Triboelectricity-assisted micro-channel electroporation estradiol transdermal patch as well as preparation method and application thereof

Abstract

The invention relates to the field of pharmacy, and discloses a triboelectricity-assisted micro-channel electroporation estradiol transdermal patch as well as a preparation method and application thereof. The transdermal patch comprises a skin fitting layer, a micro-channel electroporation layer, a medicine storage layer, a triboelectric layer and a backing layer, the medicine storage layer is prepared from estradiol, choline vanillin ionic liquid, estradiol-loaded ZIF-8 nanoparticles and a transdermal penetration enhancer; a micro-channel array and an interdigital electrode are arranged in the micro-channel electroporation layer; the friction electricity generation layer comprises a silver-plated nylon fabric layer, an elastic silica gel column layer, a polytetrafluoroethylene film and a polyurethane film. According to the transdermal patch disclosed by the invention, through a multi-layer structural design, on one hand, the problem of insolubility of estradiol is solved by utilizing the choline aromatic folic acid ionic liquid and the ZIF-8 nanoparticles; on the other hand, the triboelectricity structure and the micro-channel electroporation technology are ingeniously integrated, the flow direction of the medicine is guided through the micro-channel, the triboelectricity provides electroporation energy, and efficient transdermal drug delivery under the self-powered condition is achieved.

Description

Technical Field

[0001] This invention relates to the field of medicine, and in particular to a triboelectric-assisted microfluidic electroporation estradiol transdermal patch, its preparation method, and its application. Background Technology

[0002] Estradiol is an important estrogen widely used to treat menopausal symptoms and alleviate and treat osteoporosis. On the one hand, traditional oral administration methods suffer from problems such as the first-pass effect in the liver and low bioavailability. Transdermal patches can avoid the first-pass effect, reduce gastrointestinal irritation, improve patient compliance, and reduce the frequency of administration. On the other hand, as a hormonal drug, estradiol can cause damage to ecosystems. Improving the bioavailability of estradiol transdermal patches can reduce drug dosage, decrease environmental emissions of unabsorbed drugs, reduce pollution to water bodies and ecosystems, and promote environmental protection and sustainable development.

[0003] Existing estradiol transdermal patches face several challenges: Firstly, estradiol is a poorly soluble drug, with a solubility of only 0.001~0.01 mg / mL in water, resulting in low drug dissolution and release efficiency in traditional transdermal patches. Secondly, the stratum corneum of the skin acts as a significant barrier, making it difficult for estradiol molecules to penetrate the skin efficiently, with a transdermal absorption rate of only 1~5 μg / (cm³). 2 •h). In the prior art, microneedle technology, ionic liquid solubilization, electroporation and other methods have been attempted to improve transdermal drug delivery. For example, patent CN113521279A discloses a smart responsive soluble microneedle, but does not incorporate electroporation technology; patent CN118717650A uses ionic liquid gel to dissolve minoxidil, but does not involve electroporation assistance; patent CN113926072A proposes an electroporation microneedle composite device. Although electroporation technology can enhance transdermal efficiency, it usually relies on an external power source, and the device is large and has poor portability, limiting its clinical application. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a triboelectric-assisted microfluidic electroporation transdermal patch for estradiol, its preparation method, and its application. This transdermal patch utilizes a multi-layered structure design. On one hand, it leverages choline-geraniol ionic liquid and ZIF-8 nanoparticles to solve the problem of estradiol's poor solubility. On the other hand, it cleverly integrates a triboelectric structure with microfluidic electroporation technology. The microchannels guide drug flow, while triboelectricity provides the energy for electroporation, achieving highly efficient transdermal drug delivery under self-powered conditions.

[0005] The specific technical solution of this invention is as follows: First, this invention provides a triboelectric-assisted microfluidic electroporation estradiol transdermal patch, comprising, sequentially from the skin contact side to the outer side, a skin adhesion layer, a microfluidic electroporation layer, a drug reservoir layer, a triboelectric layer, and a backing layer. Wherein: The drug reservoir layer comprises estradiol, choline-geraniol ionic liquid, estradiol-loaded ZIF-8 nanoparticles, and a transdermal penetration enhancer. The ZIF-8 nanoparticles have a porous structure, allowing for physical encapsulation to increase the loading of poorly soluble estradiol. Furthermore, this invention reveals that ZIF-8 nanoparticles and choline-geraniol ionic liquid can synergistically solubilize estradiol, increasing solubility by 10-20 times compared to the traditional ethanol system. In addition, ZIF-8 nanoparticles and choline-geraniol ionic liquid exhibit good compatibility, forming a solvent-carrier structure that synergistically promotes the transdermal absorption of the estradiol patch.

