A viologen hydrogel / magnesium self-powered on-demand drug delivery device

Abstract

A viologen hydrogel / magnesium self-powered on-demand drug delivery device, belonging to the technical field of functional polymer materials. The present invention uses a drug-loaded viologen hydrogel prepared by free radical polymerization of double-bond functionalized viologen monomers, acrylamide monomers and N,N'-methylenebisacrylamide as the positive electrode of a biobattery, a magnesium bar as the negative electrode, and polyvinyl alcohol / phosphate buffered saline solution as a solid electrolyte to assemble and prepare an integrated self-powered on-demand drug delivery device, and apply it in the field of psoriasis treatment. The output voltage of the device is between 1.46 and 1.48 V. During use, the purpose of on-demand drug delivery is achieved by changing the resistance value of the load resistor, without the need for an additional power supply, and has great application potential in the field of psoriasis treatment.

Description

Technical Field

[0001] The invention belongs to the technical field of functional polymer materials, and in particular relates to a viologen hydrogel / magnesium self-powered on-demand drug delivery device. Background Art

[0002] The clinical treatment orientation of precision and personalized drug therapy has promoted the development of innovative stimulus-responsive drug delivery systems. External stimulus signals (i.e., temperature, light, electricity, magnetic field, and ultrasound) and internal stimulus signals (i.e., glucose and pH) trigger the stimulus-responsive system to release the loaded bioactive substances. Among various stimulus signals, electrical stimulation is one of the most promising stimulation methods. Accurate electrical signals can be generated repeatedly, remotely, and programmatically, and have great clinical application value. However, the energy systems currently used to generate electrical signals are mostly various commercial power supplies, but the solid structure of commercial power supplies limits the application of such energy systems in future remote control and smart wearable medical devices in time and space. Therefore, the concept of self-powered energy has received much attention. At present, self-powered drug delivery systems mostly use electrical energy generated by nanogenerators, biofuel cells, solar cells, and primary cells, without the need for external power supplies. As an energy device for drug release, the primary cell is a device that converts chemical energy into electrical energy. Among the above energy collection and conversion methods, it has the advantages of simple structure, easy to carry, and can be industrialized. A galvanic cell is usually composed of two different active metals or metals and other materials, with the negative electrode of the battery undergoing an oxidation reaction, while the positive electrode undergoes a reduction reaction after capturing electrons flowing in from an external circuit.

[0003] Viologens are a series of quaternary ammonium salts derived from 4,4-bipyridine. Their molecular structure determines that their electrochemical reduction process is accompanied by the removal of anions, so they can be potential carriers for the release of electrically active drugs. However, due to their well-known biological toxicity, the application of viologens in drug release is limited. Here, we prepared a new type of conductive drug-loaded viologen hydrogel by double-bond functionalized viologen monomers, and further designed and prepared a fully solid-state integrated self-powered device based on the principle of a primary cell, and applied it in the treatment of psoriasis, which is a common chronic inflammatory skin disease with a long course and easy recurrence. It is characterized by dry, thickened skin, erythema and scaling, and bacterial infection causes severe skin lesions, which brings great pain to patients. The self-powered on-demand drug delivery device prepared in this paper can output enough energy to maintain long-term, precise and controllable drug release, providing a new treatment for psoriasis that requires daily or precise drug delivery. Summary of the invention

[0004] The purpose of the present invention is to provide a drug-loaded viologen hydrogel prepared by free radical polymerization of double-bond functionalized viologen monomers, acrylamide monomers and N,N'-methylenebisacrylamide as the positive electrode of a biobattery, a magnesium bar as the negative electrode, and a polyvinyl alcohol / phosphate buffered saline solution as a solid electrolyte, to assemble and prepare an integrated self-powered on-demand drug delivery device, and apply it in the field of drug delivery. The output voltage of the device is between 1.46 and 1.48 V. The purpose of on-demand drug delivery is achieved by changing the resistance value of the load resistor during use, without the need for an additional power supply, and has great application potential in the field of drug delivery.

