A fullerol-deep eutectic solvent-agarose composite gel for electrically driven drug release

Abstract

The present invention discloses a fullerol-deep eutectic solvent-agarose gel with electric-driven controlled drug release function and a preparation method thereof. The components involved in the system include fullerol (TEGs-C 60 ), low eutectic solvent (choline chloride-malic acid or lactic acid or citric acid), agarose and loaded anti-inflammatory drugs; among them, the low eutectic solvent is used as a crosslinker and conductive medium of the gel, and TEGs-C with a large cavity 60 The gel is immobilized on the surface of the gel. The preparation process of the gel is simple and easy to scale up. It is particularly suitable as a portable drug carrier for anti-inflammatory and electrical stimulation therapy of difficult-to-heal wounds in special populations (such as diabetic patients). In addition, its conductivity, stability, mechanical strength and other indicators are good, and it also has the effect of inhibiting the growth of microorganisms. 60 The free radical scavenging effect it possesses can also cooperate with other components to achieve a comprehensive therapeutic effect on local lesions.

Description

Technical Field

[0001] The present invention belongs to the field of medical devices / flexible conductive materials, and in particular relates to a gel carrier with multiple components for electrically driven drug release and a preparation method thereof. Background Art

[0002] The rapid development of multifunctional polymer drug delivery systems is driving revolutionary changes in the field of pharmaceutical materials. Among the diverse new materials, gels with excellent physical and chemical properties are the most widely used. As a classic example of soft materials, they offer advantages such as ease of preparation, easy degradation, good biocompatibility, and customizable mechanical properties. Furthermore, compared to synthetic polymers, natural polymers offer unique advantages in the field of medical devices and flexible materials. Among them, agarose is a linear, long-chain molecule composed of D-galactose and 3,6-anhydrogalactose linked by alternating β-1,4 and α-1,3 linkages. Gels prepared from agarose exhibit excellent stability, high mechanical strength, large cavities, numerous binding sites, and strong adsorption capacity. They are used for drug release, tissue regeneration, blood purification, and the treatment of autoimmune diseases, offering promising applications and enormous potential.

[0003] When human skin is damaged by physical (such as cuts, scalds, burns) or chemical factors, the integrity of the tissue structure will be destroyed, and a wound will be formed. Wound healing can be divided into four stages: hemostasis, inflammation, cell proliferation, maturation, and remodeling. However, the healing process of chronic wounds is longer, and re-epithelialization is inhibited to varying degrees. It often remains in the inflammatory stage and cannot recover in a short period of time; especially when it exists as a complication of certain special diseases (such as diabetes), it will seriously affect the patient's body recovery and quality of life. Therefore, it is of great significance to develop a portable flexible carrier that can control the release of drugs to enhance wound healing and skin care. In addition, electrical stimulation (ES) can enhance the proliferation and migration of fibroblasts through weak currents, promote keratinocytes to secrete more extracellular matrix, and accelerate wound healing (Chemical Engineering Journal, 2021, 415:129025). However, traditional ES strategies often require the implantation of electrodes near the wound, which has high operating conditions and is not easy to achieve comprehensive treatment of the entire lesion area. At the same time, the clinical effect needs to be enhanced. In order to overcome the above shortcomings, ES can be combined with drug controlled-release gel carriers, which will provide an effective and convenient solution for the treatment of chronic wounds.

[0004] Deep Eutectic Solvents (DES) is a new type of green solvent that has attracted much attention. It is usually formed by hydrogen bonding of a hydrogen bond acceptor (HBA) and a hydrogen bond donor (HBD) in a certain molar ratio. It has unique properties such as low melting point, low toxicity, easy preparation, wide electrochemical window, and designable structure. Some DES with high stability and strong conductivity have been used as electrolytes for supercapacitors (Journal of Power Sources, 2021, 490: 229365), and its application in the medical field is still in its infancy. The present invention uses DES as an electrolyte of conductive agarose gel to synergize with ES; compared with electrolytes that usually have acute and chronic toxicity, DES with better biocompatibility is an ideal choice. In addition, the interaction between the positively charged groups in its structure and the negatively charged bacterial cell wall can destroy the integrity of the latter, thereby achieving the effect of inhibiting the growth of bacteria in the wound.

