combined arbitrarily, and these specific embodiments are only used to illustrate the invention and are not intended to limit the scope of the invention.

[0038] Example 1 By weight, it includes: 40 parts of cyclodextrin derivative A (hydroxypropyl-β-cyclodextrin), 10 parts of cyclodextrin derivative B (γ-cyclodextrin), 15 parts of active component (azelaic acid), 5 parts of co-inclusion component (nicotinamide), 20 parts of solubilizer (1,3-butanediol), 5 parts of stabilizer (glycerol), and 0.5 parts of preservative (p-hydroxyacetophenone and 2 parts of hexanediol).

[0039] Its preparation method includes the following steps: S1. Add cyclodextrin derivative A and cyclodextrin derivative B to purified water, with the total mass ratio of cyclodextrin derivative A and cyclodextrin derivative B to purified water being 1:3. Stir and dissolve at 40°C to obtain a mixed cyclodextrin aqueous solution.

[0040] S2. Azelaic acid and nicotinamide are mixed, and 1,3-butanediol is added. The mixture is ground to form a eutectic through hydrogen bonding and π-π stacking. The resulting eutectic is added to the mixed cyclodextrin aqueous solution in S1 and stirred at 55°C for 3 hours for inclusion. After inclusion, glycerol, p-hydroxyacetophenone and hexanediol are added, mixed well, pre-frozen at -60°C for 3 hours, and freeze-dried for 30 hours to obtain supramolecular inclusion powder.

[0041] Example 2 This invention provides a supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin, comprising, by weight: 45 parts of cyclodextrin derivative A (hydroxypropyl-β-cyclodextrin), 8 parts of cyclodextrin derivative B (hydroxypropylated cucurbituril derivative), 10 parts of active component (salicylic acid), 3 parts of co-inclusion component (ferulic acid), 15 parts of cosolvent (anhydrous ethanol), 3 parts of stabilizer (propylene glycol), and 0.5 parts of preservative (p-hydroxyacetophenone and 2 parts of hexanediol).

[0042] Its preparation method includes the following steps: S1. Add cyclodextrin derivative A and cyclodextrin derivative B to purified water, with the total mass ratio of cyclodextrin derivative A and cyclodextrin derivative B to purified water being 1:4. Stir and dissolve at 35°C to obtain a mixed cyclodextrin aqueous solution.

[0043] S2. Mix salicylic acid and ferulic acid, add anhydrous ethanol, and stir to form a eutectic through hydrogen bonding and π-π stacking. Add the obtained eutectic to the mixed cyclodextrin aqueous solution in S1 and stir at 50°C for 2 hours to encapsulate. After encapsulation, add propylene glycol, p-hydroxyacetophenone and hexanediol, mix well, pre-freeze at -55°C for 4 hours, and freeze-dry for 28 hours to obtain supramolecular inclusion complex powder.

[0044] Example 3 This invention provides a supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin, comprising, by weight: 35 parts of cyclodextrin derivative A (hydroxypropyl-β-cyclodextrin), 12 parts of cyclodextrin derivative B (γ-cyclodextrin), 5 parts of active component (retinol), 8 parts of co-inclusion component (nicotinamide), 25 parts of solubilizer (1,3-butanediol), 5 parts of stabilizer (glycerol), and 0.5 parts of preservative (p-hydroxyacetophenone and 2 parts of hexanediol).

[0045] Its preparation method includes the following steps: S1. Add cyclodextrin derivative A and cyclodextrin derivative B to purified water, with the total mass ratio of cyclodextrin derivative A and cyclodextrin derivative B to purified water being 1:3. Stir and dissolve at 30°C to obtain a mixed cyclodextrin aqueous solution.

[0046] S2. Retinol and nicotinamide are mixed, and 1,3-butanediol is added. The mixture is ground to form a eutectic through hydrogen bonding and π-π stacking. The resulting eutectic is added to the mixed cyclodextrin aqueous solution in S1 and ultrasonically assisted in inclusion at 30°C for 1.5 h. After inclusion, glycerol, p-hydroxyacetophenone and hexanediol are added, mixed well, and spray-dried to obtain supramolecular inclusion powder.

[0047] Example 4 This invention provides a supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin, comprising, by weight: 50 parts of cyclodextrin derivative A (hydroxypropyl-β-cyclodextrin), 5 parts of cyclodextrin derivative B (sulfobutyl ether-β-cyclodextrin), 5 parts of active component (adenosine), 10 parts of co-inclusion component (nicotinamide), 20 parts of solubilizer (1,3-butanediol), 5 parts of stabilizer (glycerol), and preservatives (0.5 parts of p-hydroxyacetophenone and 2 parts of hexanediol).

