Intelligent drug delivery system based on hydrogel microneedle, preparation method and application

Abstract

The invention provides an intelligent drug delivery system based on a hydrogel microneedle, a preparation method and application, and belongs to the technical field of biomedical materials and drug delivery, the intelligent drug delivery system comprises a flexible sensing substrate layer and a drug loading needle layer, the drug loading needle layer comprises a needle matrix and a loaded drug, and the loaded drug is a compound of fibroin and a drug. According to the intelligent drug delivery system based on the hydrogel microneedle, the preparation method and the application, the microneedle penetrates through the stratum corneum to directly deliver drugs, the drug release rate is controlled through the applied voltage value, meanwhile, the release process is fed back through the resistance change of the base plate, the drugs are loaded into silk protein and evenly dispersed in the hydrogel microneedle, and the drug delivery efficiency is improved. By utilizing excellent biocompatibility and high hydration capability of the hydrogel, long-acting slow release and intelligent monitoring of the medicine are realized, and the hydrogel is suitable for treating chronic skin diseases such as atopic dermatitis and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedical materials and drug delivery, and in particular relates to an intelligent drug delivery system based on hydrogel microneedles, a preparation method, and an application. Background Art

[0002] Atopic dermatitis (AD) is a common chronic inflammatory skin disease, characterized by dry skin, itching, and recurrent eczematous skin lesions. However, traditional drug delivery methods such as oral administration or topical application have problems such as low drug bioavailability and short action time. Summary of the Invention

[0003] The purpose of the present invention is to provide an intelligent drug delivery system based on hydrogel microneedles, a preparation method, and an application. By introducing an electrically sensitive substrate (containing Ca 2+ crosslinking), microcurrent sensing is realized to monitor the drug release dynamics in real time. At the same time, a silk fibroin-polyvinyl alcohol composite hydrogel is combined to optimize the drug loading efficiency and mechanical properties, achieving the dual goals of long-term treatment and intelligent regulation. By optimizing the microneedle structure design, improving the drug loading efficiency, and introducing an intelligent monitoring function, the problems of low drug utilization rate, short action time, and lack of real-time feedback in traditional therapies are solved, providing an efficient and safe treatment plan for atopic dermatitis. The substrate layer is composed of polyacrylamide, carboxymethyl cellulose, calcium ion solution, ammonium persulfate, and polydopamine, and has good stretchability and sensing performance. The needle layer is prepared by dissolving polyvinyl alcohol and reduced graphene oxide in dimethyl sulfoxide, and has good mechanical properties and electrical stimulation responsiveness, and can penetrate the human skin.

[0004] To achieve the above object, the present invention provides an intelligent drug delivery system based on hydrogel microneedles, including a flexible sensing substrate layer and a drug-loaded needle layer. The drug-loaded needle layer includes a needle matrix and a loaded drug. The loaded drug is a complex of silk fibroin and a drug. The drug release rate is controlled by the applied voltage value, and the drug release process is real-time feedback by monitoring the resistance change of the flexible sensing substrate layer.

[0005] Preferably, the composition of the flexible sensing substrate layer is in a weight ratio of: 20 parts of polyacrylamide, 1 - 3 parts of carboxymethyl cellulose, 1 - 3 parts of calcium ion solution, 2 parts of ammonium persulfate, 1 - 2 parts of polydopamine, and 80 parts of deionized water; The composition of the drug-loaded needle layer is in a weight ratio of: 15 parts of polyvinyl alcohol, 1 - 3 parts of reduced graphene oxide, 60 parts of dimethyl sulfoxide, and 5 - 15 parts of silk fibroin-SINH complex.

[0006] Preferably, the polyacrylamide can also be replaced by one or more of polyvinyl alcohol and sodium alginate; The calcium ion solution can also be replaced by a sodium ion solution; The ammonium persulfate can also be replaced by one or more of N, N'-methylenebisacrylamide and tetramethylethylenediamine; The polydopamine or carboxymethyl cellulose can also be replaced by polyvinyl alcohol; The reduced graphene oxide can also be replaced by carbon nanotubes or metal nanoparticles; The dimethyl sulfoxide can also be replaced by polyethylene glycol or choline-glycerol eutectic solvent.