[0005] Fullerene (C 60 Fullerene (CAS No. 99685-96-8) is the third allotropic form of carbon. It possesses a stable spherical hollow structure and significant electrophilicity (capable of accepting up to six electrons), earning it the nickname "free radical sponge." Its excellent stability, antioxidant properties, highly reactive active surface, and large surface area as nanoparticles have led to its widespread use in biomedical drug delivery. Hydroxylation not only improves fullerene's biocompatibility and enhances its targeting within the body, but also allows for a greater loading capacity when used as a controlled-release drug carrier.

[0006] Most of the existing gel drug carriers have the phenomenon of drug burst release during application. They also have problems such as complex formulation and process, need for special equipment, difficulty in recycling, and relatively single function. The present invention provides a composite gel drug carrier with fullerol, deep eutectic solvent, and agarose as main components; it has a novel composition, simple process, comprehensive functions, and is easy to prepare on a large scale; it solves the problems of uncontrolled drug release and immune rejection, improves the shelf life, antibacterial properties and synergistic therapeutic effects of the drug carrier, and expands the application of immobilized TEGs-C 60 New uses for drug release are expected to meet various complex wound healing and skin care needs. Summary of the Invention

[0007] The purpose of the present invention is to provide a fullerol-deep eutectic solvent-agarose composite gel with an electrically driven controlled drug release function and a preparation method thereof, wherein the fullerol (TEGs-C 60 ) by fullerene C 60It is prepared by reacting with tetraethylene glycol under the action of a catalyst; the low eutectic solvent is composed of a hydrogen bond acceptor choline chloride and a hydrogen bond donor malic acid or lactic acid or citric acid; the base material of the gel is agarose, and its aqueous solution can be gelled by itself after being heated at 90-100°C and cooled to room temperature. The preparation process involved is simple and easy to mass produce. It is especially suitable as a portable drug carrier for anti-inflammatory and electrical stimulation therapy of difficult-to-heal wounds in special populations (such as diabetic patients). In the present invention, the low eutectic solvent serves as a crosslinker and conductive medium for the gel, and TEGs-C has a large cavity. 60 The TEGs-C gel is immobilized on the surface of the gel, thereby achieving electrically driven controlled release of anti-inflammatory drugs. The resulting gel has good conductivity, stability, mechanical strength and other indicators, and also has the effect of inhibiting microbial growth. 60 The free radical scavenging effect it possesses can also cooperate with other components to achieve a comprehensive therapeutic effect on local lesions.

[0008] Technical solution: To achieve the above objectives, a composite gel drug carrier with electrically driven drug release and its preparation method are proposed:

[0009] The electrically driven drug-releasing composite gel drug carrier of the present invention is characterized in that the gel base material used is agarose.

[0010] The above-mentioned method for preparing a composite gel drug carrier with electrically driven drug release is characterized in that the low eutectic solvent used as a cross-linking agent and a conductive medium includes but is not limited to choline chloride-malic acid (1:1), choline chloride-lactic acid (1:1) or choline chloride-citric acid (1:1).

[0011] The above-mentioned method for preparing a composite gel drug carrier with electric drive drug release is characterized in that: the fullerene alcohol (TEGs-C 60 ) is composed of fullerene C 60 , tetraethylene glycol, and lithium hydroxide are reacted at a ratio of 1:1:1 (mg / mL / mg) at room temperature for 20 hours to prepare the drug; the drug is then immobilized on the surface of the gel to increase the drug loading capacity and to scavenge free radicals on the wound surface.