[0006] The microchannel electroporation layer comprises a microchannel array and interdigitated electrodes embedded in the gaps between the microchannel arrays; each microchannel has a through-hole structure penetrating the microchannel electroporation layer. These microchannels, through physical channels, guide drug flow to the skin surface, while the interdigitated electrodes generate an electroporation effect, further enhancing the permeability of epidermal cells and promoting rapid drug entry into the cells, thereby achieving targeted drug delivery and reducing loss.

[0007] The triboelectric layer comprises, in sequence, a silver-plated nylon fabric layer, an elastic silicone pillar layer (composed of an array of multiple columnar elastic silicone pillars), a polytetrafluoroethylene (PTFE) film, and a polyurethane film. The silver-plated nylon fabric layer is bonded to the microfluidic electroporation layer, and the polyurethane film is bonded to the backing layer. In this triboelectric layer, the upper PTFE layer is a strongly electronegative material, the lower silver-plated nylon fabric layer is an electronegative material, and the elastic silicone pillars are in the middle. When subjected to external pressure, the elastic silicone pillars are compressed, ensuring full contact between the surfaces of the two electrode materials. Electrons are transferred from the silver-plated nylon fabric to the PTFE, making the former positively charged and the latter negatively charged. Upon release, the charges cannot be neutralized, forming a momentary potential difference, which outputs electrical energy through the interdigitated electrodes. This structure, through the difference in electronegativity of the materials and the design of elastic spacing, can efficiently achieve the conversion of mechanical energy to electrical energy, and has the characteristics of simple structure and rapid response. The polyurethane film has flexibility and elasticity, which can improve the bending resistance of the patch and enhance its skin adhesion. In addition, the film has insulating properties, which can reduce charge leakage and maintain a stable potential difference between the positive and negative charges.

[0008] In summary, this invention addresses three major technical bottlenecks in existing transdermal estradiol drug delivery technologies: (1) low drug loading and release efficiency due to the poor solubility of estradiol; (2) insufficient transdermal penetration rate due to the skin barrier; and (3) the portability problem of electroporation technology relying on external power sources. The transdermal patch of this invention utilizes a multi-layer structure design. On the one hand, it leverages choline-geraniol ionic liquid and ZIF-8 nanoparticles to solve the problem of estradiol's poor solubility, increasing solubility by 10-20 times compared to the traditional ethanol system. On the other hand, it cleverly integrates a triboelectric structure with microfluidic electroporation technology, guiding drug flow through microchannels and providing electroporation energy through triboelectricity, achieving efficient transdermal drug delivery under self-powered conditions. Specifically, this invention utilizes the triboelectric effect to provide energy for electroporation. Each square centimeter of patch rubbed once (5 N, 10 cm / s) generates approximately 10 mJ of energy, sufficient to drive 100 electroporation pulses, solving the problem of traditional electroporation devices relying on external power sources. Based on this, the synergistic effect of the microfluidic structure and electroporation guides the flow of drugs through the microfluidic channels and the electroporation instantaneously opens the skin channels, increasing the transdermal rate of estradiol to 10~25μg / (cm²•h), which is 3~5 times higher than that of traditional transdermal patches.

[0009] In addition, it should be noted that the design order of each functional layer in the estradiol transdermal patch of the present invention is very important and must be strictly designed in the above order. If the order is changed, it may cause problems such as the inability to generate electricity through friction and the lack of energy in electroporation. On the other hand, it will also affect the cumulative permeation of the drug, resulting in failure to meet the treatment requirements.

[0010] Preferably, the diameter of a single through-hole in the microchannel array is 5~20μm, the depth is 100~300μm, and the spacing between holes is 50~200μm.

