Supramolecular nano-delivery hydrogel as well as preparation method and application thereof

Abstract

The invention relates to the technical field of nano materials applied to biomedicine or cosmetics, in particular to supramolecular nano delivery hydrogel as well as a preparation method and application thereof. The supramolecular nano delivery hydrogel provided by the invention has good pH value stability, excellent biocompatibility and relatively high adaptability while controllably and continuously releasing drugs and adjusting mechanical properties to match surrounding tissues; the problem of toxicity caused by the fact that gel is prepared from polymers in the prior art is solved, modification is not needed, the preparation cost is saved, the drug effect can be assisted to be exerted, and the hydrogel can be applied to delivery of hydrophobic drugs or cosmetic functional raw materials inside and outside a human body. More importantly, the nano-micelle hydrogel system is stable, the pH value can be adjusted to a human skin application range, and the nano-micelle hydrogel can be stably stored for a long time. The preparation method of the supramolecular nano delivery hydrogel is simple, mild in condition, cheap and easily available in raw materials and suitable for large-scale industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biomedical or cosmetic application of nanomaterials, in particular to a supramolecular nanodelivery hydrogel and a preparation method and application thereof. BACKGROUND

[0002] At present, in the clinical application of skin external drugs and cosmetic functional raw materials, some components often lead to unsatisfactory therapeutic effect or efficacy due to insufficient solubility, poor stability and low bioavailability, and may even cause significant toxic side effects. Therefore, it is of great significance to develop a delivery system that can improve pH stability, enhance efficacy, reduce cost and reduce toxic side effects. In view of the above problems, researchers have designed various delivery systems, such as micelles, vesicles, liposomes and hydrogels. Among them, vesicles, micelles and liposomes can effectively encapsulate hydrophobic compounds due to their special core-shell structure. However, such systems have poor stability and are easily affected by pH conditions, and have a tendency to aggregate.

[0003] The pH value range of skin external preparations is usually controlled between 4.5~7.5 to be compatible with the weakly acidic environment (pH=4.5~5.5) of healthy skin, avoiding excessive deviation leading to dry skin, inflammation or irritation, which helps to maintain skin flora balance and skin barrier function. Especially the pH value of baby skin is close to neutral (pH about 7.0), so the baby-specific preparation may need to be adjusted to a more moderate pH range. Therefore, it is of great significance to develop a supramolecular nanodelivery system with good stability and good biocompatibility in the pH value range of 4.5~7.5. SUMMARY

[0004] Therefore, the technical problem to be solved by the present application is to provide a supramolecular nanodelivery hydrogel and a preparation method and application thereof. The supramolecular nanodelivery system provided by the present application has good compatibility with hydrophobic drugs or cosmetic functional raw materials, and exhibits good pH stability and good biocompatibility while continuously releasing drugs in a controllable manner and adjusting mechanical properties to match the surrounding tissue.

[0005] The present application provides a supramolecular nanodelivery hydrogel, comprising the following components:

[0006] hydrophobic functional material;

[0007] glycyrrhizic acid;

[0008] epigallocatechin gallate;

[0009] metal ions.

[0010] Specifically, the supramolecular nanodelivery hydrogel provided by the present application comprises the following components by mass:

[0011] hydrophobic functional material: 1 part;

[0012] glycyrrhizic acid: 1-20 parts;

[0013] epigallocatechin gallate: 1-20 parts;

[0014] metal ions: 0.01-1 parts of metal salts derived therefrom.

[0015] The hydrophobic functional material according to the present application mainly includes hydrophobic functional drugs or hydrophobic functional cosmetic raw materials. Preferably, the hydrophobic functional material is at least one selected from glycyrrhetinic acid, curcumin, glabridin, resveratrol, quercetin, baicalein, rhein, emodin, vitamins, and beta-carotene.