[0007] Preferably, in the drug-loaded needle layer, the loading rate of the loaded drug is 20% to 60%, and the sustained-release time of the loaded drug is not less than 48 hours.

[0008] Preferably, the tensile strain rate of the flexible sensing substrate layer exceeds 200%, the resistance change range is 10Ω~1000Ω, the substrate layer thickness range is 50~200 microns, the needle height range is 300~800 microns, and the single-needle diameter range is 50~200 microns.

[0009] Preferably, the drug can also be replaced by any one of betamethasone, calcipotriol, tacrolimus, and sinomenine hydrochloride.

[0010] A preparation method of an intelligent drug delivery system based on hydrogel microneedles includes Flexible sensing substrate layer: Mix polyacrylamide, carboxymethyl cellulose, calcium ion solution, ammonium persulfate, and polydopamine in proportion, and crosslink to form a flexible sensing substrate; Drug-loaded needle layer: Dissolve polyvinyl alcohol and reduced graphene oxide in dimethyl sulfoxide, blend with silk fibroin-drug complex, inject into a microneedle mold for curing, and demold to obtain the drug-loaded needle layer; System assembly: Composite the drug-loaded needle layer and the flexible sensing substrate layer through the adhesion mediated by polydopamine.

[0011] Application of the intelligent drug delivery system in the preparation of drugs for treating atopic dermatitis.

[0012] Preferably, the intelligent drug delivery system significantly alleviates skin dryness, erythema, and epidermal thickening symptoms by maintaining the skin moist environment, real-time monitoring the drug release process, and adjusting the drug release rate accordingly.

[0013] Therefore, the present invention adopts the above-mentioned intelligent drug delivery system, preparation method, and application based on hydrogel microneedles, and the technical effects are as follows: (1) Efficient drug delivery: The microneedles penetrate the stratum corneum and directly deliver the drug to the dermis layer, and the bioavailability is increased to more than 3 times that of traditional patches.

[0014] (2)Controlled drug release: The polyvinyl alcohol-reduced graphene oxide composite hydrogel can continuously release drugs for more than 48 hours without applying voltage to maintain the effective blood drug concentration; after applying voltage, with the increase of the voltage value, the drug release rate accelerates.

[0015] (3)Intelligent monitoring: The change of the substrate resistance can feedback the drug release amount in real time, and patients can obtain the treatment progress through a portable device.

[0016] (4)Skin friendliness: The high water content (>90%) of the hydrogel can maintain the skin moist and relieve the dry symptoms of AD patients; polydopamine enhances the adhesion to avoid frequent replacement. Description of the Drawings

[0017] Figure 1 It is the linear relationship between the absorbance and concentration of SINH at a wavelength of 264 nm; Figure 2 It is the tensile-fracture curve of the substrate hydrogel prepared in Example 2 at a tensile speed of 20 mm / min. Detailed Embodiments

[0018] The technical solutions of the present invention will be further described below with reference to the drawings and embodiments.

[0019] Unless otherwise defined, the technical terms or scientific terms used in the present invention should have the ordinary meanings understood by those of ordinary skill in the field to which the present invention belongs.

[0020] Each drug will be described below by way of examples.

[0021] Example 1 The raw material ratio (parts by weight) of an intelligent drug delivery system based on hydrogel microneedles: Flexible sensing substrate layer: 20 parts of polyacrylamide, 1-3 parts of carboxymethyl cellulose, 1-3 parts of calcium chloride, 2 parts of ammonium persulfate, 1-2 parts of polydopamine, 80 parts of deionized water.

[0022] Drug-loaded needle layer: 15 parts of polyvinyl alcohol, 60 parts of dimethyl sulfoxide, 5-15 parts of silk fibroin-SINH complex.

