Plorizin-diosmetin two-component self-healing hydrogel as well as preparation method and application thereof

Abstract

The invention provides a two-component self-healing hydrogel and a preparation method and application thereof, according to the formula, phlorizin and diosmetin are used as active components and gelators, no extra gel material needs to be added, and an aqueous solvent system is used as a dispersion medium; an anti-solvent dispersion method is adopted for preparation, the preparation method is simple, convenient and efficient, and industrial production and application are facilitated; the obtained hydrogel is better in viscosity, the oxidation resistance is enhanced, the hydrogel has healing performance, and the application performance is remarkably improved.

Description

Technical Field

[0001] The invention relates to the technical field of medicine and food, and in particular to a phlorizin-dioscorein two-component self-healing hydrogel, and a preparation method and application of the two-component self-healing hydrogel. Background Art

[0002] Phloridzin is a dihydrochalcone compound, which is widely found in many plants such as sweet tea and citrus, especially in the roots, stems, leaves and fruits of apple trees. Its molecular formula is C 21 H 24 O 10 , molecular weight 436.41, sweetness is about 300 times that of sucrose. Because phlorizin has multiple biological activities such as lowering blood sugar, anti-oxidation, anti-inflammatory, and anti-tumor, it has potential important value in many fields such as medicine, food, beauty, and agriculture. However, the solubility of phlorizin in water is low (2.07 mg / mL), which is not conducive to formulation application and also limits its absorption and efficacy in the body.

[0003] Diosmetin is a natural flavonol with a molecular formula of C 16 H 12 O6, molecular weight 300.26, usually exists in nature in free form or glycoside form, such as chrysanthemum, spearmint, spider incense and other natural medicines and lemon, citrus, peanut and other fruits. Dioscorea lignin has a wide range of pharmacological effects such as antioxidant, anti-infective, anti-inflammatory, antibacterial, metabolic regulation, anti-tumor, improvement of cardiovascular function, estrogen effect, etc., and can be used to treat liver, lung, kidney, eye, and nervous system diseases. However, dioscorea lignin is poorly soluble in water (54.50μg / mL) and has low bioavailability, which limits the efficacy and application range of dioscorea lignin.

[0004] Hydrogel is a biomedical material with a three-dimensional network structure similar to the extracellular matrix formed by wrapping a large number of water molecules; it can absorb and retain a large amount of water while maintaining a stable structure. The above characteristics make hydrogels potentially widely used in many fields such as electronic heat dissipation, biomedicine, and tissue engineering. Two-component gel is a material made by mixing two components. Usually, after mixing, it will solidify through a cross-linking reaction to form a gel with specific functions. These two components are usually specifically selected gel materials and do not have pharmacological activity. Although there are cases where two specific active ingredients can form a gel, they are all special cases and there is no comprehensive understanding of the regularity. Therefore, for medicinal hydrogels, in addition to the active ingredients, specific gel materials are usually added to form them.

[0005] The prior art (CN117137860A) obtains a two-component gel factor by dissolving the anti-inflammatory and anti-tumor drug isoniazid and the amino acid small molecule N,N′-dibenzoyl-L-cystine in ethanol, and then distilling under reduced pressure and drying under vacuum. The gel material has a three-dimensional network structure after freeze-drying, and has good drug sustained release performance, biocompatibility, bioadhesion, low toxicity and easy degradability. It is suitable for tumor treatment, anti-inflammatory and articular cartilage repair. Another invention (CN117159450A) mixes the natural drug small molecule metformin and oleanolic acid, dissolves them in ethanol and then distills under reduced pressure to obtain an organic salt. The supramolecular gel material prepared by the organic salt has good biocompatibility and is easy to degrade, and can be used as a drug delivery system. There are also studies (CN118576539A) that mixed breviscapine and berberine hydrochloride at a total content of 1.5% and used an anti-solvent dispersion method to prepare an injectable two-component hydrogel with physical stability and self-healing properties, suitable for local injection in joint cavities, acupoints, muscles, etc.