[0005] The present invention firstly utilizes 4,4-bipyridine and methyl iodide to obtain a methyl iodide-terminated viologen monomer through a Menshutkin reaction, and then reacts the methyl iodide-terminated viologen monomer with 4-vinylbenzyl chloride to prepare a double-bond functionalized viologen monomer; secondly, the double-bond functionalized viologen monomer, acrylamide and N,N'-methylenebisacrylamide are polymerized through a free radical reaction under the initiation of potassium persulfate and N,N,N',N'-tetramethylethylenediamine to form a viologen hydrogel network, and then dexamethasone sodium phosphate is placed in the viologen hydrogel as a model drug to obtain a drug-loaded viologen hydrogel; subsequently, polyvinyl alcohol is dissolved in a phosphate buffered saline solution, and a polyvinyl alcohol / phosphate buffered saline solution solid electrolyte is prepared through a freeze-thaw cycle method; finally, the drug-loaded viologen hydrogel, the polyvinyl alcohol / phosphate buffered saline solid electrolyte, a magnesium strip and polyester resin / indium tin oxide are assembled to obtain the self-powered on-demand drug delivery device of the present invention.

[0006] The preparation method of the self-powered on-demand drug delivery device of the present invention comprises the following steps:

[0007] (1) Synthesis of a methyl iodide-terminated viologen monomer as shown in the structural formula (II): methyl iodide and 4,4-bipyridine in a molar number 3 to 5 times that of methyl iodide are added to dichloromethane, the solid content of the reaction system is 10 to 20 wt%, heated to reflux, and then reacted for 40 to 60 hours; filtered, the obtained precipitate is washed with dichloroethane 3 to 5 times, and then dried in vacuum at 35 to 45° C. for 24 to 36 hours to obtain a methyl iodide-terminated viologen monomer soluble in an organic solvent;

[0008] (2) Synthesis of a double-bond functionalized viologen monomer having a structural formula (III): adding a viologen monomer terminated with methyl iodide and 1.5 to 3 times the amount of 4-vinylbenzyl chloride as the viologen monomer terminated with methyl iodide to N,N'-dimethylformamide, wherein the solid content of the reaction system is 10 to 20 wt%, heating to reflux, and then reflux reacting for 20 to 30 hours; filtering, washing the obtained precipitate with N,N'-dimethylformamide for 3 to 5 times and then with dichloromethane for 2 to 3 times, and then drying under vacuum at 35 to 45°C for 24 to 36 hours to obtain a double-bond functionalized viologen monomer;

[0009] (3) Dissolve 0.01-0.05 g of double-bond functionalized viologen monomer, 1.5-2 g of acrylamide and 0.025-0.05 g of N,N'-methylenebisacrylamide in 5-10 mL of deionized water, mix well, add 0.03-0.08 g of potassium persulfate and 40-80 µL of N,N,N',N'-tetramethylethylenediamine to the solution to initiate free radical polymerization, and react at room temperature for 0.5-2.0 hours to obtain a viologen hydrogel; place the obtained viologen hydrogel in deionized water to fully swell to remove unreacted monomers, and then place it in a 0.1-0.3 g / mL dexamethasone sodium phosphate aqueous solution, and after 24-48 hours, obtain a drug-loaded viologen hydrogel;

[0010] (4) Dissolve 5-10 g of polyvinyl alcohol in 100 mL of 0.01 M phosphate buffered saline solution, place the solution in a polytetrafluoroethylene mold with a length of 4 cm, a width of 3 cm, and a thickness of 1 cm, and then freeze it at -30-15°C for 3-6 hours, thaw it at room temperature for 20-40 minutes, and then freeze it again at -30-15°C for 3-6 hours; repeat the "freeze-thaw" operation 3-5 times, and after the last thawing, obtain a flexible polyvinyl alcohol / phosphate buffered saline solution solid electrolyte with a film thickness of 0.3 mm to 0.5 mm;

[0011] (5) Assembling the drug-loaded viologen hydrogel obtained in step (3), polyvinyl alcohol / phosphate buffered salt solid electrolyte, magnesium strip and polyester resin / indium tin oxide to obtain the self-powered on-demand drug delivery device of the present invention.