[0012] The specific preparation steps are as follows:

[0013] (1) Add agarose and deionized water in a material-liquid ratio of 1:100 to 3:100 (g / mL) into a container and heat at 90-100°C until a homogeneous transparent solution is formed; then add the same volume of a deep eutectic solvent and stir evenly, then quickly pour into a polytetrafluoroethylene mold with a depth of 0.2-0.5 cm and cool at room temperature;

[0014] (2) According to 1:50~1:150(TEGs-C 60: agarose) mass ratio, TEGs-C 60 The saturated ethanol solution is evenly poured on the surface of the gel that is about to solidify; after the ethanol evaporates naturally, the surface of the gel with TEGs-C immobilized on it can be obtained. 60 Agarose gel, a deep eutectic solvent;

[0015] (3) freeze-drying the gel prepared in (2) at -40°C under vacuum (0.1 Pa) for 24 to 48 hours to remove moisture;

[0016] (4) The lyophilized gel was mixed with 5.0 mg / mL indomethacin or dexamethasone ethanol solution at a solid-liquid ratio of 1:50 (g / mL) and adsorbed at room temperature for 12 to 24 hours in a shaker at 100 rpm;

[0017] (5) The drug-loaded gel was removed, washed with deionized water three times, and air-dried at room temperature to a constant weight.

[0018] (6) Irradiate the drug-loaded gel with ultraviolet light for 10 minutes for sterilization, then punch, package, and seal for storage.

[0019] In the above-mentioned method for preparing a composite gel drug carrier with electrically driven drug release, the thickness of the gel ranges from but is not limited to 0.2 to 0.5 cm. The thickness or shape of the prepared gel can be adjusted based on the mold depth or shape according to the actual required drug loading and usage duration. For example, the resulting gel thickness can be 0.15 cm, 0.25 cm, 0.35 cm, 0.45 cm, 0.55 cm, etc. The loaded drugs include but are not limited to anti-inflammatory drugs. The drug carrier can be administered to sites including but not limited to the skin surface, and can also be implanted on the body surface or for wound filling. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more completely illustrate the technical solutions of the specific embodiments of the present invention, the following briefly describes the drawings required in the embodiments. The drawings described are only part of the embodiments of the present invention. Those skilled in the art should be able to derive other drawings of the embodiments based on these drawings. Among them:

[0021] Figure 1 This is the solidification process of the fullerenol-deep eutectic solvent-agarose composite gel (not loaded with drugs) in the present invention;

[0022] Figure 2 This is a front view of the field emission scanning electron microscope of the fullerenol-deep eutectic solvent-agarose composite gel in the present invention (a), the surface of which is immobilized with TEGs-C 60 (b) The local magnification of 400 times of the gel pores and (c) the local magnification of 2500 times of the gel pores;

[0023] Figure 3 The fullerol-deep eutectic solvent-agarose composite gel (TEGs-C 60 -DES-Aga-gel), deep eutectic solvent-agarose gel (DES-Aga-gel) and agarose gel (Aga-hydrogel);

[0024] Figure 4 is the current passing through the fullerenol-deep eutectic solvent-agarose composite gel of the present invention at a voltage of 1 to 10 V;

[0025] Figure 5 TG / DTG curve of the fullerenol-deep eutectic solvent-agarose composite gel of the present invention;

[0026] Figure 6 The mold growth of agarose gel (a), deep eutectic solvent-agarose gel (b), and fullerenol-deep eutectic solvent-agarose gel (c) during storage at room temperature for 60 days;

[0027] Figure 7 These are the drug release rate curves of indomethacin (a) and dexamethasone (b) from the drug-loaded fullerol-deep eutectic solvent-agarose composite gel of the present invention when a 5V electrical stimulus is applied. DETAILED DESCRIPTION

[0028] The following is a detailed description of the present invention. Although specific embodiments of the present invention are shown, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments set forth herein. Rather, these embodiments are provided to enable a more thorough understanding of the present invention and to fully convey the scope of the present invention to those skilled in the art.

[0029] This specification and claims do not distinguish components based on differences in terminology, but rather on differences in their functions. The terms "including" and "comprising" used in this application are open-ended and should be interpreted as meaning "including but not limited to." The examples described later in this specification are preferred embodiments of the present invention and are intended to serve as general guidelines for the purposes of this specification and are not intended to limit the scope of the invention.