[0048] Its preparation method includes the following steps: S1. Add cyclodextrin derivative A and cyclodextrin derivative B to purified water, with the total mass ratio of cyclodextrin derivative A and cyclodextrin derivative B to purified water being 1:4. Stir and dissolve at 35°C to obtain a mixed cyclodextrin aqueous solution.

[0049] S2. Adenosine and nicotinamide are mixed, and 1,3-butanediol is added. The mixture is ground to form a eutectic through hydrogen bonding and π-π stacking. The resulting eutectic is added to the mixed cyclodextrin aqueous solution in S1 and ultrasonically assisted in inclusion at 35°C for 1 hour. After inclusion, glycerol, p-hydroxyacetophenone and hexanediol are added, mixed well, pre-frozen at -60°C for 3 hours, and freeze-dried for 30 hours to obtain a supramolecular inclusion complex powder.

[0050] Example 5 This invention provides a supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin, comprising, by weight: 40 parts of cyclodextrin derivative A (hydroxypropyl-β-cyclodextrin), 10 parts of cyclodextrin derivative B (γ-cyclodextrin), 12 parts of active component (4-butylresorcinol), 5 parts of co-inclusion component (ferulic acid), 18 parts of cosolvent (anhydrous ethanol), 5 parts of stabilizer (glycerol), and 0.5 parts of preservative (p-hydroxyacetophenone and 2 parts of hexanediol).

[0051] Its preparation method includes the following steps: S1. Add cyclodextrin derivative A and cyclodextrin derivative B to purified water, with the total mass ratio of cyclodextrin derivative A and cyclodextrin derivative B to purified water being 1:3. Stir and dissolve at 40°C to obtain a mixed cyclodextrin aqueous solution.

[0052] S2. Mix 4-butylresorcinol and ferulic acid, add anhydrous ethanol, and stir to form a eutectic through hydrogen bonding and π-π stacking. Add the obtained eutectic to the mixed cyclodextrin aqueous solution of S1 and stir at 55°C for 3 hours to encapsulate. After encapsulation, add glycerol, p-hydroxyacetophenone and hexanediol, mix well, pre-freeze at -60°C for 3 hours, and freeze-dry for 30 hours to obtain supramolecular inclusion complex powder.

[0053] Example 6 This invention provides a supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin, comprising, by weight: 42 parts of cyclodextrin derivative A (hydroxypropyl-β-cyclodextrin), 8 parts of cyclodextrin derivative B (γ-cyclodextrin), 10 parts of active component (phenylethyl resorcinol), 6 parts of co-inclusion component (nicotinamide), 22 parts of cosolvent (1,3-butanediol), 5 parts of stabilizer (glycerol), and 0.5 parts of preservative (p-hydroxyacetophenone and 2 parts of hexanediol).

[0054] Its preparation method includes the following steps: S1. Add cyclodextrin derivative A and cyclodextrin derivative B to purified water, with the total mass ratio of cyclodextrin derivative A and cyclodextrin derivative B to purified water being 1:3. Stir and dissolve at 40°C to obtain a mixed cyclodextrin aqueous solution.

[0055] S2. Phenethyl resorcinol and nicotinamide are mixed, and 1,3-butanediol is added. The mixture is ground to form a eutectic through hydrogen bonding and π-π stacking. The resulting eutectic is added to the mixed cyclodextrin aqueous solution in S1 and stirred at 50°C for 2 hours for inclusion. After inclusion, glycerol, p-hydroxyacetophenone and hexanediol are added, mixed well, pre-frozen at -55°C for 4 hours, and freeze-dried for 28 hours to obtain supramolecular inclusion powder.

[0056] Comparative Example 1 The difference from Example 1 is that only hydroxypropyl-β-cyclodextrin is used as the main molecule, and cyclodextrin derivative B (γ-cyclodextrin) is not added. The other components and preparation methods are the same as in Example 1.

[0057] Comparative Example 2 The difference from Example 1 is that no co-inclusion component (nicotinamide) is added, while the other components and preparation methods are the same as in Example 1.

[0058] Performance testing The supramolecular inclusion complexes obtained in Examples 1-6 and Comparative Examples 1-2 were subjected to the following tests.