[0016] Glycyrrhizic acid (GA) according to the present application is a natural active ingredient extracted from the roots of licorice, widely used in the fields of medicine and health products, and has high safety. Glycyrrhizic acid not only has significant anti-inflammatory properties, can inhibit the release of inflammatory mediators, and reduce the body's inflammatory response, but also has strong antioxidant capacity, can scavenge free radicals in the body. In addition, glycyrrhizic acid is widely used in skin care, can effectively relieve skin allergies and inflammation, and is suitable for sensitive skin. It can help reduce redness and itching, and restore the health of the skin. Glycyrrhizic acid also has a whitening effect, can inhibit the production of melanin, and help improve uneven skin tone and dullness. Using skin care products containing glycyrrhizic acid can make the skin brighter.

[0017] Epigallocatechin gallate (EGCG) according to the present application is a monomer component of catechins in tea polyphenols, with a molecular structure containing 8 phenolic hydroxyl groups, strong antioxidant properties, and the ability to neutralize free radicals and reduce oxidative stress damage to cells, helping to delay aging, protect the skin and organs from oxidative damage. At the same time, it can reduce chronic inflammatory reactions by inhibiting the activity of pro-inflammatory factors such as NF-κB and COX-2, and may have some auxiliary effect on diseases such as arthritis and inflammatory bowel disease.

[0018] The metal ions according to the present application are specifically pharmaceutically acceptable metal ions, preferably at least one selected from zinc ions, magnesium ions, iron ions, copper ions, calcium ions, sodium ions, and aluminum ions. The metal ions according to the present application can form a coordination with GA and EGCG, thereby stabilizing the supramolecular nanodelivery system. The metal ions according to the present application are more preferably divalent zinc ions (Zn 2+ ), Zn 2+ have multiple effects on the body, have antibacterial, anti-inflammatory, and antioxidant functions, and can promote wound healing, improve skin metabolism, maintain skin elasticity and health.

[0019] The supramolecular nanodelivery hydrogel of this invention has a pH of 4.0-6.4, preferably 4.5-6.4, and more preferably 4.0-6.0. The supramolecular nanodelivery hydrogel of this invention can be stably stored for a long time within a pH range of 4.5-7.5, which is suitable for use in human skin medications and skincare products.

[0020] This invention employs glycyrrhizic acid, epigallocatechin gallate, and metal ions to construct a supramolecular nanodelivery system for hydrophobic functional materials, combining the advantages of micelles and hydrogels. It can spontaneously deencapsulate hydrophobic functional materials and also possesses the advantages of hydrogels. While controlling and continuously releasing drugs and having adjustable mechanical properties to match surrounding tissues, it also exhibits good pH stability and good biocompatibility.

[0021] The present invention also provides a method for preparing supramolecular nanodelivery hydrogels as described above, comprising the following steps: mixing hydrophobic functional materials, glycyrrhizic acid, epigallocatechin gallate and metal salt in a solvent, removing the solvent, hydrating, gelling, and obtaining supramolecular nanodelivery hydrogels.

[0022] Specifically, hydrophobic functional materials, glycyrrhizic acid, epigallocatechin gallate, and metal salts are dissolved in a solvent to obtain a mixed solution; the mixed solution is evaporated to remove the solvent, resulting in a film or solid powder; water or PBS solution is added to the film or solid powder for hydration to obtain a micelle solution; the micelle solution is gelled to obtain the supramolecular nanodelivery hydrogel.

[0023] More specifically, after obtaining the micelle solution, the present invention further includes filtering the micelle solution using a filter membrane with a pore size of 0.22 μm or 0.45 μm. Filtration removes sparingly soluble compounds from the micelle solution that are not encapsulated by the micelles.

[0024] The mass ratio of the hydrophobic functional material, glycyrrhizic acid, epigallocatechin gallate, and metal salt described in this invention is 1:(1~20):(1~20):(0.01~1). The ratio of the first three components is one of the important parameters for the formation of a micelle solution. If the mass ratio of the three components is too low or too high, it will be difficult to form a micelle solution. The content of the metal salt determines whether the system is stable and whether it can form a hydrogel.