[0012] The specific assembly method is to first cut a visual window from the medical tape to facilitate observation of whether the device is working, attach a polyvinyl alcohol / phosphate buffer salt solid electrolyte to the adhesive side surface of the medical tape, and then place a magnesium strip and a commercial polyester resin / indium tin oxide substrate separately and parallel to each other on the polyvinyl alcohol / phosphate buffer salt solid electrolyte, and place the drug-loaded violaceous hydrogel on the polyester resin / indium tin oxide substrate; place a resistor on the non-adhesive side of the medical tape, and pass the metal wires at both ends of the resistor through the polyvinyl alcohol / phosphate buffer salt solid electrolyte to connect with the magnesium strip and the polyester resin / indium tin oxide substrate, thereby obtaining the self-powered on-demand drug delivery device described in the present invention.

[0013] Among them, the structural formula of the iodomethane-terminated viologen monomer is:

[0014]

[0015] (II)

[0016] The structural formula of the double-bond functionalized viologen monomer is:

[0017]

[0018] (III)

[0019] The structural formula of acrylamide is:

[0020]

[0021] (IV)

[0022] The structural formula of N,N'-methylenebisacrylamide is:

[0023]

[0024] (V)

[0025] The structural formula of dexamethasone sodium phosphate is:

[0026]

[0027] (VI) BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 : The NMR spectrum of the double-bond functionalized viologen monomer synthesized by the present invention;

[0029] Figure 2 : Infrared spectra of the drug-loaded viologen hydrogel (VH20) and polyacrylamide hydrogel (PAAm) synthesized by the present invention;

[0030] Figure 3: The drug loading diagram of the drug-loaded viologen hydrogel and polyacrylamide hydrogel synthesized by the present invention for dexamethasone sodium phosphate;

[0031] Figure 4 : Cyclic voltammetry curves of the drug-loaded viologen hydrogel synthesized by the present invention at different scan rates;

[0032] Figure 5 : Epidermal impedance test spectra of the drug-loaded viologen hydrogel and polyacrylamide hydrogel synthesized by the present invention;

[0033] Figure 6 : The biocompatibility bar graph of the drug-loaded viologen hydrogel synthesized by the present invention when the extraction concentration is 0.02g / mL, 0.04g / mL, 0.06g / mL, 0.08g / mL, and 0.1g / mL and co-cultured with mouse fibroblast L929 for 1, 2, and 3 days respectively;

[0034] Figure 7 : The volumes are 1 cm 3 , 2 cm 3 , 3cm 3 The bar graph of the antibacterial rate of the drug-loaded viologen hydrogel and Escherichia coli after co-culture for 24h, 48h, 72h, and 96h;

[0035] Figure 8 : The volumes are 1 cm 3 , 2 cm 3 , 3cm 3 The bar graph of the antibacterial rate of the drug-loaded viologen hydrogel and Staphylococcus aureus co-cultured for 24h, 48h, 72h, and 96h;

[0036] Fig. 9 : The discharge curve diagram of the self-powered on-demand drug delivery device prepared by the present invention when connected to different external resistors; the inset shows a photo of two self-powered on-demand drug delivery devices connected in series lighting up the light-emitting diodes.

[0037] Fig.10 : The standard curve of dexamethasone sodium phosphate in phosphate buffered saline solution involved in the present invention;

[0038] Fig.11 : The cumulative drug release amount and cumulative release efficiency curve within 3 hours when the self-powered on-demand drug delivery device prepared by the present invention is connected to different resistors;

[0039] Fig.12 : The drug cumulative release amount and cumulative release efficiency curve of the self-powered on-demand drug delivery device prepared by the present invention when a resistor with different resistance values ​​is connected every day for 30 minutes for 6 consecutive days;

[0040] Fig.13: The self-powered on-demand drug delivery device prepared by the present invention promotes the drug to penetrate into the pig skin when different external resistors are connected;

[0041] Fig.14 : A schematic diagram of the structure of the self-powered on-demand drug delivery device of the present invention;

[0042] Fig.15 : Skin tissue section image of a mouse model of psoriasis treated with the self-powered on-demand drug delivery device of the present invention.