[0006] In the previous research of the inventor's team, we observed that phlorizin in dihydrochalcone compounds can spontaneously form hydrogels alone when the concentration reaches 3% or above (see patent 202411080175.8: "A self-supporting hydrogel based on dihydrochalcone sweeteners and its preparation method"). However, such gels usually have a fibrous structure and weak stability. In addition, these gels are easily damaged by external factors and lack self-healing properties. These characteristics limit their application in certain specific fields. Therefore, we are committed to improving the performance of these gels in order to develop more stable composite hydrogel materials with excellent performance. Summary of the invention

[0007] The invention prepares the phlorizin-diosmin two-component gel without adding any gel factor. The two drugs themselves can be used as gel factors. The obtained composite gel has strong viscosity and is more transparent. After dilution, it is closer to nano-size and has self-healing property.

[0008] The present invention proposes an innovative phlorizin-diosmin two-component hydrogel, which not only effectively reduces the minimum gel concentration of phlorizin, but also has better viscosity and stability than single-component hydrogels, and has healing properties, which are characteristics that traditional gels do not have. In terms of size, the hydrogel assembly is nanoscale, with a uniform and fine texture, and can form a translucent gel without the addition of other auxiliary materials.

[0009] Specifically, the present invention aims to provide a two-component self-healing hydrogel. Without any excipients, the two-component phlorizin-dioscorein self-assembles to form a gel through non-covalent bonds, maximizing the drug loading while avoiding the irritation of residual excipients; and has self-healing properties after shearing, and is more transparent, more stable, and more viscous than single-drug gels.

[0010] The invention provides a phlorizin-diosmethicone two-component self-healing hydrogel, which is characterized by being composed of phlorizin, diosmethicone and an aqueous solvent; wherein the phlorizin and diosmethicone are both active ingredients and gel factors.

[0011] It can be understood that as active ingredients and gel factors, the content of phlorizin and diosmethicone in the hydrogel is important, which will affect whether the gel can be prepared, the specific properties of the gel, the applicable scope of the gel, the drug loading and other aspects. The preferred content of the phlorizin and diosmethicone in the gel system by mass is given in the technical solution of this application. That is, preferably, the total content by mass in the gel system is greater than or equal to 1%; further preferably, the total content of the phlorizin and diosmethicone in the gel system by mass is 1%-4%; further preferably, the total content of the phlorizin and diosmethicone in the gel system by mass is 1%-3%; most preferably, the total content of the phlorizin and diosmethicone in the gel system by mass is 2%.

[0012] In the present invention, the hydrogel is formed by the non-covalent self-assembly of the two components of phlorizin and diosmetin. It can be understood that the molar ratio of phlorizin and diosmetin will affect the formation and performance of the hydrogel to a certain extent. Preferably, the molar ratio of phlorizin and diosmetin is less than 2:1; more preferably, the molar ratio of phlorizin and diosmetin is 2:1-1:3; most preferably, the molar ratio of phlorizin and diosmetin is 1:2.

[0013] The aqueous solvent of the present invention refers to an aqueous solvent that occupies the main body in the entire solvent system, and mainly exhibits the properties of water. Specifically, it means that water accounts for more than 45% of the entire solvent system. Specifically, the aqueous solvent is composed of a good solvent and a poor solvent for phlorizin and diosmylin, and the good solvent refers to a phlorizin and diosmylin that can be easily dissolved therein, but due to the relatively small amount of good solvent, the aqueous poor solvent occupies the main body in the entire solvent system, so that the aqueous solvent as a whole exhibits the properties of a poor solvent. After a lot of experimental exploration, the good solvent is selected from one or more of dimethyl sulfoxide, N-methylpyrrolidone, and N,N-dimethylformamide. The poor solvent refers to a phlorizin and diosmylin that can be insoluble or difficult to dissolve therein, which is mainly water, specifically water accounts for more than 50% of the entire poor solvent. After a lot of experimental exploration, the poor solvent is selected from water, milk, or a mixed system of water and one selected from glycerol, propylene glycol or PEG400. Further, by weight, the ratio of good solvent to poor solvent is in the range of 1:39-1:9. More preferably, the ratio of the solvent to the poor solvent is in the range of 1:19 by weight.

[0014] The hydrogel of the present invention does not flow down when inverted in a container, or the storage modulus is higher than the loss modulus. Furthermore, the viscosity of the hydrogel is significantly higher than that of a single-component hydrogel, and it can recover quickly after shear thinning and has self-healing properties.

[0015] Another object of the present invention is to provide a method for preparing the above hydrogel: dissolving the drug in a good solvent to form a saturated solution, and uniformly dispersing the drug in a poor solvent to obtain a self-healing hydrogel containing a certain concentration of the drug. It is understood that the good solvent may or may not be removed after the gel is formed.