[0025] The hydrophobic functional material, glycyrrhizic acid, and epigallocatechin gallate ester described in this invention are the same as those described above and will not be repeated. The metal salt described in this invention is specifically a pharmaceutically acceptable metal salt, preferably selected from at least one of zinc, magnesium, iron, copper, calcium, sodium, and aluminum salts. The metal ions released during the preparation of the metal salt described in this invention are the same as those described above and will not be repeated. The solvent described in this invention is selected from at least one of methanol, ethanol, acetone, chloroform, and tetrahydrofuran, preferably ethanol. These solvents have good solubility for the compounds in the system, are inexpensive, and readily available, which helps control preparation costs.

[0026] This invention removes the solvent from the mixed solution by evaporation, specifically by rotary evaporation at a temperature of 35°C to 70°C and a rotation speed of 30 rpm to 150 rpm. The hydration temperature is 25°C to 50°C, and the hydration time is 5 min to 30 min. In some embodiments, the hydration process is carried out under these conditions by heating the solution in an oil bath at 40°C to 70°C with a stirring speed of 100 rpm to 1000 rpm for 5 to 30 min. The micelle solution is gelled by cooling and settling, specifically by allowing the hydrated material to stand at 0°C to 30°C for 30 min to 100 min. The hydration is specifically performed using ultrapure water, resulting in a system pH between 2.0 and 4.0. The pH is subsequently adjusted to 4.0 to 6.4 to prevent oxidation and discoloration.

[0027] The preparation method provided in this application is simple, mild, and uses readily available raw materials. It utilizes glycyrrhizic acid and epigallocatechin gallate to spontaneously assemble into micelles to encapsulate hydrophobic drugs or functional cosmetic raw materials. At the same time, it introduces metal ions to stabilize the supramolecular nanodelivery system, avoiding the toxicity problems caused by polymer-based gel preparation in existing technologies. The spontaneous assembly of micelles can be achieved through the hydrophobic and hydrophilic structures of glycyrrhizic acid / epigallocatechin gallate without modification, saving the preparation cost of the delivery system and making it suitable for large-scale industrial production.

[0028] This invention also provides the application of supramolecular nanodelivery hydrogels as described above, or supramolecular nanodelivery hydrogels obtained by any of the preparation methods described above, in the preparation of cosmetics and / or pharmaceuticals. The supramolecular nanodelivery hydrogels provided in this application, on the one hand, introduce no toxicity during the preparation process; on the other hand, glycyrrhizic acid and epigallocatechin gallate themselves possess pharmaceutical properties and pharmacological activity, which can assist in the exertion of drug effects, and even form a synergistic effect with the encapsulated drug or cosmetic functional raw materials, improving the efficacy of the drug or the functional raw materials in the cosmetic, making them highly suitable for application in the preparation of cosmetics and / or pharmaceuticals.

[0029] This invention provides a supramolecular nanodelivery hydrogel, its preparation method, and its applications. The supramolecular nanodelivery hydrogel provided by this invention combines the advantages of micelles and hydrogels. It exhibits controllable and sustained drug release and adjustable mechanical properties to match surrounding tissues, while also demonstrating good pH stability, excellent biocompatibility, and high adaptability. Furthermore, it avoids the toxicity issues associated with polymer-based gel preparations in existing technologies, requires no modification, saves on the preparation cost of the delivery system, and can also assist in enhancing drug efficacy. It can be applied to the delivery of hydrophobic drugs or functional raw materials for cosmetics, both internally and externally. More importantly, its nanomicelle hydrogel system is stable, with a pH adjustable to a range suitable for human skin and stable preservation over long periods. The preparation method of the supramolecular nanodelivery hydrogel described in this invention is simple, uses mild conditions, and utilizes inexpensive and readily available raw materials, making it suitable for large-scale industrial production. Attached Figure Description

[0030] Figure 1 These are morphology images of nanomicelle solutions formed by different loadings of hydrophobic pharmaceutical or cosmetic functional raw materials obtained in Examples 1 and 4-6 of the present invention.