[0030] Example 1

[0031] Weigh 0.1g agarose and mix it with 10mL water, heat it at 100℃ for about 5min to form a homogeneous transparent solution; add 10mL choline chloride-malic acid (1:1) and stir evenly, then quickly pour it into a polytetrafluoroethylene mold with a depth of 0.3cm. 60Prepare a saturated ethanol solution and pour it evenly on the surface of the gel that is about to solidify. After the ethanol evaporates naturally, the surface of the gel with TEGs-C immobilized on it can be obtained. 60 The solid-liquid ratio of agarose: water: deep eutectic solvent is 1:100:100 (g / mL / mL), and the TEGs-C 60 : the mass ratio of agarose is 1:50 (g / g);

[0032] The gel was freeze-dried at -40°C under vacuum (0.1 Pa) for 48 hours to remove moisture; 5.0 g of the dry gel was weighed and mixed with a 5.0 mg / mL anti-inflammatory drug ethanol solution at a material-liquid ratio of 1:50 (g / mL), and adsorbed at room temperature for 24 hours in a shaker at 100 rpm;

[0033] The drug-loaded gel was taken out, washed with deionized water for three times, and air-dried in air at room temperature until constant weight was reached. The drug-loaded gel was sterilized by ultraviolet irradiation for 10 minutes, and then punched, packaged, and sealed for storage.

[0034] Example 2

[0035] Weigh 0.2g agarose and mix it with 10mL water, heat it at 100℃ for about 5min to form a homogeneous transparent solution; add 10mL choline chloride-malic acid (1:1) and stir evenly, then quickly pour it into a polytetrafluoroethylene mold with a depth of 0.3cm. Then weigh 2.0mg TEGs-C 60 Prepare a saturated ethanol solution and pour it evenly on the surface of the gel that is about to solidify. After the ethanol evaporates naturally, the surface of the gel with TEGs-C immobilized on it can be obtained. 60 The solid-liquid ratio of agarose: water: deep eutectic solvent is 1:100:100 (g / mL / mL), and the TEGs-C 60 : The mass ratio of agarose is 1:100 (g / g);

[0036] The gel was freeze-dried at -40°C under vacuum (0.1 Pa) for 48 hours to remove moisture; 5.0 g of the dry gel was weighed and mixed with a 5.0 mg / mL anti-inflammatory drug ethanol solution at a material-liquid ratio of 1:50 (g / mL), and adsorbed at room temperature for 24 hours in a shaker at 100 rpm;

[0037] The drug-loaded gel was taken out, washed with deionized water for three times, and air-dried in air at room temperature until constant weight was reached. The drug-loaded gel was sterilized by ultraviolet irradiation for 10 minutes, and then punched, packaged, and sealed for storage.

[0038] Example 3

[0039] Weigh 0.3g agarose and mix it with 10mL water, heat it at 100℃ for about 5min to form a homogeneous transparent solution; add 10mL choline chloride-malic acid (1:1) and stir evenly, then quickly pour it into a polytetrafluoroethylene mold with a depth of 0.3cm. Then weigh 2.0mg TEGs-C 60 Prepare a saturated ethanol solution and pour it evenly on the surface of the gel that is about to solidify. After the ethanol evaporates naturally, the surface of the gel with TEGs-C immobilized on it can be obtained. 60 The solid-liquid ratio of agarose: water: deep eutectic solvent is 3:100:100 (g / mL / mL), and the TEGs-C 60 : The mass ratio of agarose is 1:150 (g / g);

[0040] The gel was freeze-dried at -40°C under vacuum (0.1 Pa) for 48 hours to remove moisture; 5.0 g of the dry gel was weighed and mixed with a 5.0 mg / mL anti-inflammatory drug ethanol solution at a material-liquid ratio of 1:50 (g / mL), and adsorbed at room temperature for 24 hours in a shaker at 100 rpm;

[0041] The drug-loaded gel was taken out, washed with deionized water for three times, and air-dried in air at room temperature until constant weight was reached. The drug-loaded gel was sterilized by ultraviolet irradiation for 10 minutes, and then punched, packaged, and sealed for storage.