[0043] like Figure 1 As shown, 1 H NMR (400 MHz, D 2 O) δ 9.10 (d, J = 6.9 Hz, 2H), 8.99 (d, J= 6.7 Hz, 2H), 8.47 (dd, J = 13.1, 6.7 Hz, 4H), 7.56 (d, J = 8.2 Hz, 2H), 7.45(d, J = 8.2 Hz, 2H), 6.77 (dd, J = 17.7, 11.0 Hz, 1H), 5.87 (t, J = 8.8Hz, 3H), 5.34 (d, J = 11.0 Hz, 1H), 4.70 (s, 12H), 4.44 (s, 3H). The proton signal peaks at 6.75 ppm, 5.80 ppmhe and 5.33 ppm correspond to the hydrogen on the double bond in the monomer, 8.47 ppm corresponds to the hydrogen on the benzene ring, 7.45-7.53 ppm and 8.95-9.13 ppm correspond to the hydrogen on the pyridine ring in the viologen unit, 7.70-6.30 ppm corresponds to the hydrogen on the benzene ring, and 5.82 ppm corresponds to the -CH 2 -, and 4.48 ppm is -CH 3 .

[0044] like Figure 2 As shown, 3245 cm -1 It is the stretching vibration absorption peak of the CH bond on the pyridine ring. 1650 cm -1 Vibration absorption peak of C=C bond in benzene ring and pyridine ring. 625 cm -1 It is the characteristic absorption peak of the CH bond on the benzene ring.

[0045] like Figure 3As shown, the prepared drug-loaded viologen hydrogel and polyacrylamide hydrogel were placed in deionized water to fully swell to remove unreacted monomers, and then placed in a freeze dryer to fully dry to obtain a freeze-dried hydrogel sample. 1 g of the freeze-dried hydrogel sample was accurately weighed and placed in a phosphate buffered saline solution of dexamethasone sodium phosphate. After 24 hours, the hydrogel was placed in deionized water to remove free drugs. The hydrogel sample was then freeze-dried again and digested with a mixed solution of hydrochloric acid and nitric acid. The volume ratio of the mixed solution was V(HCL):V(HNO 3 )=1:3. After complete digestion, the drug loading of the hydrogel was determined by measuring the phosphoric acid content in the solution through plasma coupled spectroscopy. The drug loading of the polyacrylamide hydrogel was calculated to be 1.81 mg / g, and the drug loading of the viologen hydrogel was 7.16 mg / g.

[0046] like Figure 4 The cyclic voltammetry curves of the drug-loaded viologen hydrogel at different scan rates. A three-electrode system was adopted, with the Ag / AgCl electrode as the reference electrode, the platinum electrode as the counter electrode, the drug-loaded viologen hydrogel / ITO electrode as the working electrode, and the electrolyte solution being a 0.01M phosphate buffered saline solution. The cyclic voltammetry curves of the drug-loaded viologen hydrogel at scan rates of 20mV / s, 40mV / s, 60mV / s, 80mV / s, and 100mV / s were tested by an electrochemical workstation. It can be seen from the curve that the drug-loaded viologen hydrogel has two pairs of redox peaks, corresponding to the two redox processes of viologen. In addition, it can be seen that the viologen hydrogel electrode is controlled by a diffusion process.

[0047] like Figure 5 As shown in FIG. 1 , a circular hydrogel sample with a diameter of 1 cm was first prepared and placed under a commercial ECG electrode sheet, wherein the center distance between two circular ECG electrodes was 5 cm. A two-electrode system was used with a scanning frequency of 10 5 ~10 0 The skin impedance value. It can be seen from the figure that at a frequency of 10 0 The epidermal impedance of polyacrylamide hydrogel was 2.6×10 6 Ω, the epidermal impedance of the drug-loaded viologen hydrogel was 4.8×10 5 Ω.