[0031] Figure 2 The glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn obtained in Example 1 of this invention 2+ SEM image of nanomicelle hydrogel;

[0032] Figure 3 The glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn prepared in Examples 1-3 of this invention 2+ Figure showing the rheological properties of the nanomicelle hydrogel;

[0033] Figure 4 The glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn prepared in Example 1 of this invention 2+ Figure showing the modulus change test results of nanomicelle hydrogels;

[0034] Figure 5 The glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn obtained in Example 1 of this invention 2+ Drug release capacity curves of nanomicelle solutions and hydrogels;

[0035] Figure 6 The glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn obtained in Example 1 of this invention 2+ Stability test results of nanomicelle hydrogels;

[0036] Figure 7The images show the appearance of the nanomicelle solution of Comparative Example 1 at pH 4.0, 5.0, and 6.0, respectively.

[0037] Figure 8 The images show the appearance of the nanomicelle solution of Comparative Example 2 at pH 9.0, 8.0, and 7.0, respectively.

[0038] Figure 9 The images show the appearance of the nanomicelle solution of Comparative Example 3 at pH 9.0, 8.0, and 7.0, respectively.

[0039] Figure 10 The images show the appearance of the nanomicelle solution of Example 7 at pH 4.0, 5.0, and 6.0, respectively.

[0040] Figure 11 The images show the appearance of the nanomicelle solution of Example 7 after storage at pH 4.0, 5.0, and 6.0 for one day and one month, respectively.

[0041] Figure 12 The graph shows the test results of the effect of different zinc ion concentrations on the gel of the delivery system described in this invention. Detailed Implementation

[0042] This invention discloses supramolecular nanodelivery hydrogels, their preparation methods, and applications. Those skilled in the art can refer to the content of this document and appropriately modify the process parameters to achieve the desired results. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments; those skilled in the art will clearly be able to modify or appropriately alter and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0043] The present invention will be further described below with reference to the embodiments:

[0044] Example 1

[0045] This embodiment uses glycyrrhizic acid / epigallocatechin gallate / Zn 2+ A novel supramolecular nanodelivery system can be used for the delivery of hydrophobic drugs or functional ingredients in cosmetics in vivo. The specific preparation process includes the following steps:

[0046] (1) Weigh 10 mg of glycyrrhetinic acid and place it in a round-bottom flask. Add 50 mg of glycyrrhetinic acid, 20 mg of epigallocatechin gallate and 3 mg of zinc chloride. Then add 5 mL of ethanol solution and sonicate at 37°C to completely dissolve it to obtain a mixed solution.

[0047] (2) The mixed solution was placed on a rotary evaporator to remove the ethanol solvent. The temperature was set at 50℃ and the rotation speed at 80 rpm. After solvent removal, a uniform thin film was obtained. Then, 5 mL of water was added and the mixture was ultrasonically hydrated for 20 min. The unencapsulated hydrophobic compound was removed by filtration through a 0.22 μm filter membrane to obtain glycyrrhetinic acid@glycyrrhizic acid-epigallocatechin gallate-Zn 2+ Nanomicelle solution.

[0048] (3) The nanomicelle solution obtained above was allowed to stand at room temperature for 24 h to obtain glycyrrhetinic acid@glycyrrhizic acid-epigallocatechin gallate-Zn 2+ Nanomicelle hydrogels containing 1 wt% glycyrrhizic acid (based on 10 mg glycyrrhizic acid per mL of water).

[0049] Example 2

[0050] The difference from Example 1 is that 50 mg of glycyrrhizic acid was changed to 75 mg of glycyrrhizic acid, while everything else remained the same, and the final concentration of glycyrrhizic acid in the hydrogel was 1.5 wt%.

[0051] Example 3

[0052] The difference from Example 1 is that 50 mg of glycyrrhizic acid was changed to 100 mg of glycyrrhizic acid, while everything else remained the same, and the final concentration of glycyrrhizic acid in the hydrogel was 2 wt%.

[0053] Example 4

[0054] The difference from Example 1 is that glycyrrhetinic acid in (1) is replaced with curcumin, while the others remain unchanged, ultimately yielding curcumin@glycyrrhetinic acid-epigallocatechin gallate-Zn 2+ Nanomicelle hydrogel.