[0042] Example 4

[0043] Weigh 0.2g agarose and mix it with 8mL water, heat it at 100℃ for about 5min to form a homogeneous transparent solution; add 12mL choline chloride-malic acid (1:1) and stir evenly, then quickly pour it into a polytetrafluoroethylene mold with a depth of 0.3cm. Then weigh 2.0mg TEGs-C 60 Prepare a saturated ethanol solution and pour it evenly on the surface of the gel that is about to solidify. After the ethanol evaporates naturally, the surface of the gel with TEGs-C immobilized on it can be obtained. 60 The material-liquid ratio of agarose: water: low eutectic solvent is 1:40:60 (g / mL / mL), and the TEGs-C 60 : The mass ratio of agarose is 1:100 (g / g);

[0044] The gel was freeze-dried at -40°C under vacuum (0.1 Pa) for 48 hours to remove moisture; 5.0 g of the dry gel was weighed and mixed with a 5.0 mg / mL anti-inflammatory drug ethanol solution at a material-liquid ratio of 1:50 (g / mL), and adsorbed at room temperature for 24 hours in a shaker at 100 rpm;

[0045] The drug-loaded gel was taken out, washed with deionized water for three times, and air-dried in air at room temperature until constant weight was reached. The drug-loaded gel was sterilized by ultraviolet irradiation for 10 minutes, and then punched, packaged, and sealed for storage.

[0046] Example 5

[0047] Weigh 0.2g agarose and mix it with 12mL water, heat it at 100℃ for about 5min to form a homogeneous transparent solution; add 8mL choline chloride-malic acid (1:1) and stir evenly, then quickly pour it into a polytetrafluoroethylene mold with a depth of 0.3cm. Then weigh 2.0mg TEGs-C 60 Prepare a saturated ethanol solution and pour it evenly on the surface of the gel that is about to solidify. After the ethanol evaporates naturally, the surface of the gel with TEGs-C immobilized on it can be obtained. 60 The solid-liquid ratio of agarose: water: deep eutectic solvent is 1:60:40 (g / mL / mL), and the TEGs-C 60 : The mass ratio of agarose is 1:100 (g / g);

[0048] The gel was freeze-dried at -40°C under vacuum (0.1 Pa) for 48 hours to remove moisture; 5.0 g of the dry gel was weighed and mixed with a 5.0 mg / mL anti-inflammatory drug ethanol solution at a material-liquid ratio of 1:50 (g / mL), and adsorbed at room temperature for 24 hours in a shaker at 100 rpm;

[0049] The drug-loaded gel was taken out, washed with deionized water for three times, and air-dried in air at room temperature until constant weight was reached. The drug-loaded gel was sterilized by ultraviolet irradiation for 10 minutes, and then punched, packaged, and sealed for storage.

[0050] Example 6

[0051] Weigh 0.2g agarose and mix it with 10mL water, heat it at 100℃ for about 5min to form a uniform transparent solution; add 10mL choline chloride-malic acid (1:1) and stir evenly, then quickly pour it into a polytetrafluoroethylene mold with a depth of 0.3cm. Then weigh 3.0mg TEGs-C 60 Prepare a saturated ethanol solution and pour it evenly on the surface of the gel that is about to solidify. After the ethanol evaporates naturally, the surface of the gel with TEGs-C immobilized on it can be obtained. 60 The solid-liquid ratio of agarose: water: deep eutectic solvent is 1:50:50 (g / mL / mL), and the TEGs-C 60 : the mass ratio of agarose is 3:200 (g / g);

[0052] The gel was freeze-dried at -40°C under vacuum (0.1 Pa) for 48 hours to remove moisture; 5.0 g of the dry gel was weighed and mixed with a 5.0 mg / mL anti-inflammatory drug ethanol solution at a material-liquid ratio of 1:50 (g / mL), and adsorbed at room temperature for 24 hours in a shaker at 100 rpm;

[0053] The drug-loaded gel was taken out, washed with deionized water for three times, and air-dried in air at room temperature until constant weight was reached. The drug-loaded gel was sterilized by ultraviolet irradiation for 10 minutes, and then punched, packaged, and sealed for storage.