[0048] like Figure 6As shown, the prepared drug-loaded violet hydrogel was placed in DMEM culture medium for extraction, and the extract was diluted with DMEM culture medium in proportion to obtain hydrogel extracts with concentrations of 0.02g / mL, 0.04g / mL, 0.06g / mL, 0.08g / mL, and 0.1g / mL. Mouse fibroblasts were cultured with the hydrogel extract, and the biocompatibility of the hydrogel was obtained by MTT test. The analysis showed that with the increase of the extract concentration, the cell viability value gradually decreased, but the overall value remained above 90%, and with the increase of the number of culture days, the cell viability value remained basically unchanged, which shows that the drug-loaded violet hydrogel has excellent biocompatibility and has no obvious inhibitory effect on cell proliferation.

[0049] like Figure 7 As shown in the figure, it can be seen that as the volume of the drug-loaded viologen hydrogel increases, the ability to inhibit the proliferation of E. coli gradually increases. Among them, the inhibitory effect of the drug-loaded viologen hydrogel on E. coli is most significant after 24 hours of co-culture. As the number of culture days increases, E. coli proliferates, which is in line with the normal proliferation law of E. coli.

[0050] like Figure 8 As shown in the figure, the antibacterial rate is the ratio of the absorbance of the co-culture solution of the drug-loaded violet hydrogel and bacteria to the absorbance of the control group. It can be seen from the figure that as the volume of the drug-loaded violet hydrogel increases, the inhibitory ability to the proliferation of Staphylococcus aureus gradually increases. Among them, the inhibitory effect of the drug-loaded violet hydrogel on Staphylococcus aureus is most significant after 24 hours of co-culture. With the increase of the number of culture days, Staphylococcus aureus proliferates, which is in line with the normal proliferation law of bacteria.

[0051] like Fig. 9 As shown, it can be seen from the figure that the open circuit voltage of the device prepared by the present invention is about 1.5V. As the resistance value of the external resistor increases, the output current of the device gradually decreases, the speed at which the drug-loaded violet hydrogel inside the device is reduced decreases, and the discharge time gradually becomes longer. It shows that the reduction speed of the drug-loaded violet hydrogel can be controlled by changing the resistance, thereby controlling the drug release rate and dosage of the device to achieve the effect of on-demand drug administration. Because the drug-loading mechanism of the drug-loaded violet hydrogel is that the positively charged violet and the anionic drug molecules are combined through electrostatic interaction, when the violet is reduced to 0 valence under the action of electric current, the binding force between the drug molecules and the violet is reduced, and the drug molecules overflow from the drug-loaded violet hydrogel through diffusion, achieving the effect of electrically stimulated drug controlled release. The internal illustration is a photo of a red light-emitting diode that lights up after two devices are connected in series and output a voltage of 3V.

[0052] like Fig.10As shown, 2.5µg / mL, 5µg / mL, 7.5µg / mL, 10µg / mL, 15µg / mL, 20µg / mL, 25µg / mL, and 50µg / mL of dexamethasone sodium phosphate standard solutions were accurately prepared, the absorbance of the standard solutions at 242nm was tested by UV-visible spectrophotometer, and the standard curve y=0.0304x-0.0417 was obtained by calculation (y represents the absorbance of the standard solution at 242nm, and x represents the concentration of the dexamethasone sodium phosphate solution).

[0053] like Fig.11 As shown in the figure, it can be seen that when the resistance values ​​are 10 2 Ω, 10 3 Ω, 10 4 Ω and natural release (Diffusion), through Fig.10 The standard curve of dexamethasone sodium phosphate is used to calculate the cumulative release of the drug by the absorbance of the solution at 242nm. After calculation, the cumulative release of the drug was 2.69 mg / g, 1.85 mg / g, 0.91 mg / g and 0.5 mg / g, respectively. The cumulative release efficiency of the drug is the ratio of the cumulative release of the drug to the drug loading of the hydrogel. The cumulative release efficiency of the drug loaded with violaceum hydrogel was calculated to be 37.57%, 25.84%, 12.71% and 6.98%, respectively. Analysis of the data shows that as the resistance of the external resistor gradually increases, the drug release gradually decreases within 3 hours.