[0016] Specifically, the above-mentioned drug refers to a solvent co-evaporation product or a physical mixture of phlorizin and diosgenin in a certain proportion.

[0017] Preferably, the drug is selected from methanol co-evaporation of phlorizin and diosgenin in a certain ratio, because the gel prepared by methanol co-evaporation is more stable and is not easy to precipitate crystals.

[0018] The method for preparing the co-evaporation product of the solvent in a certain molar ratio is as follows: weighing a physical mixture of phlorizin and diosmin in a molar ratio, adding a solvent to completely dissolve the mixture, and then slowly evaporating the solvent to obtain a co-evaporation product powder.

[0019] The molar ratio of phlorizin: diosmin is not higher than 2:1.

[0020] More preferably, the co-evaporation product has a molar ratio of phlorizin to diosmin of 1:2.

[0021] The good solvent refers to a solvent in which phlorizin and diosmin can be easily dissolved, but due to the relatively small amount of good solvent, the aqueous solvent occupies the main part in the entire solvent system, so the aqueous solvent as a whole exhibits the properties of a poor solvent. After a lot of experimental exploration, the good solvent is selected from dimethyl sulfoxide, N-methylpyrrolidone, and N,N-dimethylformamide.

[0022] Preferably, dimethyl sulfoxide is selected as the good solvent.

[0023] The poor solvent means that phlorizin and diosmin are insoluble or poorly soluble in the poor solvent. Considering the requirements of the application field, toxic side effects and cost, the poor solvent is selected from water, milk, a mixed system of water and glycerol or propylene glycol or PEG400 in different proportions.

[0024] Preferably, water is selected as the poor solvent.

[0025] The ratio of good solvent to poor solvent is 1:39-1:9, and more preferably 1:19.

[0026] The gel factor concentration in the solvent system is not less than 1%; preferably, the concentration is 1%-4%; more preferably, the concentration is 1%-3%; most preferably, the gel factor concentration is 2%.

[0027] The dispersion method includes ultrasonic method and vortex method; preferably, ultrasonic method is selected.

[0028] The hydrogel formation means that it does not remain when inverted in the container, or the ratio of the system viscosity to the viscosity of the solvent used is not less than 10, or the storage modulus (G') of the system is higher than the loss modulus (G") in rheological testing; the recoverability means that in rheological testing, after a period of time after shearing, the storage modulus (G') is higher than the loss modulus (G").

[0029] The nano-crystallization refers to diluting the prepared gel to 2 mg / mL and measuring the particle size to be less than 500 nm.

[0030] Another object of the present invention is to provide the use of the phlorizin-diosmin two-component self-healing hydrogel in the preparation of antioxidant products. Experiments show that the phlorizin-diosmin two-component self-healing hydrogel of the present invention has significantly better antioxidant properties. Based on the use of hydroxyl free clearance rate and DPPH clearance rate, it can be seen that the phlorizin-diosmin two-component self-healing hydrogel of the present invention has a significantly higher antioxidant effect than the single-drug group of phlorizin or diosmin at the same concentration, that is, the hydrogel preparation of the present invention has a significant synergistic antioxidant effect, which broadens the application range of the hydrogel.

[0031] Furthermore, the phlorizin-diosmin two-component self-healing hydrogel can be used as a drug carrier, which provides a preparation scheme for a gel. For example, adding breviscapine or mangiferin as an active ingredient to the self-healing hydrogel will form a gel preparation suitable for clinical use.

[0032] In summary, the inventors have found through unexpected research that the use of an appropriate solvent system can prepare a phloridzin-dioscorea lignin composite hydrogel, which forms a high-strength gel preparation by itself without adding a gel material, and has recoverability, has a self-healing property that is significantly better than a single drug, and is more nano. And in the process of preparing the gel above, no auxiliary materials and special equipment are needed, which saves costs, is convenient for large-scale production, and the solubility of the obtained gel is improved. Further, the phloridzin-dioscorea lignin two-component self-healing hydrogel of the present invention has a stronger antioxidant effect, can save costs in antioxidant applications, and improve efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 Figure ar is an inverted appearance diagram of the phlorizin-dioscorea lignin two-component hydrogel prepared in Example 1-18.