[0054] Example 7

[0055] Weigh 0.2g agarose and mix it with 10mL water, heat it at 100℃ for about 5min to form a homogeneous transparent solution; add 10mL choline chloride-malic acid (1:1) and stir evenly, then quickly pour it into a polytetrafluoroethylene mold with a depth of 0.3cm. Then weigh 4.0mg TEGs-C 60 Prepare a saturated ethanol solution and pour it evenly on the surface of the gel that is about to solidify. After the ethanol evaporates naturally, the surface of the gel with TEGs-C immobilized on it can be obtained. 60 The solid-liquid ratio of agarose: water: deep eutectic solvent is 1:50:50 (g / mL / mL), and the TEGs-C 60 : the mass ratio of agarose is 1:50 (g / g);

[0056] The gel was freeze-dried at -40°C under vacuum (0.1 Pa) for 48 hours to remove moisture; 5.0 g of the dry gel was weighed and mixed with a 5.0 mg / mL anti-inflammatory drug ethanol solution at a material-liquid ratio of 1:50 (g / mL), and adsorbed at room temperature for 24 hours in a shaker at 100 rpm;

[0057] The drug-loaded gel was taken out, washed with deionized water for three times, and air-dried in air at room temperature until constant weight was reached. The drug-loaded gel was sterilized by ultraviolet irradiation for 10 minutes, and then punched, packaged, and sealed for storage.

[0058] Example 8

[0059] Weigh 0.2g agarose and mix it with 10mL water, heat it at 100℃ for about 5min to form a homogeneous transparent solution; add 10mL choline chloride-lactic acid (1:1) and stir evenly, then quickly pour it into a polytetrafluoroethylene mold with a depth of 0.3cm. Then weigh 3.0mg TEGs-C 60 Prepare a saturated ethanol solution and pour it evenly on the surface of the gel that is about to solidify. After the ethanol evaporates naturally, the surface of the gel with TEGs-C immobilized on it can be obtained. 60The solid-liquid ratio of agarose: water: deep eutectic solvent is 1:50:50 (g / mL / mL), and the TEGs-C 60 : the mass ratio of agarose is 3:200 (g / g);

[0060] The gel was freeze-dried at -40°C under vacuum (0.1 Pa) for 48 hours to remove moisture; 5.0 g of the dry gel was weighed and mixed with a 5.0 mg / mL anti-inflammatory drug ethanol solution at a material-liquid ratio of 1:50 (g / mL), and adsorbed at room temperature for 24 hours in a shaker at 100 rpm;

[0061] The drug-loaded gel was taken out, washed with deionized water for three times, and air-dried in air at room temperature until constant weight was reached. The drug-loaded gel was sterilized by ultraviolet irradiation for 10 minutes, and then punched, packaged, and sealed for storage.

[0062] Example 9

[0063] Weigh 0.2g agarose and mix it with 10mL water, heat it at 100℃ for about 5min to form a uniform transparent solution; add 10mL choline chloride-citric acid (1:1) and stir evenly, then quickly pour it into a polytetrafluoroethylene mold with a depth of 0.3cm. Then weigh 3.0mg TEGs-C 60 Prepare a saturated ethanol solution and pour it evenly on the surface of the gel that is about to solidify. After the ethanol evaporates naturally, the surface of the gel with TEGs-C immobilized on it can be obtained. 60 The solid-liquid ratio of agarose: water: deep eutectic solvent is 1:50:50 (g / mL / mL), and the TEGs-C 60 : the mass ratio of agarose is 3:200 (g / g);

[0064] The gel was freeze-dried at -40°C under vacuum (0.1 Pa) for 48 hours to remove moisture; 5.0 g of the dry gel was weighed and mixed with a 5.0 mg / mL anti-inflammatory drug ethanol solution at a material-liquid ratio of 1:50 (g / mL), and adsorbed at room temperature for 24 hours in a shaker at 100 rpm;

[0065] The drug-loaded gel was taken out, washed with deionized water for three times, and air-dried in air at room temperature until constant weight was reached. The drug-loaded gel was sterilized by ultraviolet irradiation for 10 minutes, and then punched, packaged, and sealed for storage.