[0023] A preparation method of an intelligent drug delivery system based on hydrogel microneedles, comprising the following steps: 1) Dissolve polyacrylamide and carboxymethyl cellulose in water, and add calcium chloride and stir until completely dissolved.

[0024] 2) Add ammonium persulfate to initiate free radical polymerization, and then dropwise add the polydopamine solution and crosslink at room temperature.

[0025] 3) Dialyze to remove unreacted monomers, and obtain a flexible sensing substrate after drying.

[0026] 4) Dissolve polyvinyl alcohol in dimethyl sulfoxide and stir at 60 °C until a transparent colloid is obtained.

[0027] 5) Add the silk fibroin-SINH complex and disperse it evenly by ultrasonic treatment.

[0028] 6) Inject it into a polydimethylsiloxane (PDMS) microneedle mold, irradiate it with a 365 nm ultraviolet lamp, and cure and demold it at room temperature.

[0029] 7) System assembly: Composite the needle layer and the substrate layer through the adhesion mediated by polydopamine.

[0030] Drug release test Drug loading and release mechanism 1) SINH is loaded onto the silk fibroin network through hydrogen bonding and hydrophobic interaction, and the polyvinyl alcohol hydrogel regulates the sustained release of the drug through the swelling-diffusion mechanism.

[0031] 2) Ca 2+ The change in the resistance of the crosslinked substrate is linearly correlated with the drug release amount, and the release dynamics are monitored in real time through microcurrent sensing.

[0032] In vitro simulation: Attach the system to ex vivo porcine skin, and it is detected that the SINH release amount reaches 85% in 48 hours, and the correlation coefficient R between the resistance change and the release amount 2 = 0.98.

[0033] Ca 2+ Monitoring mechanism for the resistance change of the crosslinked substrate: The dynamic ion crosslinked network formed by carboxymethyl cellulose (CMC) and Ca 2+ endows the substrate with sensing performance. When the drug is released, the swelling of the gel causes the distance between crosslinking points to increase, and the ion migration path length and impedance change, resulting in a change in the overall resistance. The resistance change is detected in real time through microcurrent sensing, and it has a linear relationship with the release amount (R 2 = 0.98, see Example 1).

[0034] Animal experiment: After 15 days of using the product of Example 1 on AD model mice, the erythema and epidermal thickening were significantly reduced, and the curative effect was better than that of the traditional cream group (p < 0.01).

[0035] Example 2 Raw material ratio (parts by weight) of an intelligent drug delivery system based on hydrogel microneedles: Flexible sensing substrate layer: 20 parts of polyacrylamide, 1 - 3 parts of carboxymethyl cellulose, 1 - 3 parts of calcium chloride, 2 parts of ammonium persulfate, 1 - 2 parts of polydopamine, 80 parts of deionized water.

[0036] Drug-loaded needle layer: 15 parts of polyvinyl alcohol, 1 - 3 parts of reduced graphene oxide, 60 parts of dimethyl sulfoxide, 5 - 15 parts of silk fibroin-SINH complex.

[0037] A preparation method of an intelligent drug delivery system based on hydrogel microneedles, comprising the following steps: 1) Dissolve polyacrylamide and carboxymethyl cellulose in water, add calcium chloride and stir until completely dissolved.

[0038] 2) Add ammonium persulfate to initiate free radical polymerization, then dropwise add polydopamine solution and crosslink at room temperature.

[0039] 3) Dialyze to remove unreacted monomers, and obtain a flexible sensing substrate after drying.

[0040] 4) Dissolve polyvinyl alcohol and reduced graphene oxide in dimethyl sulfoxide, and stir at 60 °C until a transparent colloid is obtained.

[0041] 5) Add silk fibroin-SINH complex and disperse evenly by ultrasonic wave.

[0042] 6) Inject into a polydimethylsiloxane (PDMS) microneedle mold, cure at room temperature after irradiation with a 365 nm ultraviolet lamp, and demold.

[0043] 7) System assembly: Composite the needle layer and the substrate layer through the adhesion mediated by polydopamine.