[0034] Figure 2 Figures a to e are characterization images in Example 19. a is a transmission electron microscope image; b is an infrared image; c is an XRD image; and D is a DSC image.

[0035] Figure 3 These are the rheological investigation graphs of the gel prepared in Example 3, where a is the viscosity investigation graph; b is the strain investigation graph; c is the angular frequency investigation graph; and d is the temperature change graph.

[0036] Figure 4 The graphs are the viscosity and self-healing properties of the gel of Example 3, and the single-drug gel or suspension of the same concentration. a is a viscosity comparison; b is the self-healing property investigation of lignin self-gel; c is the self-healing property investigation of phlorizin suspension; and d is the self-healing property investigation graph of the composite gel.

[0037] Figure 5 The darkroom laser images after the gel prepared by the method of Example 3 was diluted. a is the appearance image of the two-component hydrogel prepared in Example 3 after being diluted 10 times; b is the appearance image of the lignin autogel after being diluted 10 times; c is the appearance image of the phlorizin suspension after being diluted 10 times.

[0038] Figure 6 a is the antioxidant investigation, b is the DPPH scavenging rate investigation, and b is the hydroxyl radical scavenging rate investigation.

[0039] Figure 7 a in the middle is a pure milk picture of the phlorizin-diosmin complex gel of the present invention (the left tube contains the phlorizin-diosmin complex, and the right tube does not), b / c are gels formed by breviscapine / mangiferin respectively.

[0040] Figure 8 Figures a to f are diagrams of the two-component mixture of phlorizin and diosmin corresponding to comparative examples 1-6. DETAILED DESCRIPTION

[0041] Example 1: Weigh the methanol co-evaporation product with a molar ratio of phlorizin: diosmin of 2:1, dissolve it in dimethyl sulfoxide to form a 40% drug solution, and mix the above solution (1 part) with water (19 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 a).

[0042] Example 2: Weigh the methanol co-evaporation product with a molar ratio of 1:1 of phlorizin and diosmin, dissolve it in dimethyl sulfoxide to form a 40% drug solution, and mix the above solution (1 part) with water (19 parts) under ultrasonic conditions (80 kHz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 b).

[0043] Example 3: Weigh the methanol co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in dimethyl sulfoxide to form a 40% drug solution, and mix the above solution (1 part) with water (19 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 c).

[0044] Example 4: Weigh the methanol co-evaporation product with a molar ratio of 1:3 of phlorizin: diosmin, dissolve it in dimethyl sulfoxide to form a 40% drug solution, and mix the above solution (1 part) with water (19 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 d).

[0045] Example 5: Weigh the methanol co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in dimethyl sulfoxide to form a 40% drug solution, and mix the above solution (1 part) with water (9 parts) under vortex conditions to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 e).

[0046] Example 6: Weigh the methanol co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in N-dimethylpyrrolidone to form a 40% drug solution, and mix the above solution (1 part) with water (19 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 f).

[0047] Example 7: Weigh the methanol co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in N,N-dimethylformamide to form a 40% drug solution, and mix the above solution (1 part) with water (19 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 g).

[0048] Example 8: Weigh the methanol co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in DMSO to form a 40% drug solution, and mix the above solution (1 part) with glycerol: water (19 parts) in a ratio of 1:9 under ultrasonic conditions (80 kHz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 h).

[0049] Example 9: Weigh the methanol co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in DMSO to form a 40% drug solution, and mix the above solution (1 part) with glycerol: water (3:7) (19 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 i).

[0050] Example 10: Weigh the methanol co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in DMSO to form a 40% drug solution, and mix the above solution (1 part) with glycerol: water 5:5 (19 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 j).

[0051] Example 11: Weigh the methanol co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in DMSO to form a 40% drug solution, and mix the above solution (1 part) with propylene glycol: water (19 parts) in a ratio of 1:9 under ultrasonic conditions (80 kHz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 k).

[0052] Example 12: Weigh the methanol co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in DMSO to form a 40% drug solution, and mix the above solution (1 part) with propylene glycol: water (3:7) (19 parts) under ultrasonic conditions (80 kHz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 l).

[0053] Example 13: Weigh the methanol co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in DMSO to form a 40% drug solution, and mix the above solution (1 part) with propylene glycol: water (5:5) (19 parts) under ultrasonic conditions (80 kHz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 m).