[0055] Example 5

[0056] The difference from Example 1 is that glycyrrhetinic acid in (1) is replaced with quercetin, while the others remain unchanged, ultimately yielding quercetin@glycyrrhetinic acid-epigallocatechin gallate-Zn 2+ Nanomicelle hydrogel.

[0057] Example 6

[0058] The difference from Example 1 is that glycyrrhetinic acid in (1) is replaced with resveratrol, while the others remain unchanged, ultimately yielding resveratrol@glycyrrhetinic acid-epigallocatechin gallate-Zn 2+ Nanomicelle hydrogel.

[0059] The nanomicelle solutions obtained in Examples 1 and 4-6 above were photographed, such as... Figure 1 As shown,Figure 1 These are morphology images of nanomicelle solutions formed by different loadings of hydrophobic pharmaceutical or cosmetic functional raw materials obtained in Examples 1 and 4-6 of the present invention.

[0060] The microstructure of the nanomicelle hydrogel obtained in Example 1 was tested. The micelle solution was dropped onto a silica gel plate, allowed to air dry, and then photographed using a scanning electron microscope. Figure 2 As shown, Figure 2 The glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn obtained in Example 1 of this invention 2+ SEM image of the nanomicelle hydrogel.

[0061] The glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn prepared in Examples 1-3 above... 2+ Rheological properties of nanomicelle hydrogels were studied. Results are as follows: Figure 3 As shown, Figure 3 The glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn prepared in Examples 1-3 of this invention 2+ Figure showing the rheological properties of the nanomicelle hydrogel. Figure 3 It can be seen that the viscosity-shear thinning curve shows that the viscosity of the gel decreases with increasing shear rate, indicating that glycyrrhetinic acid@glycyrrhizic acid-epigallocatechin gallate-Zn 2+ Nanomicelle hydrogels exhibit excellent shear-thinning properties.

[0062] The changes in the storage modulus (G′) and loss modulus (G″) of the hydrogel prepared in Example 1 were tested to detect the glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn 2+ The state of the nanomicelle hydrogel sample was determined to test its self-healing performance. When G′>G″, it was in a gel state; when G′<G″, it was in a solution state. The specific steps were as follows: The glycyrrhetinic acid@glycyrrhizic acid-epigallocatechin gallate-Zn 2+ The nanomicelle hydrogel was placed on a rheometer, and experimental parameters were set as follows: temperature 25℃, parallel plate diameter 50 mm, and gap 0.2 mm. Viscosity-shear rate scanning: frequency 10 rad / s, shear rate 0.1–100 / s. Cyclic strain scanning: the experiment was divided into three stages: the first stage under low stress (1% stress, 2 min); the second stage under high stress (80% stress, 2 min); the third stage transitioning from high stress to low stress (1% stress, 2 min). The changes in G′ and G″ were observed in each stage. The results are as follows: Figure 4 As shown, Figure 4The glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn prepared in Example 1 of this invention 2+ The graph shows the modulus change test results of the nanomicelle hydrogel. (From...) Figure 4 As can be seen from the time-strain scanning, in the first stage, under low stress of 1%, the storage modulus (G′) was consistently higher than the loss modulus (G″), indicating that the surface sample was in a gel state. In the second stage, when the stress increased to 80%, the storage modulus (G′) was consistently lower than the loss modulus (G″), indicating that the surface sample was in a solution state. In the third stage, when the stress changed from high to low, the storage modulus (G′) was greater than the loss modulus (G″), indicating that when the stress decreased, the sample changed from a solution state back to a gel state. Figure 3 and Figure 4 The experimental results show that glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn 2+ Nanomicelle hydrogels exhibit excellent shear-thinning and self-healing capabilities.