[0044] Drug release test Divide the hydrogel microneedles prepared by the method in this example into 3 groups, and measure the average concentration of sinomenine hydrochloride released by an electrochemical workstation without applying electrical stimulation, applying 1 V voltage and 3 V voltage respectively. The experimental results are shown in Table 1.

[0045] rGO electric field response control mechanism: Reduced graphene oxide (rGO) has good conductivity and charge response characteristics. When an external voltage is applied, the π-electrons in its sheet structure will rearrange in response to the electric field, thereby promoting the migration of surrounding ions. In the hydrogel system, this electric field drive enhances the movement rate of ions in the hydration channels, accelerates gel swelling and drug diffusion; at the same time, electrical stimulation can also cause the silk fibroin molecular chains to relax, reduce the hydrogen bond or hydrophobic interaction between the drug and the carrier, and make sinomenine hydrochloride (SINH) easier to release; the drug release curve shows that under the conditions of 0 V, 1 V, and 3 V, the cumulative drug release amounts in 48 hours are 84.8%, 88.5%, and 91.7% respectively, showing obvious voltage dependence, as shown in Table 1.

[0046] Table 1 Influence of voltage stimulation on drug release rate ;

[0047] Example 3 Treat eczema patients with the hydrogel microneedles prepared by the method in Example 2: 500 eczema patients: 470 cases were cured, 83 cases showed marked improvement, 22 cases were effective, and 3 cases were ineffective. The healing time was within 9 days for 460 cases, within 7 days for 399 cases, within 5 days for 286 cases, and within 3 days for 198 cases.

[0048] Example 4

[0049] Raw material ratio (parts by weight) of an intelligent drug delivery system based on hydrogel microneedles: Flexible sensing substrate layer: 20 parts of polyacrylamide, 1 - 3 parts of carboxymethyl cellulose, 1 - 3 parts of calcium chloride, 2 parts of ammonium persulfate, 1 - 2 parts of polydopamine, 80 parts of deionized water.

[0050] Drug - loaded needle layer: 15 parts of polyvinyl alcohol, 1 part of reduced graphene oxide, 60 parts of dimethyl sulfoxide, 5 - 15 parts of silk fibroin - betamethasone.

[0051] According to the above raw material ratio, prepare the drug delivery system by using the same preparation method of an intelligent drug delivery system based on hydrogel microneedles as in Example 2.

[0052] Drug release test Drug loading and release mechanism 1) Betamethasone is loaded into the silk fibroin network through hydrophobic interaction, and the polyvinyl alcohol hydrogel regulates the sustained release of the drug through the swelling - diffusion mechanism.

[0053] 2) The resistance change of the Ca 2+ cross - linked substrate is linearly correlated with the drug release amount, and the release dynamics are monitored in real - time through micro - current sensing.

[0054] In vitro simulation: Attach the system to ex vivo porcine skin. It is detected that the drug release amount is 25% at 6 h, 63% at 24 h, and 81% at 48 h. After applying 3 V, the drug release amount at 48 h is increased to 92%. At the same time, the correlation coefficient R between the resistance change and the betamethasone release amount is measured 2 = 0.97.

[0055] Animal experiment: After 14 days of using the product in Example 4 on AD model mice, the erythema and epidermal thickening were significantly reduced, and the curative effect was better than that of the traditional betamethasone cream group (p < 0.01).

[0056] Example 5

[0057] Raw material ratio (parts by weight) of an intelligent drug delivery system based on hydrogel microneedles: Flexible sensing substrate layer: 20 parts of polyacrylamide, 1 - 3 parts of carboxymethyl cellulose, 1 - 3 parts of calcium chloride, 2 parts of ammonium persulfate, 1 - 2 parts of polydopamine, 80 parts of deionized water.

[0058] Drug-loaded needle layer: 15 parts of polyvinyl alcohol, 1 part of reduced graphene oxide, 60 parts of dimethyl sulfoxide, 5 - 15 parts of silk fibroin-calcipotriol.