[0054] Example 14: Weigh the methanol co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in DMSO to form a 40% drug solution, and mix the above solution (1 part) with PEG400: water (1:9) (19 parts) under ultrasonic conditions (80 kHz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 n).

[0055] Example 15: Weigh the methanol co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in DMSO to form a 40% drug solution, and mix the above solution (1 part) with PEG400: water (3:7) (19 parts) under ultrasonic conditions (80 kHz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 o).

[0056] Example 16: Weigh the methanol co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in DMSO to form a 40% drug solution, and mix the above solution (1 part) with PEG400: water 5:5 (19 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 p).

[0057] Example 17: Weigh the methanol co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in dimethyl sulfoxide to form a 40% drug solution, and mix the above solution (1 part) with water (39 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 q).

[0058] Example 18: A physical mixture of phlorizin and diosmin in a molar ratio of 1:2 was weighed and dissolved in dimethyl sulfoxide to form a 40% drug solution. The above solution (1 part) was fully mixed with water (19 parts) under ultrasonic conditions (80 kHz, 5 min) to obtain a composite hydrogel of phlorizin and diosmin (see attached Figure 1 r).

[0059] Example 19: Characterization of properties of phlorizin-dioscorein composite hydrogel Take an appropriate amount of the phlorizin-diosmin composite hydrogel in Example 3, dilute the hydrogel 10 times with pure water, rinse it with distilled water, and then quickly stain it twice with 2% sodium phosphotungstate staining solution for 10 seconds each time. Dry the stained copper mesh completely and take a transmission electron microscope image, as shown in FIG. Figure 2 a, The two-component hydrogel of the present invention is aggregated in a fibrous form with a diameter of about 5-8 nm.

[0060] Take an appropriate amount of the phlorizin-diosmin composite co-evaporation product and its hydrogel in Example 3, freeze-dry the hydrogel to obtain a xerogel, and grind it into powder; take an appropriate amount of the raw material drug, the co-evaporation product, and the xerogel powder respectively, add a certain amount of KBr, grind and uniformly press the tablets, and use Fourier transform infrared spectrometer to measure the sample at 4000~400cm -1 Infrared absorption in the range, the results are shown in Figure 2 b, at 3409cm -1At 1663 cm, the co-evaporate and gel move to the right relative to the API, 803 cm -1 The peaks of the co-evaporated product and gel were reduced relative to the raw material drug peak, indicating that there was a certain interaction between phlorizin and dioscorea glycosides.

[0061] Take an appropriate amount of the phlorizin-diosmin composite co-evaporation product and its hydrogel in Example 3, freeze-dry the hydrogel to obtain a xerogel, and grind it into powder; take an appropriate amount of the raw material drug, the co-evaporation product, and the xerogel powder respectively, and test them using a powder X-ray diffractometer under nitrogen protection, with a 2θ range of 5~90˚, a scanning speed of 5˚ / min, and a step length of 0.02˚. The results are as follows Figure 2 c, compared with the other groups, the gel peak was weakened as a whole, and the main peak disappeared, indicating that the two drugs interacted to promote the formation of gel.

[0062] Take an appropriate amount of the phlorizin-diosmin composite co-evaporation product and its hydrogel in Example 3, freeze-dry the hydrogel to obtain a xerogel, and grind it into powder; take an appropriate amount of the raw material drug, the co-evaporation product, and the xerogel powder, and measure the differential scanning calorimetry. The result is as follows: Figure 2 d. The melting point peaks of gel and co-evaporation product tend to weaken relative to that of the raw material drug, indicating that phlorizin and dioscorea lignin have certain interactions under certain conditions.

[0063] Example 20: The phlorizin-dioscorein hydrogel obtained in Example 3 was tested for rheological properties using a rheometer. The viscosity was measured at a shear rate range of 0.01 / s-1 to 100 / s at (32±1)°C and a frequency of 1 Hz. The results are as follows: Figure 3 a; Scanning was performed in the strain range of 0.01%~100%, and the results are as follows Figure 3 b; Scanning in the angular frequency range of 0.1r / s~100r / s, the results are as follows Figure 3 c. Scan the temperature in the range of 25℃~110℃ to determine the critical temperature for the transformation from gel to sol. The results are as follows: Figure 3 d; From Figure 3a / b / c / d, it can be seen that the gel prepared by the present invention has a larger viscosity and better stability, and the temperature has little effect on its stability.