[0063] The glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn obtained in Example 1 above 2+ Nanomicelle solution and glycyrrhetinic acid@glycyrrhizic acid-epigallocatechin gallate-Zn 2+ The in vitro drug release capacity of the nanomicellar hydrogel was tested. The specific testing method was as follows: 1 mL of the above-mentioned nanomicellar solution and the above-mentioned nanomicellar hydrogel were added to a culture dish, followed by 1 mL of PBS buffer solution (0.01 M, pH = 7.0). The dish was then placed in a 37℃ constant temperature water bath with a shaker. At different time points, 0.1 mL of the upper layer solution was collected, and 0.1 mL of fresh PBS solution at the same temperature was added. The absorbance of the drug was then detected by liquid chromatography, the cumulative drug release was calculated, and a cumulative drug release curve was plotted. The results are as follows: Figure 5 As shown, Figure 5 The glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn obtained in Example 1 of this invention 2+ Drug release capacity curves of nanomicelle solutions and hydrogels, by Figure 5 It can be seen that, compared to sol, glycyrrhetinic acid@glycyrrhizic acid-epigallocatechin gallate-Zn 2+ Nanomicelle hydrogels have the ability to provide long-lasting sustained release, capable of slow release for more than 7 days.

[0064] The glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn obtained in Example 1 of this invention 2+ The stability of the nanomicelle hydrogel was tested, and the results are as follows: Figure 6 As shown, Figure 6The glycyrrhetinic acid@glycyrrhetinic acid-epigallocatechin gallate-Zn obtained in Example 1 of this invention 2+ The stability test results of the nanomicelle hydrogel show that the delivery system of the present invention has good stability and can be stored for at least 3 months.

[0065] Comparative Example 1

[0066] (1) Weigh 10 mg of glycyrrhetinic acid and place it in a round-bottom flask. Add 70 mg of glycyrrhetinic acid and then add 5 mL of ethanol solution. Sonicate the solution at 37°C until it is completely dissolved to obtain a mixed solution.

[0067] (2) The mixed solution was placed on a rotary evaporator to remove the ethanol solvent. The temperature was set at 50℃ and the rotation speed was 80 rpm. After the solvent was removed, a uniform thin film was obtained. Then, 6 mL of water was added and the mixture was ultrasonically hydrated for 20 min in an ultrasonic instrument. The unencapsulated hydrophobic compounds were removed by filtration through a 0.22 μm filter membrane to obtain glycyrrhetinic acid@glycyrrhizic acid nanomicelle solution.

[0068] (3) Divide the obtained nanomicelle solution into three portions and add an appropriate amount of sodium hydroxide to adjust their pH to 4.0, 5.0 and 6.0 respectively.

[0069] Comparative Example 2

[0070] (1) Weigh 10 mg of glycyrrhetinic acid and place it in a round-bottom flask. Add 70 mg of DL-arginine and then add 6 mL of ethanol solution. Sonicate at 37°C to obtain a suspension.

[0071] (2) The mixed solution was placed on a rotary evaporator to remove the ethanol solvent. The temperature was set at 50℃ and the rotation speed was 80 rpm. After the solvent was removed, a uniform thin film was obtained. Then, 6 mL of water was added and the mixture was ultrasonically hydrated for 20 min in an ultrasonic instrument. The unencapsulated hydrophobic compounds were removed by filtration through a 0.22 μm filter membrane to obtain a glycyrrhetinic acid@arginine nanomicelle solution.

[0072] (3) Divide the obtained nanomicelle solution into three portions and add appropriate amounts of hydrochloric acid to adjust their pH to 9.0, 8.0 and 7.0 respectively.

[0073] Comparative Example 3

[0074] (1) Weigh 10 mg of glycyrrhetinic acid and place it in a round-bottom flask. Add 50 mg of DL-arginine, 20 mg of epigallocatechin gallate and 3 mg of zinc chloride. Then add 5 mL of ethanol solution and sonicate at 37°C to obtain a suspension.

[0075] (2) The mixed solution was placed on a rotary evaporator to remove the ethanol solvent. The temperature was set at 50℃ and the rotation speed at 80 rpm. After solvent removal, a uniform thin film was obtained. Then, 6 mL of water was added and the mixture was ultrasonically hydrated for 20 min. The unencapsulated hydrophobic compounds were removed by filtration through a 0.22 μm filter membrane to obtain glycyrrhetinic acid@arginine-epigallocatechin gallate-Zn 2+ Nanomicelle solution.