[0066] The fullerenol-deep eutectic solvent-agarose gel prepared in Example 6 was subjected to a thermogravimetric / derivative thermogravimetric (TG / DTG) curve test.

[0067] The TG / DTG curve in item

[0066] is attached. Figure 5The following is a simple analysis of the TG / DTG curve:

[0068] Figure a shows the thermogravimetric (TG) curve, and b shows the derivative thermogravimetric (DTG) curve. Within the temperature range of 25–200°C, the fullerenol-deep eutectic solvent-agarose gel loses 14.45% of its mass. This weight loss is attributed to the evaporation of both free and bound water. Within the temperature range of 200–280°C, the gel experiences a maximum weight loss rate of 0.880% / °C, corresponding to the third peak of the DTG curve (271.33°C). This process likely involves the continued thermal and oxidative decomposition of the eutectic solvent and polymer agarose, accompanied by the evaporation and elimination of volatile products (such as carbon dioxide). As the thermal degradation temperature increases to the third stage (280–600°C), the TG curve reveals a 10.93% mass loss. These analytical results confirm the excellent thermal stability of the composite gel at temperatures below 200°C.

[0069] A comparative study was conducted on the fungal growth in an exposed environment of the fullerenol-deep eutectic solvent-agarose gel prepared in Example 6 and the deep eutectic solvent-agarose gel and agarose gel prepared under the same conditions.

[0070] The results of fungal growth on agarose gel (a), deep eutectic solvent-agarose gel (b) and fullerol-deep eutectic solvent-agarose gel (c) in item

[0069] within 60 days after preparation are shown in the attached table. Figure 6 . Perform a simple analysis:

[0071] It can be clearly observed in the figure that agarose hydrogel (a) will quickly breed a large number of black-gray microorganisms in the air. Their morphology can be confirmed as filamentous molds under a microscope. This is because agarose can provide sufficient C, H, O sources and other substances required for their growth. The gel (b) formed by self-polymerization of the low eutectic solvent and agarose showed strong antibacterial ability and could still maintain its original morphology after being exposed to air for 60 days; the surface-immobilized TEGs-C 60 The low eutectic solvent-agarose gel (c) also showed no microbial contamination after being stored for 2 months, demonstrating its ideal stability and long shelf life.

[0072] The overall properties and indomethacin loading capacity of the fullerenol-deep eutectic solvent-agarose composite gels described in Examples 1 to 9 were compared. The specific operation of the loading capacity test was as follows:

[0073] 5.0 g of freeze-dried fullerol-deep eutectic solvent-agarose gel was placed in 250 mL of 5.0 mg / mL indomethacin ethanol solution and allowed to adsorb the latter for 24 hours at room temperature. Finally, the absorbance of the indomethacin ethanol solution before and after gel adsorption was measured using a UV-visible spectrophotometer.320nm , by quantitative standard curve (y=0.0095+0.0161x, R 2 =0.9999) to calculate the concentration of indomethacin. The formula for calculating the loading LC% is LC%=(C i -C f )*V*100 / m; where C i , C f are the concentrations of the drug in the solution before and after adsorption, mg / mL; V is the volume of the solution, mL; m is the mass of the gel carrier, mg; the test results are shown in Table 1.

[0074] Table 1. Comparison of overall properties and indomethacin loading of fullerenol-deep eutectic solvent-agarose composite gels obtained in different examples:

[0075] Serial number Overall characteristics Loading capacity (%) Example 1 Good uniformity, good flexibility and good load-bearing capacity 8.61±0.22 Example 2 Good uniformity, good flexibility and good load-bearing capacity 9.45±0.13 Example 3 Good uniformity, good flexibility and good load-bearing capacity 10.10±0.15 Example 4 Poor uniformity, good flexibility and good load-bearing capacity 9.56±0.43 Example 5 Good uniformity, good flexibility, average load-bearing capacity 9.29±0.33 Example 6 Good uniformity, good flexibility and good load-bearing capacity 13.54±0.34 Example 7 Good uniformity, good flexibility and good load-bearing capacity 15.97±0.51 Example 8 Good uniformity, poor flexibility, good load-bearing capacity 11.70±0.12 Example 9 Good uniformity, poor flexibility, poor load-bearing capacity 10.22±0.38