[0064] Example 21: The composite gel obtained in Example 3, the dioscorea lignin single-drug gel with the same concentration, and the phlorizin suspension were taken and the viscosity was measured at (32±1)°C and a frequency of 1 Hz in the shear rate range of 0.01 / s-1 to 100 / s. The viscosities of the three were compared. Figure 4a. The composite gel of the present invention has a higher viscosity than the gel or suspension of the same concentration of a single drug. At the same time, the strain of the above three was increased from 0.01% to 100%, maintained at 100% for 120s, and then reduced from 100% to 0.01%, and the storage and loss moduli of the gel were observed. The cycle was carried out to investigate the self-healing properties of the hydrogel. The results are as follows: Figure 4 , 4b is a single gel of dioscorea ginseng, 4c is a suspension of phlorizin, and 4d is a composite gel. Although dioscorea ginseng has a certain self-healing property, it tends to weaken during the repeated shearing process; phlorizin is directly destroyed and has no self-healing property. The composite gel of the present invention has self-healing property, and its strength increases slowly, indicating that the gel prepared by the present invention has good self-healing property.

[0065] Example 22: The phlorizin-diosmin composite hydrogel in Example 3 was diluted 10 times with ultrapure water, and the diluted laser was photographed in a darkroom. Figure 5 a. Meanwhile, the same process as that for preparing the composite hydrogel in Example 1 was used to prepare the phlorizin and diosmin gels, which were diluted 10 times with ultrapure water, and the diluted gels were photographed in the darkroom. Figure 5 b / c, the phlorizin-dioscorea glycosides two-component hydrogel prepared by the present invention has a stronger Tyndall effect after dilution compared with a single drug, indicating that the gel is composed of substances with smaller particle sizes; the particle size and potential of the phlorizin-dioscorea glycosides composite hydrogel after dilution are measured, as shown in the following table. The particle size of the gel after dilution is less than 500nm, indicating that the present invention prepares phlorizin and dioscorea glycosides into a gel that is close to nanometer size, and the potential is around -38, indicating that the particles are relatively stable after dilution.

[0066] Serial number Particle size (nm) distributed Zata potential 1 319.82 0.330 -38.42 2 431.05 0.296 -38.28 3 421.43 0.290 -38.12 Mean 404.95 0.30 -38.27 SD 61.63 0.02 0.15 .

[0067] Example 23: The composite gel of Example 3 of the present invention and the single drug and physical mixture of the same concentration were diluted in multiples to a certain concentration gradient, and the DPPH (%) and hydroxyl radical scavenging rate (%) were measured, n=3, and the DPPH scavenging rate (%) was as follows: Figure 6 a, hydroxyl radical scavenging rate (%) Figure 6 b. The DPPH clearance rate of all samples increased with the increase of concentration. At the same concentration, the clearance rate of VC was usually the highest, while the clearance rates of other samples were relatively low. However, the gel group was higher than the single-drug group. With the increase of concentration, the hydroxyl free clearance rate increased slowly. The DPPH clearance rate increased to the maximum value at 62.5μg / mL and then remained stable, indicating that geraniol-phlorizin has an antioxidant effect.

[0068] Example 24: The water in Example 3 of the present invention is replaced with pure milk, and the pure milk is gelled into a semi-solid state using phlorizin-dioscorein co-evaporation product, such as Figure 7a; at the same time, phlorizin: diosmin: scutellarin (or mangoside) are dissolved in dimethyl sulfoxide at a ratio of 1:2:0.5 to form a 40% drug solution, and the above solution (1 part) is fully mixed with water (19 parts) under ultrasonic conditions (80khz, 5min) to form a composite hydrogel of phlorizin and diosmin loaded with scutellarin (or mangoside), such as Figure 7 b / c.

[0069] The following experiments were also conducted during the screening process, which are used as comparative experiments:

[0070] Comparative Example 1: Weigh the co-evaporation product with a molar ratio of 5:2 of phlorizin: diosmin, dissolve it in dimethyl sulfoxide to form a 40% drug solution, and fully mix the above solution (1 part) with water (19 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite system of phlorizin and diosmin (see attached Figure 8 a).

[0071] Comparative Example 3: Weigh the co-evaporation product with a molar ratio of phlorizin to diosmin of 3:1, dissolve it in dimethyl sulfoxide to form a 40% drug solution, and fully mix the above solution (1 part) with water (19 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite system of phlorizin and diosmin (see attached Figure 8 b).