[0011] The basis for this invention in selecting the size and spacing of the vias within the aforementioned range is as follows: Estradiol is a small molecule with a molecular weight of approximately 272.38, but due to its poor solubility, it relies on ZIF-8 nanoparticles (typically 50-200 nm in diameter) for transport. If the pore size is less than 5 μm, the ZIF-8 nanoparticles and drug will aggregate and block the channels, hindering directional transport; if it is greater than 20 μm, the drug diffusion path widens, making it impossible to accurately guide the drug to the skin target area through the microchannels, and the electric field distribution within the channels is uneven during electroporation, weakening the opening effect of the stratum corneum barrier. The pore depth needs to match the thickness of the stratum corneum (approximately 10-40 μm) and the drug diffusion distance: if it is less than 100 μm, the distance between the microchannel and the skin surface is too close, and the drug is prone to premature leakage due to deformation of the triboelectric layer; if it is greater than 300 μm, the drug needs to traverse a longer path, significantly increasing diffusion resistance and reducing transdermal efficiency by more than 30%. If the pore spacing is less than 50 μm, the electric fields of adjacent microchannels will interfere with each other, resulting in excessive local electric fields that damage the skin; if it is greater than 200 μm, the electric field coverage area is insufficient, the transdermal area is dispersed, and the drug penetration rate per unit area is reduced by about 40%.

[0012] Preferably, the width and spacing of each individual electrode in the interdigitated electrode are both 50~100μm.

[0013] The basis for this invention's preference for the width and spacing of the individual electrodes within the aforementioned range is that the electroporation effect depends on the electric field strength between the electrodes (E=U / d, where U is the triboelectric voltage and d is the spacing). Previous experiments have shown that estradiol transdermal absorption requires an electric field strength maintained at 0.5~1.5kV / cm (a single friction of the triboelectric layer can generate a voltage of 10~30V). Therefore, if the width / spacing is less than 50μm, the electrode resistance increases (2~3 times when <50μm), easily causing Joule heating and skin burns. Furthermore, too small a spacing results in E>2kV / cm, excessively damaging the integrity of the stratum corneum. Conversely, if it is greater than 100μm, an excessively large spacing results in E<0.3kV / cm, failing to effectively open the skin channel, weakening the electroporation assistance effect, and reducing the transdermal rate to 5μg / (cm²). 2 •h) and below (only 1 / 2 to 1 / 5 of the preferred range).

[0014] Preferably, the substrate of the microchannel electroporation layer is formed by 3D printing of polylactic acid-glycolic acid copolymer (PLGA), and the molar ratio of LA to GA is (70:30) to (80:20).

[0015] Preferably, the interdigitated electrodes are formed by printing PEDOT:PSS onto the substrate surface of the microchannel electroporation layer.

[0016] Preferably, the triboelectric layer consists of a silver-plated nylon fabric as the lower triboelectric layer with a thickness of 20-50 μm, a polytetrafluoroethylene film as the upper triboelectric layer with a thickness of 10-20 μm, and is separated by elastic silicone pillars with a thickness of 50-100 μm.

[0017] The reason why the thickness of each layer in this invention is preferably within the above-mentioned range is as follows: (a) Silver-plated nylon fabric layer: When the thickness is <20μm, the silver plating layer is prone to breakage, the conductivity is unstable (resistance fluctuation ±30%), and the frictional charge generation decreases; when the thickness is >50μm, the flexibility decreases, the skin adhesion is poor, and it is difficult to generate effective friction with limb movement; (b) Polytetrafluoroethylene film: When the thickness is <10μm, it is easily damaged by friction, resulting in a decrease in charge storage capacity (charge loss >40%); when the thickness is >20μm, the material... The resistance to internal charge migration increases, and the energy generated by single friction decreases from 10mJ to below 5mJ, which cannot drive the electroporation pulse; (c) Elastic silicone pillar layer: When the thickness is <50μm, the compression is insufficient (<20%), the contact area between the upper and lower friction layers is small, and the amount of charge transfer is small; when the thickness is >100μm, a larger external force (>8N) is required to trigger compression, the fit and comfort decrease, and the charge neutralization speed is accelerated when released, and the potential difference maintenance time is shortened to <10ms (preferred range is 20~50ms).

[0018] Preferably, the drug reservoir layer contains the following components by mass percentage: 2-8% estradiol, 10-30% choline geraniol ionic liquid, 5-15% ZIF-8 nanoparticles loaded with estradiol, 3-10% transdermal penetration enhancer, and the balance being composed of hyaluronic acid and polyvinylpyrrolidone K90, which enhances the adhesion of the patch to the skin.