[0059] (1) The inclusion rate and drug loading were determined by high performance liquid chromatography (HPLC).

[0060] Inclusion rate = (mass of active component in inclusion complex / mass of added active component) × 100%.

[0061] Drug loading = (mass of active component in inclusion complex / total mass of inclusion complex) × 100%.

[0062] The results are shown in Table 1.

[0063] Table 1. Encapsulation efficiency and drug loading of Examples 1-6 and Comparative Examples 1-2

[0064] As shown in Table 1, the inclusion rates of Examples 1-6 were all above 90%, and the drug loading was between 15% and 30%, all of which were superior to Comparative Examples 1-2. This indicates that the synergistic inclusion of cyclodextrin derivative A and cyclodextrin derivative B, as well as the co-crystallization followed by inclusion, significantly improved the inclusion rate and drug loading of the present invention.

[0065] (2) Stability study: Samples from Examples 1-3 and Comparative Example 1 were placed at 4℃, 25℃, and 40℃ respectively. Samples were taken at 0d, 30d, 60d, and 90d to observe appearance, determine inclusion rate, and measure content retention rate. Results are as follows: Figures 1-2As shown, in Examples 1-6, the inclusion rate and content retention rate were >90% within 3 months at 4℃, 25℃, and 40℃; in Comparative Example 1, the inclusion rate and content retention rate decreased significantly after 30 days at 40℃. The results indicate that the synergistic inclusion of the cyclodextrin derivative A and cyclodextrin derivative B, along with the co-crystallization and subsequent inclusion, significantly improves the long-term stability of the inclusion complex.

[0066] (3) Cytotoxicity test: The MTT assay was used to test the cytotoxicity of the common active ingredient and the supramolecular inclusion complex on human immortalized keratinocytes (HaCaT) at the same concentration of active ingredient. The results are shown in Table 2.

[0067] Cell culture: HaCaT cells were cultured in DMEM medium (containing 10% FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin) at 37°C in a 5% CO2 incubator.

[0068] Inoculation: HaCaT cells were inoculated at a rate of 1 × 10⁻⁶. 4 Cells / well were seeded into 96-well plates and cultured for 24 hours.

[0069] Drug administration: Take culture medium and add culture medium containing common active component or supramolecular inclusion complex (based on active component concentration) at concentration gradients of 0, 0.5, 5, 50, 500, 1000, and 2000 μg / mL, with 6 replicates per group.

[0070] Incubation: Continue culturing for 24 hours.

[0071] Detection: Add 20 μL MTT solution (5 mg / mL) to each well, continue culturing for 4 h, discard the supernatant, add 150 μL LDMSO, shake for 10 min, and measure the absorbance at 570 nm.

[0072] Cell viability = (OD value of sample group / OD value of blank group) × 100%.

[0073] Table 2 Cytotoxicity test results

[0074] Table 2 shows that at a concentration of 2000 μg / mL, the cell viability rate was 38.37 ± 2.01% in the ordinary azelaic acid group and 57.34 ± 1.59% in the Example 1 group; the viability rate was 28.27 ± 2.73% in the ordinary salicylic acid group and 37.57 ± 2.08% in the Example 2 group. The keratinocyte cytotoxicity of the supramolecular inclusion complex was significantly lower than that of the ordinary active component, indicating that the active component was shielded by the cyclodextrin cavity after inclusion, reducing direct contact with cells and lowering irritation.

[0075] (4) In vitro release: The in vitro release of the common active component and the supramolecular inclusion complex was tested by dialysis. The results are shown in Table 3.

[0076] Experimental conditions: 37℃, 1000kDa dialysis membrane, pure water as the dissolving medium.

[0077] Procedure: Place the common active component or supramolecular inclusion complex (in the same amount as the active component) into a dialysis bag, immerse it in the release medium, and shake at 37°C and 100 rpm.

[0078] Sampling: Take 5 mL samples at 0, 1, 2, 4, 8, 12, and 24 hours, and add 5 mL of fresh medium at the same time.

[0079] Detection: The content of azelaic acid or salicylic acid was determined by HPLC, and the cumulative release rate was calculated.

[0080] Table 3 Results of in vitro release test

[0081] Table 3 shows that ordinary azelaic acid / salicylic acid cumulatively releases approximately 60%~70% / 50%~60% within 0~2 hours, exhibiting a significant burst release effect; Examples 1 / 2 show cumulative releases of <15% / <10% within 0~2 hours and approximately 74% / 50% within 24 hours, with no burst release peak, demonstrating a significant sustained-release effect. The results indicate that the supramolecular inclusion complex of this invention can effectively delay the release of the active ingredient and reduce skin irritation caused by burst release.