[0076] The fullerol-deep eutectic solvent-agarose composite gel loaded with indomethacin and dexamethasone prepared in Example 6 was tested for drug release rate through isolated mouse skin under 5V electrical stimulation. The test results are shown in the attached Figure 7 , the specific test conditions are as follows:

[0077] Drug release rate determination: This experiment was conducted in a Franz diffusion cell apparatus (YB-P6, Tianguang Instrument Co., Ltd., Tianjin). Six- to eight-week-old mice were euthanized by cervical dislocation. Subcutaneous fat and hair were carefully removed, and the abdominal skin was cut into appropriate sizes and placed between the donor and receptor compartments of the Franz diffusion cell. The receptor compartment was filled with 15 ml of PBS (0.2 mol / L, pH 7.4), resulting in an effective diffusion area of ​​1.77 cm. 2 The stirring rate was maintained at 350 rpm. At the beginning of the experiment, a 2.0 g, 1.5 cm diameter, 0.3 cm thick, drug-loaded (indomethacin or dexamethasone) gel disc was inserted into the Franz cell donor chamber, ensuring complete contact with the mouse skin. During the controlled release test, the drug carrier was periodically stimulated with 5 V electricity. At the corresponding time points, 1.0 ml of solution was collected from the receptor chamber for quantitative analysis, and the same volume of fresh buffer solution was added to maintain the total volume constant. The experimental temperature was maintained at 37°C. The drug permeation experiment was repeated four times, and the average value was used to plot the release rate curve.

Claims

1. A fullerol-deep eutectic solvent-agarose composite gel for electrically driven drug release, characterized in that: Follow the steps below to prepare and load the drug: (1) Fullerene C 60 Fullerene alcohol TEGs-C was prepared by reacting tetraethylene glycol and lithium hydroxide at a ratio of 1:1:1 mg / mL / mg at room temperature for 20 hours. 60 ; (2) Agarose was mixed with deionized water and heated at 100°C until a homogeneous transparent solution was formed. A 1:1 molar ratio of choline chloride-malic acid eutectic solvent was added and stirred evenly. The mixture was then quickly poured into a polytetrafluoroethylene mold and cooled at room temperature. (3) Fullerol TEGs-C 60 The saturated ethanol solution was evenly poured onto the surface of the gel that was about to solidify. After the ethanol evaporated naturally, the surface of the gel was immobilized with fullerol TEGs-C. 60 Agarose gel, a deep eutectic solvent; (4) freeze-drying the gel prepared in (3) at -40°C and 0.1 Pa vacuum conditions to remove moisture; (5) The lyophilized gel was mixed with a 5.0 mg / mL ethanol solution of indomethacin or dexamethasone and adsorbed at room temperature in a shaker at 100 rpm; (6) The drug-loaded gel was removed, washed with deionized water, and air-dried at room temperature in an air stream to a constant weight; (7) Irradiate the drug-loaded gel with ultraviolet light for 10 minutes for sterilization, then punch, package, and seal for storage.

2. The electrically driven drug release fullerol-deep eutectic solvent-agarose composite gel according to claim 1, characterized in that: The solid-liquid ratio of agarose to deionized water in step (2) is 1:100 to 3:100 g / mL.

3. The fullerenol-deep eutectic solvent-agarose composite gel for electrically driven drug release according to claim 1, characterized in that: In the step (3), fullerene TEGs-C 60 Prepare a saturated ethanol solution at a mass ratio of 1:50 to 1:150 g / g with agarose.

4. The fullerenol-deep eutectic solvent-agarose composite gel for electrically driven drug release according to claim 1, characterized in that: In the step (5), the ethanol solution of indomethacin or dexamethasone is mixed with the gel at a liquid-to-solid ratio of 50:1 mL / g.

5. The fullerenol-deep eutectic solvent-agarose composite gel for electrically driven drug release according to claim 1, characterized in that: In the step (5), the adsorption time of the ethanol solution of indomethacin or dexamethasone on the gel is 12 to 24 hours.

Images