[0019] The basis for selecting the preferred content of each raw material within the above-mentioned range in this invention is as follows: When the estradiol content is <2%, even with complete transdermal absorption, a therapeutic concentration cannot be achieved (blood drug concentration needs to be ≥20 pg / mL); when it is >8%, due to its poor solubility and tendency to crystallize, the release rate fluctuates (RSD > 25%), and the risk of environmental emission of unabsorbed drug increases. When the choline-germicol ionic liquid content is <10%, the solubilizing effect on estradiol is insufficient (solubility <0.1 mg / mL), and it cannot dissolve free drug; when it is >30%, excessive ionic liquid will destroy the ZIF-8 nanoparticle structure (particle size increases by 2-3 times), weakening the synergistic drug loading capacity. When the ZIF-8 nanoparticle content is <5%, the loading is insufficient, making it difficult to maintain long-term release (<24h); when it is >15%, the nanoparticles agglomerate (particle size >500 nm), increasing the probability of clogging microchannels to >30%. When the transdermal penetration enhancer is <3%, lauroyl acetone and propylene glycol cannot effectively disrupt the lipid arrangement of the stratum corneum; when it is >10%, excessive penetration will cause skin irritation (erythema incidence >20%).

[0020] Preferably, the molar ratio of choline to geranilic acid in the choline-geranilic acid ionic liquid is 1:2 to 1:4.

[0021] Preferably, the drug loading of the ZIF-8 nanoparticles is 5~15wt%.

[0022] Preferably, the transdermal penetration enhancer is a mixture of lauryl acetone and propylene glycol in a volume ratio of 1:1.5~2.5.

[0023] Preferably, the skin-adhesive layer is composed of hyaluronic acid and polyvinylpyrrolidone K90 in a mass ratio of 1:1 to 3:1, with a thickness of 50 to 100 μm, and is used to enhance the adhesion between the patch and the skin.

[0024] Secondly, this invention provides a method for preparing a triboelectric-assisted microfluidic electroporation estradiol transdermal patch, which includes the following steps: 1) Hyaluronic acid, polyvinylpyrrolidone, estradiol, ZIF-8 nanoparticles loaded with estradiol, choline geraniol ionic liquid and transdermal penetration enhancer are mixed, film-formed and dried to form a drug reservoir layer.

[0025] 2) 3D printing is used to prepare a substrate containing a microchannel array, and inkjet printing is used to form interdigitated electrodes on the surface of the substrate.

[0026] 3) Assemble the triboelectric layer.

[0027] 4) Layer by layer composite skin bonding layer, microfluidic electroporation layer, drug reservoir layer, triboelectric layer and backing layer.

[0028] Finally, this invention provides the application of the above-mentioned triboelectric-assisted microfluidic electroporation estradiol transdermal patch in the preparation of drugs for treating menopausal syndrome or osteoporosis.

[0029] Compared with the prior art, the beneficial effects of the present invention are: (1) Structural innovation: By combining the triboelectric structure with microchannel electroporation technology, a self-powered transdermal drug delivery system was constructed. On the one hand, it does not require an external power source, thus improving portability. On the other hand, the synergistic effect of the microchannel structure and electroporation guides the flow of drugs through the microchannels and the electroporation instantly opens the skin channels, improving the transdermal efficiency of the estradiol transdermal patch and enhancing its bioavailability.

[0030] (2) Material innovation: Choline geranium ionic liquid and ZIF-8 nanoparticles are used to synergistically solubilize estradiol. At the same time, ZIF-8 nanoparticles and choline geranium ionic liquid have good compatibility and can form a "solvent-carrier" structure. The two can synergistically promote the transdermal absorption of estradiol patch. Attached Figure Description

[0031] Figure 1This is a schematic diagram of the microchannel electroporation layer of the present invention; Figure 2 This is a schematic diagram of the structure and working principle of the triboelectric layer of the present invention; Figure 3 This is a schematic diagram of the structure of the estradiol transdermal patch of the present invention; Figure 4 Figure showing the results of in vitro transdermal experiments with different transdermal patches. Detailed Implementation

[0032] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0033] Example 1: Preparation of estradiol transdermal patch (1) Preparation of ZIF-8 nanoparticles loaded with estradiol: 0.01 mol of zinc nitrate hexahydrate and 0.01 mol of estradiol were dissolved in 50 mL of methanol to obtain solution A; 0.08 mol of 2-methylimidazole was dissolved in 50 mL of methanol to obtain solution B; solution B was added dropwise to solution A while stirring at 300 rpm. After reacting for 1 hour, the mixture was centrifuged at 10,000 rpm for 10 minutes and washed three times with ultrapure water to obtain ZIF-8 nanoparticles loaded with estradiol with a drug loading of 20 wt%.