[0054] like Fig.12 As shown in the figure, it can be seen that the device is connected to 10 1 Ω, 10 2 Ω, 10 3 After half an hour, the cumulative release of the drug after 6 consecutive days was 6.38 mg / g, 5.10 mg / g and 3.36 mg / g, respectively, and the cumulative release efficiency of the drug was 89.11%, 71.23% and 46.93%, respectively. The cumulative working time of the device is 3 hours, but the cumulative efficiency is much higher than the cumulative release efficiency of 3 consecutive hours. This is because the violet hydrogel is reduced when connected for half an hour every day, and the current of the battery gradually decreases. However, as the device is left alone, the reduced violet hydrogel is oxidized by oxygen in the air again, and the open circuit voltage of the device returns to the initial value, resulting in the cumulative release efficiency of the drug within 6 days being much greater than the cumulative release efficiency of 3 consecutive hours.

[0055] like Fig.13As shown, the device prepared by the present invention is attached to the surface of fresh pig skin and connected to different resistors. After 3 hours, the residual drug on the surface of the pig skin is simply rinsed, and then the pig skin is chopped and placed in a phosphate buffered saline solution. After soaking for 24 hours, the transdermal drug amount is measured and calculated using a UV-visible spectrophotometer. Through analysis, it is found that as the resistance value gradually increases, the transdermal drug amount of the device gradually decreases. This is because after the resistance increases, the current output by the device gradually decreases, resulting in a decrease in the transdermal drug amount.

[0056] like Fig.14 As shown, firstly, a visual window is cut out of the medical tape, and a polyvinyl alcohol / phosphate buffer salt solid electrolyte is attached to the adhesive side surface of the medical tape. Then, a magnesium strip and a commercial polyester resin / indium tin oxide substrate are placed separately and parallel to each other on the polyvinyl alcohol / phosphate buffer salt solid electrolyte, and a drug-loaded viologen hydrogel is placed on the polyester resin / indium tin oxide substrate; a resistor is placed on the non-adhesive side of the medical tape, and the metal wires at both ends of the resistor are passed through the polyvinyl alcohol / phosphate buffer salt solid electrolyte and connected to the magnesium strip and the polyester resin / indium tin oxide substrate, thereby obtaining the self-powered on-demand drug delivery device of the present invention.

[0057] like Fig.15 As shown, 20 mice were first randomly divided into 5 groups, with 4 mice in each group. Except for the normal skin group, the other mice were smeared with 5% imiquimod cream on the back of the mice every day, and the psoriasis mouse model was obtained after 6 days. Except for the normal skin group and the psoriasis model group, the other three groups were treated with dexamethasone sodium phosphate solution (0.5 mg / mL, 0.1mL), drug-loaded violet hydrogel and self-powered on-demand drug delivery device, respectively, and the treatment time was 1 hour per day. After 5 days of treatment, photos of the skin tissue sections of the mice were obtained. The photos show that the epidermal thickness of the mice treated with the self-powered on-demand drug delivery device returned to normal, the inflammatory cells decreased, and the scales disappeared. Compared with the dexamethasone sodium phosphate solution group and the drug-loaded violet hydrogel group, the self-powered on-demand drug delivery device showed the best therapeutic effect during the 5-day treatment time. DETAILED DESCRIPTION

[0058] Example 1

[0059] (1) Synthesis of a viologen monomer terminated with iodomethane as shown in the structural formula (II): iodomethane (2 mmol) and 4,4-bipyridine (3 times the molar number of iodomethane) were added to 50 mL of dichloromethane, the solid content of the reaction system was 15 wt%, heated to reflux, and then refluxed for 48 hours. Filtered, the precipitate was washed with dichloromethane 4 times and then dried in a vacuum oven at 40°C for 24 hours to obtain an iodomethane-terminated viologen diamine monomer soluble in an organic solvent, with a yield of 77%.