[0072] Comparative Example 3: Weigh the co-evaporation product with a molar ratio of 1:2 of phlorizin and diosmin, dissolve it in dimethyl sulfoxide to form a 40% drug solution, and fully mix the above solution (1 part) with water: glycerol 3:7 (19 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite system of phlorizin and diosmin (see attached Figure 8 c).

[0073] Comparative Example 4: Weigh the co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in dimethyl sulfoxide to form a 40% drug solution, and fully mix the above solution (1 part) with water: propylene glycol 3:7 (19 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite system of phlorizin and diosmin (see attached Figure 8 d).

[0074] Comparative Example 5: Weigh the co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in dimethyl sulfoxide to form a 40% drug solution, and fully mix the above solution (1 part) with water: PEG400 3:7 (19 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite system of phlorizin and diosmin (see attached Figure 8 e).

[0075] Comparative Example 6: Weigh the co-evaporation product with a molar ratio of 1:2 of phlorizin: diosmin, dissolve it in dimethyl sulfoxide to form a 40% drug solution, and fully mix the above solution (1 part) with water (79 parts) under ultrasonic conditions (80 khz, 5 min) to obtain a composite system of phlorizin and diosmin (see the attached figure (see the attached figure) Figure 8 f)).

[0076] The above are only preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be regarded as limiting the present invention, and the protection scope of the present invention should be based on the scope defined by the claims. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A phlorizin-dioscorein two-component self-healing hydrogel, characterized in that: The invention is composed of phlorizin, diosmetin and an aqueous solvent; wherein the phlorizin and diosmetin are both active ingredients and gelling factors, and their total content in the gel system is greater than or equal to 1% by mass, and the molar ratio of the phlorizin and diosmetin is lower than 2:1; the aqueous solvent is composed of a good solvent and a poor solvent for phlorizin and diosmetin, and the ratio of the good solvent to the poor solvent is in the range of 1:39-1:9 by weight.

2. The phlorizin-dioscorein two-component self-healing hydrogel according to claim 1, characterized in that: The total content of the phlorizin and diosmin in the gel system is 1%-4% by mass.

3. The phlorizin-dioscorein two-component self-healing hydrogel according to claim 2, characterized in that: The total content of the phlorizin and diosmin in the gel system is 2% by mass.

4. The phlorizin-dioscorein two-component self-healing hydrogel according to claim 1, characterized in that: The molar ratio of phlorizin to diosmetin is 2:1-1:

3.

5. The phlorizin-dioscorein two-component self-healing hydrogel according to claim 4, characterized in that: The molar ratio of phlorizin to diosmin is 1:

2.

6. The phlorizin-dioscorein two-component self-healing hydrogel according to claim 1, characterized in that: The hydrogel does not flow down when inverted in a container, or the storage modulus is higher than the loss modulus; the viscosity of the hydrogel is significantly higher than that of a single-component hydrogel, and it can recover quickly after shear thinning and has self-healing properties.

7. The method for preparing the phlorizin-dioscorein two-component self-healing hydrogel according to claims 1-6, characterized in that: The hydrogel is prepared by adopting the anti-solvent dispersion method. Firstly, the mixture of phlorizin and diosmin is dissolved in a good solvent, and then the good solvent is uniformly dispersed in a poor solvent. The good solvent may or may not be removed to obtain the hydrogel.

8. The method for preparing the phlorizin-dioscorein two-component self-healing hydrogel according to claim 7, characterized in that: The good solvent is one or more of dimethyl sulfoxide, N-methylpyrrolidone, and N,N-dimethylformamide; the poor solvent is water, milk, or a mixed system of water and one selected from glycerol, propylene glycol, or PEG400.

9. The method for preparing the phlorizin-dioscorein two-component self-healing hydrogel according to claim 7, characterized in that: The mixture of phlorizin and diosmylin is a solvent co-evaporation product or a physical mixture.

10. Use of the phlorizin-dioscorein two-component self-healing hydrogel according to claims 1 to 6 in the preparation of antioxidant products.

11. Use of the phlorizin-dioscorein two-component self-healing hydrogel according to claims 1 to 6 in the preparation of medicines, wherein the self-healing hydrogel is used as a gel carrier of the medicine.

Images