[0034] (2) Preparation of drug reservoir layer: The drug reservoir layer contains the following components (by weight percentage) as shown in Table 1: Table 1 Sodium hyaluronate (5 kDa) and polyvinylpyrrolidone K90 were weighed and dissolved in 20 mL of deionized water at a mass ratio of 2:1 to make the total weight ratio approximately 69.6%. 2.4 g of the above-mentioned free estradiol, 12 g of estradiol-loaded ZIF-8 nanoparticles, 10 g of choline-germic acid ionic liquid (the molar ratio of choline to germic acid was 1:3), 2 g of lauryl acetone, and 4 g of propylene glycol were added. The mixture was ultrasonically mixed for 30 minutes to prepare a drug reservoir solution, which was then cast onto a silicon wafer and dried at 40 °C for 12 hours to obtain a drug reservoir layer with a thickness of 80 μm.

[0035] Fabrication of the microchannel electroporation layer: A substrate containing a microchannel array was 3D printed using PLGA (molar ratio LA:GA = 75:25). Each microchannel had a pore diameter of 10 μm, a depth of 200 μm, and a spacing of 100 μm. A PEDOT:PSS solution (10% solids content) was inkjet printed into the gaps between the microchannels to form interdigitated electrodes. These electrodes had a width of 50 μm, a spacing of 100 μm, and a thickness of 8 μm. See the schematic diagram below. Figure 1 .

[0036] Preparation of the triboelectric layer: A 20μm thick polytetrafluoroethylene film and a 30μm thick silver-plated nylon fabric are fixed together by a 40μm thick elastic silicone pillar layer to form a triboelectric layer. See the schematic diagram below. Figure 2 .

[0037] (5) Overall assembly: The transdermal patch, consisting of a skin adhesion layer, a drug reservoir layer, a microfluidic electroporation layer, a triboelectric layer, and a backing layer, is assembled via hot pressing (60℃, 0.5 MPa, 10 min) to produce a square transdermal patch with sides of 2cm × 3cm. See the structural diagram below. Figure 3 .

[0038] The differences between Comparative Groups 1-11 and Example 1 are shown in Table 2.

[0039] Table 2 Test Results (1) In vitro transdermal experiment: A Franz diffusion cell was used, the receiving solution was PBS (containing 5% polyoxyethylene 20 oil ether) at pH 7.4, the temperature was 32℃, and the magnetic stirring speed was 600 rpm. The transdermal patches prepared in Example 1 and Comparative Groups 2-11 (Comparative Group 6 was not tested because we found that the electrode size of Comparative Group 6 was too small, the electrode resistance increased, which could easily generate heat and burn the skin, destroy the integrity of the stratum corneum, and was not practical, so it was not tested later) were fixed on the surface of pig skin (the stratum corneum side faces the drug reservoir layer). The patch surface was rubbed with fingers at a pressure of 5 N and a speed of 10 cm / s, 10 times every 5 minutes, to trigger the triboelectric layer to generate electrical pulses.

[0040] The results of the in vitro transdermal patch experiment are shown in Table 2 and Figure 4The results showed that the in vitro transdermal effect of Example 1 of the present invention was significantly better than that of the control groups. Control group 1 was a conventional commercially available estradiol transdermal patch without power generation and electroperforation effects, and control group 2 was powered by an external power source; both showed inferior transdermal effects compared to Example 1. Control group 3, due to its excessively large pore size, had a wider drug diffusion path, making it impossible to accurately guide the drug to the skin target area through the microchannels, thus weakening the opening effect of the stratum corneum barrier, resulting in a lower cumulative transdermal volume over 24 hours. Similarly, control groups 4-5 and 7-11 showed inferior transdermal effects compared to Example 1 because parameters such as microchannel size, electrode size, triboelectric layer structure, and drug reservoir composition were not within the optimal range.

[0041] Therefore, it can be seen that Embodiment 1 of the present invention solves the three major bottlenecks of transdermal estradiol delivery by optimizing factors such as microchannel size, electrode parameters, triboelectric layer structure and drug reservoir composition: (1) the synergistic effect of choline geraniol ionic liquid and ZIF-8 nanoparticles increases the solubility of estradiol by 10 to 20 times; (2) the triboelectric layer achieves self-powered operation (10 mJ / twitch), eliminating the need for an external power source and significantly improving portability; (3) the synergistic effect of microchannels and electroporation achieves a transdermal rate of 10 to 25 μg / (cm²). 2 •h), which is 3-5 times more potent than traditional patches, making it suitable for the treatment of menopausal syndrome and osteoporosis. Ultimately, it improves the bioavailability of estradiol and reduces the environmental excretion of unabsorbed drugs.