[0082] (5) Skin penetration test: The skin penetration ability of the common active ingredients and supramolecular inclusion complexes was tested by the Franz diffusion cell method. The results are shown in Table 4.

[0083] Experimental conditions: isolated guinea pig abdominal skin, temperature 37℃, dissolving medium pure water, three parallel groups, three batches of independent experiments.

[0084] Procedure: Fix the excised skin in the Franz diffusion cell, add the common active ingredient or supramolecular inclusion complex (in equal amounts based on the active ingredient) to the supply chamber, and add pure water to the receiving chamber.

[0085] Sampling: Take 0.5 mL samples at 0, 1, 2, 4, 8, 12, and 24 hours, and add 0.5 mL of fresh medium at the same time.

[0086] Detection: The content of azelaic acid or salicylic acid was determined by HPLC, and the cumulative skin penetration rate was calculated.

[0087] Table 4 Results of skin penetration test

[0088] As shown in Table 4, at the end of the 24-hour experiment, the cumulative skin penetration rate of Example 1 (supramolecular azelaic acid) was 38.9±1.8%, which was approximately 54.2% higher than that of ordinary azelaic acid (25.2±1.5%); the cumulative skin penetration rate of Example 2 (supramolecular salicylic acid) was 38.8±1.7%, which was approximately 65% ​​higher than that of ordinary salicylic acid (23.5±1.4%) (mean ± SD of 3 independent experiments). The results indicate that the supramolecular inclusion complex significantly improves the transdermal penetration efficiency of the active ingredient.

[0089] (6) Efficacy test 6.1 Anti-inflammatory efficacy (azelaic acid): The anti-inflammatory efficacy of ordinary azelaic acid and supramolecular azelaic acid (supramolecular inclusion complex in Example 1) was evaluated by testing the IL-8 level in human keratinocytes.

[0090] Cell culture: HaCaT cells were cultured in DMEM medium to the logarithmic growth phase.

[0091] Inoculation: 1×10 5 Cells / well were seeded into 24-well plates and cultured for 24 h.

[0092] Modeling: TNF-α (10 ng / mL) and IL-1β (10 ng / mL) were added to induce an inflammation model, while a blank group (without inducing agents) was set up.

[0093] Drug administration: The model group was given ordinary azelaic acid or supramolecular azelaic acid (based on the effective azelaic acid concentration) at concentrations of 32 and 64 μg / mL, respectively, and cultured for another 24 h.

[0094] Detection: Collect the supernatant and determine the IL-8 level by ELISA.

[0095] Inhibition rate = (IL-8 level in model group - IL-8 level in sample group) / (IL-8 level in model group - IL-8 level in blank group) × 100%.

[0096] Table 5. Results of anti-inflammatory efficacy test

[0097] Table 5 shows that the IL-8 level in the model group increased significantly by 391.73% compared with the control group. After incubation with 32 μg / mL azelaic acid, 64 μg / mL azelaic acid, 43.24 μg / mL supramolecular azelaic acid, and 86.48 μg / mL supramolecular azelaic acid, the IL-8 level in keratinocytes decreased significantly, with the supramolecular azelaic acid group showing significantly better results than the regular azelaic acid group. Based on the effective azelaic acid concentration, at concentrations of 32 μg / mL and 64 μg / mL, the inhibitory effect of supramolecular azelaic acid on IL-8 was increased by 24.83% and 35.76% compared with ordinary azelaic acid, respectively.

[0098] 6.2 Antibacterial efficacy (salicylic acid): The antibacterial abilities of salicylic acid and supramolecular salicylic acid were tested using the agar inhibition zone method. The results are shown in Table 6.

[0099] Bacterial strains: Staphylococcus aureus, Bacillus subtilis, Escherichia coli.

[0100] Culture medium: Nutrient agar medium.

[0101] Procedure: Prepare the bacterial suspension (1×10⁻⁶) 6 CFU / mL) was spread on an agar plate, placed in an Oxford cup, and 40 mg / mL of ordinary salicylic acid and 80 mg / mL of supramolecular salicylic acid (the supramolecular inclusion complex of Example 2) were added respectively (calculated according to the actual drug loading to make the effective salicylic acid concentration of the two groups consistent). The plates were then incubated at 37°C for 24 h.