[0060] (2) Synthesis of a double-bond functionalized viologen monomer having a structural formula (III): iodomethane-terminated viologen monomer (2 mmol) and 4-vinylbenzyl chloride (3 times the molar amount of the iodomethane-terminated viologen diamine monomer) were added to 50 mL of N,N'-dimethylformamide. The solid content of the reaction system was 15 wt%, and the mixture was heated to reflux and then refluxed for 24 hours. The precipitate was filtered, washed with N,N'-dimethylformamide 4 times and then with dichloromethane 3 times, and then dried in a vacuum oven at 40°C for 24 hours to obtain a double-bond functionalized viologen monomer with a yield of 49%.

[0061] (3) 0.045 g of double-bond functionalized viologen monomer, 1.80 g of acrylamide, and 0.035 g of N, N-methylenebisacrylamide were dissolved in 10 mL of deionized water. After mixing evenly, 60 µL of N, N, N', N'-tetramethylethylenediamine and 0.06 g of potassium persulfate were added to the solution to initiate polymerization. After reacting at room temperature for 1 hour, viologen hydrogel was formed. For comparison purposes, 1.80 g of acrylamide and 0.035 g of N,N'-methylenebisacrylamide was dissolved in 10 mL of deionized water, and after being mixed evenly, 60 µL of N,N,N',N'-tetramethylethylenediamine and 0.06 g of potassium persulfate were added to the solution to initiate polymerization. After reacting at room temperature for 1 hour, a polyacrylamide hydrogel without double-bond functionalized viologen monomers was formed; the obtained viologen hydrogel was placed in deionized water to fully swell to remove unreacted monomers, and then placed in a 0.2 g / mL dexamethasone sodium phosphate aqueous solution, and after 36 hours, a drug-loaded viologen hydrogel was obtained; the obtained polyacrylamide hydrogel was placed in deionized water to fully swell to remove unreacted monomers, and then placed in a 0.2 g / mL dexamethasone sodium phosphate aqueous solution, and after 36 hours, a drug-loaded polyacrylamide hydrogel was obtained;

[0062] (4) 8 g of polyvinyl alcohol was dissolved in 100 mL of 0.01 M phosphate buffered saline solution, and the solution was placed in a polytetrafluoroethylene mold with a length of 4 cm, a width of 3 cm, and a thickness of 1 cm, and then frozen at -20°C for 3 hours. After thawing at room temperature for 20 minutes, the solution was frozen again at -20°C for 3 hours. After repeating the "freeze-thaw" operation 3 times, a flexible polyvinyl alcohol / phosphate buffered saline solution solid electrolyte with a film thickness of 0.3 mm was obtained after the last thawing.

[0063] (5) The drug-loaded viologen hydrogel, polyvinyl alcohol / phosphate buffer salt solid electrolyte, magnesium strip and polyester resin / indium tin oxide obtained in step (3) are assembled as shown in Figure (I) to obtain the self-powered on-demand transdermal drug delivery device of the present invention. The specific assembly method is to first cut a visual window from the medical tape, attach the polyvinyl alcohol / phosphate buffer salt solid electrolyte to the adhesive side of the medical tape, then place the magnesium strip and the commercial polyester resin / indium tin oxide substrate separately and parallel to each other on the polyvinyl alcohol / phosphate buffer salt solid electrolyte, and place the drug-loaded viologen hydrogel on the polyester resin / indium tin oxide substrate; the resistor is placed on the non-adhesive side of the medical tape, and the metal wires at both ends of the resistor are passed through the polyvinyl alcohol / phosphate buffer salt solid electrolyte and connected to the magnesium strip and the polyester resin / indium tin oxide substrate, thereby obtaining the self-powered on-demand drug delivery device of the present invention.