Claims

1. A triboelectric-assisted microfluidic electroporation estradiol transdermal patch, characterized in that: It includes, in sequence from the skin contact side to the outside, a skin adhesion layer, a microfluidic electroporation layer, a drug reservoir layer, a triboelectric layer, and a backing layer; The drug reservoir layer contains estradiol, choline geraniol ionic liquid, estradiol-loaded ZIF-8 nanoparticles, and a transdermal penetration enhancer. The microchannel electroporation layer is provided with a microchannel array and interdigitated electrodes embedded in the gaps between the microchannel arrays; the structure of a single microchannel is a through hole that penetrates the microchannel electroporation layer. The triboelectric layer comprises a silver-plated nylon fabric layer, an elastic silicone pillar layer, a polytetrafluoroethylene film, and a polyurethane film bonded together in sequence; the silver-plated nylon fabric layer is bonded to the microchannel electroporation layer, and the polyurethane film is bonded to the backing layer.

2. The estradiol transdermal patch as described in claim 1, characterized in that: The diameter of a single through-hole in the microchannel array is 5~20μm, the depth is 100~300μm, and the spacing between holes is 50~200μm; The width and spacing of each individual electrode in the interdigitated electrode are both 50~100μm.

3. The estradiol transdermal patch as described in claim 1 or 2, characterized in that: The substrate of the microchannel electroporation layer is formed by 3D printing of PLGA, and the molar ratio of LA to GA is (70:30) to (80:20). The interdigitated electrodes are formed by printing PEDOT:PSS onto the substrate surface of the microchannel electroporation layer.

4. The estradiol transdermal patch as described in claim 1, characterized in that: The triboelectric layer consists of a silver-plated nylon fabric as the lower triboelectric layer with a thickness of 20-50 μm, a polytetrafluoroethylene film as the upper triboelectric layer with a thickness of 10-20 μm, and is separated by elastic silicone pillars with a thickness of 50-100 μm.

5. The estradiol transdermal patch as described in claim 1, characterized in that: The drug reservoir layer contains the following components by mass percentage: 2-8% estradiol, 10-30% choline geraniol ionic liquid, 5-15% ZIF-8 nanoparticles loaded with estradiol, 3-10% transdermal penetration enhancer, and the balance being hyaluronic acid and polyvinylpyrrolidone K90.

6. The estradiol transdermal patch as described in claim 1 or 5, characterized in that: The molar ratio of choline to geranilic acid in the choline-geranilic acid ionic liquid is 1:2 to 1:

4. The drug loading of the ZIF-8 nanoparticles is 15~20wt%.

7. The estradiol transdermal patch as described in claim 1 or 5, characterized in that: The transdermal penetration enhancer is a mixture of lauryl acetone and propylene glycol in a volume ratio of 1:1.5~2.

5.

8. The estradiol transdermal patch as described in claim 1, characterized in that: The skin adhesive layer is composed of hyaluronic acid and polyvinylpyrrolidone K90 in a mass ratio of 1:1 to 3:1, with a thickness of 50 to 100 μm.

9. A method for preparing a triboelectric-assisted microfluidic electroporation estradiol transdermal patch as described in any one of claims 1-8, characterized in that... Includes the following steps: 1) Hyaluronic acid, polyvinylpyrrolidone, estradiol, ZIF-8 nanoparticles loaded with estradiol, choline geraniol ionic liquid and transdermal penetration enhancer are mixed, film-formed and dried to form a drug reservoir layer. 2) 3D printing is used to prepare a substrate containing a microchannel array, and inkjet printing is used to form interdigitated electrodes on the surface of the substrate; 3) Assemble the triboelectric layer; 4) Layer by layer composite skin bonding layer, microfluidic electroporation layer, drug reservoir layer, triboelectric layer and backing layer.

10. The use of the triboelectric-assisted microfluidic electroporation estradiol transdermal patch as described in any one of claims 1-8 in the preparation of a drug for treating menopausal syndrome or osteoporosis.

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