[0102] Testing: Measure the diameter of the inhibition zone and calculate the inhibition rate.

[0103] Antibacterial rate = (diameter of inhibition zone in sample group - diameter of inhibition zone in blank group) / diameter of inhibition zone in sample group × 100%.

[0104] Table 6 Results of Antibacterial Efficacy Test

[0105] Table 6 shows that both 40 mg / mL salicylic acid and 80 mg / mL supramolecular salicylic acid significantly inhibited the growth of Staphylococcus aureus, Bacillus subtilis, and Escherichia coli. After adjusting for actual drug loading to ensure consistent effective salicylic acid concentrations in both groups, supramolecular salicylic acid, compared to ordinary salicylic acid, increased the inhibition rates against Staphylococcus aureus, Bacillus subtilis, and Escherichia coli by 6.95%, 17.90%, and 13.43%, respectively. These results indicate that supramolecular inclusion complexes significantly enhance the antibacterial efficacy of salicylic acid.

[0106] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin, characterized in that: The product comprises, by weight, 20-60 parts of cyclodextrin derivative, 5-30 parts of active ingredient, 1-20 parts of co-inclusion component, 10-40 parts of cosolvent, 1-10 parts of stabilizer, and 0.5-5 parts of preservative. The cyclodextrin derivative includes cyclodextrin derivative A and cyclodextrin derivative B. Cyclodextrin derivative A is hydroxypropyl-β-cyclodextrin, and cyclodextrin derivative B is selected from γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and hydroxypropylated cucurbituril derivative. The mass ratio of cyclodextrin derivative A to cyclodextrin derivative B is 1:0.1 to 1:

1.

2. The supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin according to claim 1, characterized in that: The active ingredients include one or more of the following: salicylic acid, phenylethyl resorcinol, azelaic acid, 4-butylresorcinol, retinol, adenosine, glycyrrhizin, nicotinamide, and ferulic acid.

3. The supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin according to claim 1, characterized in that: The co-inclusion component is selected from one or more of ferulic acid and nicotinamide.

4. The supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin according to claim 1, characterized in that: The cosolvents include one or more of 1,3-butanediol, anhydrous ethanol, and propylene glycol.

5. The supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin according to claim 1, characterized in that: Stabilizers include one or more of glycerol and propylene glycol.

6. The supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin according to claim 1, characterized in that: Preservatives include one or more of p-hydroxyacetophenone and hexanediol.

7. A method for preparing a supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin as described in any one of claims 1-6, characterized in that: Includes the following steps: S1. Add cyclodextrin derivative A and cyclodextrin derivative B to purified water, stir to dissolve, and obtain a mixed cyclodextrin aqueous solution; S2. Mix the active component with the co-inclusion component, add a co-solvent, and grind or stir to allow the active component and the co-inclusion component to form a eutectic through hydrogen bonding and π-π stacking; The obtained eutectic was added to the mixed cyclodextrin aqueous solution of S1 and inclusion was carried out under stirring conditions. After inclusion was completed, stabilizers and preservatives were added, mixed well, and then freeze-dried, spray-dried or vacuum-dried to obtain supramolecular inclusion powder.

8. The method for preparing a supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin according to claim 7, characterized in that: In S1, the total mass ratio of cyclodextrin derivative A and cyclodextrin derivative B to purified water is 1:2 to 1:5; the stirring and dissolving temperature is 25 to 50℃.

9. The method for preparing a supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin according to claim 7, characterized in that: In S2, when the active component is one or more of salicylic acid, phenylethyl resorcinol, azelaic acid, 4-butylresorcinol, glycyrrhizin, nicotinamide, and ferulic acid, the inclusion temperature is 40~60℃ and the inclusion time is 0.5~4h. When the active component is one or more of retinol and adenosine, the inclusion temperature is 25~40℃, and ultrasonic-assisted inclusion is used for 0.5~2h. The pre-freezing temperature for freeze drying is -45 to -75℃, the pre-freezing time is 2 to 5 hours, and the freeze drying time is 24 to 36 hours.

10. The application of a supramolecular inclusion complex based on hydroxypropyl-β-cyclodextrin as described in any one of claims 1-6, characterized in that: Used in the preparation of cosmetics; the dosage forms of cosmetics are essence water, lotion, cream, gel, mask, shampoo or hair growth solution; the pH of cosmetics is 4.5~6.5.

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