Claims

1. A viologen hydrogel / magnesium self-powered on-demand drug delivery device, which is prepared by the following steps: Synthesis of a viologen monomer terminated by iodomethane as shown in the structural formula (II): adding iodomethane and 4,4-bipyridine whose molar number is 3 to 5 times that of iodomethane to dichloromethane, the solid content of the reaction system is 10 to 20 wt%, heating to reflux, and then reacting for 40 to 60 hours; filtering, washing the obtained precipitate with dichloroethane for 3 to 5 times, and drying it in vacuum at 35 to 45° C. for 24 to 36 hours to obtain a viologen monomer terminated by iodomethane soluble in an organic solvent; Synthesis of a double-bond functionalized viologen monomer having a structural formula (III): adding a viologen monomer terminated with methyl iodide and 1.5 to 3 times the amount of 4-vinylbenzyl chloride of the viologen monomer terminated with methyl iodide to N,N'-dimethylformamide, wherein the solid content of the reaction system is 10 to 20 wt%, heating to reflux, and then reflux reaction for 20 to 30 hours; filtering, washing the obtained precipitate with N,N'-dimethylformamide for 3 to 5 times and then with dichloromethane for 2 to 3 times, and then drying under vacuum at 35 to 45°C for 24 to 36 hours to obtain a double-bond functionalized viologen monomer; 0.01-0.05 g of double-bond functionalized viologen monomer, 1.5-2 g of acrylamide and 0.025-0.05 g of N,N'-methylenebisacrylamide were dissolved in 5-10 mL of deionized water, and after being evenly mixed, 0.03-0.08 g of potassium persulfate and 40-80 µL of N,N,N',N'-tetramethylethylenediamine were added to the solution to initiate free radical polymerization, and the reaction was carried out at room temperature for 0.5-2.0 hours to obtain a viologen hydrogel; the obtained viologen hydrogel was placed in deionized water to fully swell to remove unreacted monomers, and then placed in a 0.1-0.3 g / mL dexamethasone sodium phosphate aqueous solution, and the drug-loaded viologen hydrogel was obtained after 24-48 hours; The structural formula of the iodomethane-terminated viologen monomer is: （Ⅱ） The structural formula of the double-bond functionalized viologen monomer is: （Ⅲ） The structural formula of acrylamide is: （Ⅳ） The structural formula of N,N'-methylenebisacrylamide is: （Ⅴ） The structural formula of dexamethasone sodium phosphate is: （Ⅵ） Dissolve 5-10 g of polyvinyl alcohol in 100 mL of 0.01 M phosphate buffered saline solution, put the solution into a polytetrafluoroethylene mold, and then freeze it at -30-15°C for 3-6 hours, thaw it at room temperature for 20-40 minutes, and then freeze it again at -30-15°C for 3-6 hours; repeat the "freeze-thaw" operation 3-5 times, and after the last thawing, obtain a flexible polyvinyl alcohol / phosphate buffered saline solution solid electrolyte with a film thickness of 0.3 mm to 0.5 mm; The drug-loaded viologen hydrogel obtained in step (3), polyvinyl alcohol / phosphate buffer salt solid electrolyte, magnesium strip, polyester resin / indium tin oxide and resistor are assembled, and the purpose of on-demand drug delivery is achieved by changing the resistance value of the load resistor, thereby obtaining a self-powered on-demand drug delivery device.

2. A viologen hydrogel / magnesium self-powered on-demand drug delivery device as claimed in claim 1, characterized in that: A polyvinyl alcohol / phosphate buffer salt solid electrolyte is attached to the adhesive side surface of a medical tape, a magnesium strip and a commercial polyester resin / indium tin oxide substrate are placed separately and parallel to each other on the polyvinyl alcohol / phosphate buffer salt solid electrolyte, and a drug-loaded violet hydrogel is placed on the polyester resin / indium tin oxide substrate; a resistor is placed on the non-adhesive side of the medical tape, and metal wires at both ends of the resistor are passed through the polyvinyl alcohol / phosphate buffer salt solid electrolyte and connected to the magnesium strip and the polyester resin / indium tin oxide substrate respectively, thereby obtaining a self-powered on-demand drug delivery device.

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