[0059] According to the above raw material ratio, a drug delivery system is prepared by using the same preparation method of an intelligent drug delivery system based on hydrogel microneedles as in Example 2.

[0060] Drug release test Drug loading and release mechanism 1) Calcipotriol binds to silk fibroin through hydrogen bonds, and the polyvinyl alcohol hydrogel regulates the sustained release of drugs through a swelling-diffusion mechanism.

[0061] 2) Ca 2+ The resistance change of the cross-linked substrate is linearly correlated with the drug release amount, and the release dynamics are monitored in real time through microcurrent sensing.

[0062] In vitro simulation: The system is attached to ex vivo porcine skin, and the drug release amounts are detected as 18% at 6 h, 47% at 24 h, and 67% at 48 h. After applying 3 V, the drug release amount at 48 h is increased to 82%. At the same time, the correlation coefficient R between the resistance change and the calcipotriol release amount is measured 2 = 0.98.

[0063] Cell experiment: After HaCaT keratinocytes are exposed to high-dose TNF-α, the slow release of calcipotriol from the microneedles can significantly reduce the expression of inflammatory factors IL-6 and IL-8, indicating good anti-inflammatory effects.

[0064] Example 6

[0065] The raw material ratio (parts by weight) of an intelligent drug delivery system based on hydrogel microneedles: Flexible sensing substrate layer: 20 parts of polyacrylamide, 1 - 3 parts of carboxymethyl cellulose, 1 - 3 parts of calcium chloride, 2 parts of ammonium persulfate, 1 - 2 parts of polydopamine, 80 parts of deionized water.

[0066] Drug-loaded needle layer: 15 parts of polyvinyl alcohol, 1 part of reduced graphene oxide, 60 parts of dimethyl sulfoxide, 5 - 15 parts of silk fibroin-tacrolimus.

[0067] According to the above raw material ratio, a drug delivery system is prepared by using the same preparation method of an intelligent drug delivery system based on hydrogel microneedles as in Example 2.

[0068] Drug release test Drug loading and release mechanism 1) Tacrolimus binds to silk fibroin through electrostatic interaction, and the polyvinyl alcohol hydrogel regulates the sustained release of drugs through a swelling-diffusion mechanism.

[0069] 2) Ca2+ The resistance change of the cross-linked substrate is linearly correlated with the drug release amount, and the release dynamics are monitored in real time through microcurrent sensing.

[0070] In vitro simulation: The system was attached to ex vivo porcine skin, and the drug release amounts were detected as 23% at 6 h, 53% at 24 h, and 79% at 48 h. After applying 3 V, the drug release amount at 48 h increased to 87%. At the same time, the correlation coefficient R between the resistance change and the tacrolimus release amount was measured 2 = 0.98.

[0071] Cell experiment: After 14 days of using the product of Example 6 on AD model mice, the erythema and epidermal thickening were significantly reduced, and the curative effect was better than that of the commercially available tacrolimus cream group (p < 0.01), and the systemic side effects were significantly reduced.

[0072] In the concentration range of 10 - 80 μg / ml, the concentration of SINH and the absorbance of the solution at a wavelength of 264 nm were linearly related, and Figure 1 was obtained, verifying the feasibility of the quantitative analysis of drug loading in Examples 1 - 3. For example, the loading rate in Example 1 was 20% - 60%.

[0073] For the hydrogel sample prepared in Example 2, a universal tensile testing machine was used, the stretching rate was set at 20 mm / min, and it was stretched uniformly until the sample broke, and Figure 2 the curve shown was obtained. From Figure 2 it can be seen that for the hydrogel sample prepared in Example 2, the maximum strain rate exceeded 200%, and the breaking strength reached 1.5 MPa, proving that it can withstand skin deformation, and at the same time proving the stability after attachment in Example 3.