[0076] (3) Divide the obtained nanomicelle solution into three portions and add appropriate amounts of hydrochloric acid to adjust their pH to 9.0, 8.0 and 7.0 respectively.

[0077] Example 7

[0078] (1) Weigh 10 mg of glycyrrhetinic acid and place it in a round-bottom flask. Add 50 mg of glycyrrhetinic acid, 20 mg of epigallocatechin gallate and 3 mg of zinc chloride. Then add 5 mL of ethanol solution and sonicate at 37°C to obtain a transparent mixed solution.

[0079] (2) The mixed solution was placed on a rotary evaporator to remove the ethanol solvent. The temperature was set at 50℃ and the rotation speed at 80 rpm. After solvent removal, a uniform thin film was obtained. Then, 6 mL of water was added and the mixture was ultrasonically hydrated for 20 min. The unencapsulated hydrophobic compounds were removed by filtration through a 0.22 μm filter membrane to obtain glycyrrhetinic acid@glycyrrhizic acid-epigallocatechin gallate-Zn 2+ Nanomicelle solution.

[0080] (3) Divide the obtained nanomicelle solution into three portions and add appropriate amounts of hydrochloric acid to adjust their pH to 4.0, 5.0 and 6.0 respectively.

[0081] The appearance of the nanomicelle solutions of Comparative Examples 1-3 and Example 7 at different pH values ​​was observed, and the results are as follows: Figures 7-11 As shown, Figure 7 The images show the appearance of the nanomicelle solution of Comparative Example 1 at pH 4.0, 5.0, and 6.0, respectively. Figure 8 The images show the appearance of the nanomicelle solution of Comparative Example 2 at pH values ​​of 9.0, 8.0, and 7.0. Figure 9 The images show the appearance of the nanomicelle solution of Comparative Example 3 at pH values ​​of 9.0, 8.0, and 7.0. Figure 10 The images show the appearance of the nanomicelle solution from Example 7 at pH values ​​of 4.0, 5.0, and 6.0. Figure 11 The images show a comparison of the appearance of the nanomicelle solution from Example 7 after storage at pH 4.0, 5.0, and 6.0 for one day and one month, respectively. Figure 11In the figure, the figure labeled A shows the appearance of the nanomicelle solution of Example 7 after being stored at pH 4.0, 5.0 and 6.0 for one day, and the figure labeled B shows the appearance of the nanomicelle solution of Example 7 after being stored at pH 4.0, 5.0 and 6.0 for one month.

[0082] Depend on Figure 7 As can be seen, in Comparative Example 1, the nanomicelle solution began to become turbid and precipitate poorly soluble drugs when the pH was adjusted to 5.0, with precipitates appearing at the bottom after a period of time; when the pH was adjusted to 6.0, the solution became almost completely turbid. Figure 8 As can be seen, in Comparative Example 2, the nanomicelle solution began to change color when the pH was adjusted to 8.0; when the pH was adjusted to 7.0, the solution began to become cloudy, and a precipitate appeared at the bottom after standing for a period of time. Figure 9 As can be seen, in Comparative Example 3, the nanomicelle solution began to change color when the pH was adjusted to 8.0; when the pH was adjusted to 7.0, the solution began to become cloudy, and a precipitate appeared at the bottom after standing for a period of time. Figure 10 and Figure 11 As can be seen, the nanomicelle solution of Example 7 showed no significant changes when the pH was adjusted from 4.0 to 6.0, and remained stable after one month at room temperature.

[0083] Example 8

[0084] (1) Weigh 40 mg of glycyrrhizic acid and place it in a round-bottom flask, add 16 mg of epigallocatechin gallate, then add 5 mL of ethanol solution and sonicate at 37°C to obtain a transparent mixed solution.

[0085] (2) The mixed solution was placed on a rotary evaporator to remove the ethanol solvent. The temperature was set at 50℃ and the rotation speed was 80 rpm. After the solvent was removed, a uniform thin film was obtained. Then 16 mL of water was added and the mixture was ultrasonically hydrated for 20 min in an ultrasonic instrument to obtain a 0.25 wt% glycyrrhizic acid@epigallocatechin gallate nanomicelle solution.