[0074] Therefore, the present invention adopts the above-mentioned intelligent drug delivery system, preparation method, and application based on hydrogel microneedles. Through the silk fibroin - polyvinyl alcohol composite hydrogel, high - efficient drug loading and long - acting sustained release are achieved. Combining the electrical sensitivity characteristics of the Ca 2+ cross - linked substrate and the microcurrent sensing technology, the drug release dynamics are monitored in real time, and it has obvious curative effects on eczema, with a total effective rate of nearly 100%. This system has the functions of high transdermal efficiency, intelligent feedback, and skin microenvironment regulation, providing an innovative solution for the treatment of atopic dermatitis.

[0075] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions of the present invention or make equivalent replacements, and these modifications or equivalent replacements cannot make the modified technical solutions deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. An intelligent drug delivery system based on hydrogel microneedles, characterized in that, It includes a flexible sensing substrate layer and a drug-loaded needle layer. The drug-loaded needle layer includes a needle matrix and a loaded drug. The loaded drug is a complex of silk fibroin and a drug. The drug release rate is controlled by the applied voltage value, and the drug release process is feedback in real time by monitoring the resistance change of the flexible sensing substrate layer. The composition of the flexible sensing substrate layer is in a weight ratio of: 20 parts of polyacrylamide, 1 - 3 parts of carboxymethyl cellulose, 1 - 3 parts of calcium ion solution, 2 parts of ammonium persulfate, 1 - 2 parts of polydopamine, and 80 parts of deionized water. The composition of the drug-loaded needle layer is in a weight ratio of: 15 parts of polyvinyl alcohol, 1 - 3 parts of reduced graphene oxide, 60 parts of dimethyl sulfoxide, and 5 - 15 parts of loaded drug.

2. The intelligent drug delivery system based on hydrogel microneedles according to claim 1, wherein The polyacrylamide can also be replaced by one or more of polyvinyl alcohol and sodium alginate. The calcium ion solution can also be replaced by a sodium ion solution. The ammonium persulfate can also be replaced by one or more of N, N’-methylenebisacrylamide and tetramethylethylenediamine. The polydopamine or carboxymethyl cellulose can also be replaced by polyvinyl alcohol. Reduced graphene oxide can also be replaced by carbon nanotubes and metal nanoparticles. The dimethyl sulfoxide can also be replaced by polyethylene glycol and choline-glycerol eutectic solvent.

3. The intelligent drug delivery system based on hydrogel microneedles according to claim 1, wherein In the drug-loaded needle layer, the loading rate of the loaded drug is 20% to 60%, and the sustained release time of the loaded drug is not less than 48 hours.

4. The intelligent drug delivery system based on hydrogel microneedles according to claim 1, wherein The tensile strain rate of the flexible sensing substrate layer exceeds 200%, the resistance change range is 10Ω - 1000Ω, the thickness range of the substrate layer is 50 - 200 microns, the height range of the needle is 300 - 800 microns, and the single needle diameter range is 50 - 200 microns.

5. An intelligent drug delivery system based on hydrogel microneedles according to claim 1, characterized in that, The drug includes any one of betamethasone, calcipotriol, tacrolimus, and sinomenine hydrochloride.

6. The preparation method of an intelligent drug delivery system based on hydrogel microneedles according to any one of claims 1-5, characterized in that, It includes Flexible sensing substrate layer: Mix polyacrylamide, carboxymethyl cellulose, calcium ion solution, ammonium persulfate, and polydopamine in proportion, and crosslink to form a flexible sensing substrate. Drug-loaded needle layer: Dissolve polyvinyl alcohol and reduced graphene oxide in dimethyl sulfoxide, blend with the silk fibroin-drug complex, inject into a microneedle mold for curing, and demold to obtain the drug-loaded needle layer. System assembly: Composite the drug-loaded needle layer and the flexible sensing substrate layer through the adhesion mediated by polydopamine.

7. Use of the intelligent drug delivery system according to claim 1 in the preparation of a drug for treating atopic dermatitis.

8. The application according to claim 7, characterized in that, The intelligent drug delivery system significantly relieves skin dryness, erythema, and epidermal thickening symptoms by maintaining a moist skin environment, monitoring the drug release process in real time, and adjusting the drug release rate accordingly.

Images