[0086] (3) Add 1.9 mL of the above nano micelle solution to each of the 7 glass bottles, and add 0.1 mL of zinc chloride mother liquor of different concentrations, with zinc chloride concentrations of 0, 1, 5, 10, 25, 50 and 100 mM, to obtain 7 samples of 0.25 wt% glycyrrhizic acid@epigallocatechin gallate nano micelle solution with different zinc ion concentrations.

[0087] (4) Prepare 1 wt% glycyrrhizic acid@epigallocatechin gallate nanomicelle solution according to the above steps (1) and (2), repeat operation (3) to obtain 7 samples of 1 wt% glycyrrhizic acid@epigallocatechin gallate nanomicelle solution with different zinc ion concentrations.

[0088] Gel tests were performed on the above 14 nanomicelle solution samples, and the results are as follows: Figure 12 As shown, Figure 12 The graph shows the test results of the effect of different zinc ion concentrations on the gel of the delivery system described in this invention. Figure 12 It is known that low concentrations of zinc ions can promote gel formation, but as the concentration increases, zinc ions will destroy the gel structure of glycyrrhizic acid / epigallocatechin gallate.

[0089] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A supramolecular nanodelivery hydrogel, characterized in that, Includes the following components: Hydrophobic functional materials; Glycyrrhizic acid; Epigallocatechin gallate; Metal ions.

2. The supramolecular nanodelivery hydrogel according to claim 1, characterized in that, The components include the following parts by weight: Hydrophobic functional material: 1 part; Glycyrrhizic acid: 1-20 parts; Epigallocatechin gallate: 1-20 parts; Metal ions: calculated as 0.01 to 1 part of the metal salt from which they originate.

3. The supramolecular nanodelivery hydrogel according to claim 1, characterized in that, The metal ion is selected from at least one of zinc ion, magnesium ion, iron ion, copper ion, calcium ion, sodium ion, and aluminum ion; The hydrophobic functional material is selected from at least one of glycyrrhetinic acid, curcumin, glycyrrhizin, resveratrol, quercetin, scutellarin, rhein, emodin, vitamins, and β-carotene.

4. A method for preparing supramolecular nanodelivery hydrogels, characterized in that, Includes the following steps: Hydrophobic functional materials, glycyrrhizic acid, epigallocatechin gallate and metal salts were mixed in a solvent, the solvent was removed, hydration was performed, and gelation was carried out to obtain supramolecular nanodelivery hydrogels.

5. The method for preparing supramolecular nanodelivery hydrogel according to claim 4, characterized in that, The mass ratio of the hydrophobic functional material, glycyrrhizic acid, epigallocatechin gallate and metal salt is 1:(1~20):(1~20):(0.01~1).

6. The method for preparing supramolecular nanodelivery hydrogel according to claim 4, characterized in that, The metal salt is selected from at least one of zinc salt, magnesium salt, iron salt, copper salt, calcium salt, sodium salt, and aluminum salt; The hydrophobic functional material is selected from at least one of glycyrrhetinic acid, curcumin, glycyrrhizin, resveratrol, quercetin, scutellarin, rhein, emodin, vitamins and β-carotene; The solvent is selected from at least one of methanol, ethanol, acetone, chloroform, and tetrahydrofuran.

7. The method for preparing supramolecular nanodelivery hydrogel according to claim 4, characterized in that, The pH of the hydrated system is 2.0~4.

0.

8. The method for preparing supramolecular nanodelivery hydrogel according to claim 4, characterized in that, The hydration temperature is 25℃~50℃, and the hydration time is 5 min~30 min.

9. The method for preparing supramolecular nanodelivery hydrogel according to claim 4, characterized in that, The gel is specifically formed by allowing the hydrated material to stand at 0℃~30℃ for 30 min~100 min.

10. The use of the supramolecular nanodelivery hydrogel according to any one of claims 1 to 3 or the supramolecular nanodelivery hydrogel obtained by any one of the preparation methods according to claims 4 to 9 in the preparation of cosmetics and / or pharmaceuticals.

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