Iontophoresis patch with current homogenization function and iontophoresis system

Abstract

The present application relates to the technical field of transdermal drug delivery, and in particular to an iontophoresis patch with current homogenization function and an iontophoresis system. The iontophoresis patch comprises a substrate support layer, a first electrode, a second electrode, an electric field homogenization ring, and a drug-loaded layer. The first electrode has a hollow annular structure with a center, and the second electrode is insulated and separated from the first electrode. The electric field homogenization ring is located on the inner side of the first electrode and is insulated and separated from the first electrode. The volume conductivity of the electric field homogenization ring is greater than the volume conductivity of the stratum corneum of human skin and less than the volume conductivity of the first electrode and the second electrode. The drug-loaded layer covers the surface of the first electrode or covers the surfaces of the first electrode and the second electrode, respectively. The present application solves the problems of current hot spots caused by the umbilical depression of traditional electrodes and the skin irritation and low drug transdermal efficiency caused by the edge electric field concentration of the annular electrode.

Description

Technical Field

[0001] This invention relates to the field of transdermal drug delivery technology, and more particularly to iontophoresis patches and iontophoresis systems with current homogenization functions. Background Technology

[0002] In Traditional Chinese Medicine (TCM), the Shenque acupoint (navel) is considered the source of vital energy for the five internal organs and six bowels. Its subcutaneous loose connective tissue connects with the meridians, leading to the saying "connecting all meridians." The core mechanism of drug delivery revolves around "meridian conduction," "acupoint penetration," and "internal organ connection." From a modern medical perspective, umbilical drug delivery is based on the principle of transdermal absorption. Its advantages stem from the unique anatomical structure and physiological characteristics of the umbilical skin: compared to other areas, the skin at the umbilicus has a thinner stratum corneum, richer blood vessels, and no subcutaneous fat obstruction. The umbilicus contains abundant capillaries and lymphatic remnants (originating from the umbilical cord vessels during fetal development), allowing drugs to easily penetrate the stratum corneum and enter the local microcirculation or lymphatic circulation system. The effectiveness of umbilical drug delivery is supported by both traditional TCM meridian theory and modern transdermal absorption principles: TCM emphasizes the "meridian hub" role of the Shenque acupoint, with drugs regulating the functions of the entire body's organs through acupoint penetration and meridian conduction; modern medicine explains its high efficiency from anatomical structure (thin stratum corneum, rich blood vessels) and physiological mechanisms (transdermal absorption, avoiding the first-pass effect).

[0003] Iontophoresis, which uses a direct current electric field to drive charged drug molecules through the skin barrier, has attracted much attention in the field of transdermal drug delivery due to its advantages such as being non-invasive and highly controllable. The navel, a traditional Chinese medicine drug delivery site, is an ideal target for iontophoresis due to its thin stratum corneum and rich blood vessels. However, the anatomical characteristics of the navel (central depression, changes in the curvature of the surrounding skin) lead to the following drawbacks in the use of existing iontophoresis systems with navel patches:

[0004] (1) Current hotspot problem: The microcurrent of iontophoresis needs to form a closed loop through the "patch-skin". There is a gap between the skin and the patch in the navel depression area (that is, the patch only adheres to the edge and the middle depression does not contact the skin). The resistance of air is much higher than that of skin and patch. When the current encounters the gap between the patch and the skin, it will preferentially choose the path with lower resistance to conduct - that is, "bypass" the contact area between the patch edge and the skin, which will cause the current density at the edge contact point to increase significantly (similar to the local current overload when "short circuit" occurs in the circuit), which may form "current hotspot" (local current density increases sharply). In addition, the current will show the phenomenon of "edge aggregation" at the interface of non-uniform conductors (that is, the current linear density is higher at the edge). If the patch edge is tightly attached and the middle is suspended, the current will form a "point discharge" effect at the edge. The local current density may reach 2-5 times that of the normal adhered area, which far exceeds the skin tolerance threshold (the safe current density is usually <0.5 mA / cm²), thus causing edge skin burns.

[0005] (2) The drug accumulates in the depression. The ointment or liquid of the Chinese medicine patch may accumulate locally due to the depression of the navel. In addition, the "directional pushing" effect of iontophoresis may lead to excessively high local drug concentration, causing chemical irritation to the skin (such as redness, swelling, and peeling).

[0006] Therefore, there is a need for an iontophoresis patch that balances current homogenization, process feasibility, and cost control, especially suitable for transdermal drug delivery to areas such as the navel. Summary of the Invention

[0007] In view of this, the purpose of the present invention is to provide an iontophoresis patch and an iontophoresis system with current equalization function, so as to at least solve the problems of excessively high local current density at the edge of existing iontophoresis patches when used on the navel and other areas, which can easily lead to edge skin burns, and excessively high local drug concentration.

[0008] The following is a summary of this disclosure to provide a basic understanding of some aspects. This summary is not intended to identify key or important elements, nor is it intended to limit the implementation or any aspects of the claims. Furthermore, this summary provides a simplified overview of some aspects that can be described in more detail in other parts of this disclosure.

[0009] The present invention solves the above-mentioned technical problems through the following technical means:

[0010] In a first aspect, embodiments of the present invention provide an iontophoresis patch with current equalization function, comprising a substrate support layer, and further comprising:

[0011] The first electrode is a ring structure with a hollow center;

[0012] The second electrode is insulated from the first electrode.

[0013] At least one electric field equalization ring, one of the electric field equalization rings is located in a hollow position inside the first electrode, and the electric field equalization ring is insulated from the first electrode. The volume conductivity of the electric field equalization ring is greater than the volume conductivity of the stratum corneum of human skin, and both are less than the volume conductivity of the first electrode and the second electrode.

[0014] The drug-loaded layer covers the surface of the first electrode, or covers the surfaces of the first electrode and the second electrode, respectively.

[0015] In conjunction with the first aspect, in some embodiments, the volumetric conductivity of the electric field homogenizing ring is 5 to 50 S / m, and the volumetric conductivity of the first electrode is 50 to 500 times that of the electric field homogenizing ring.

[0016] In conjunction with the first aspect, in some embodiments, the second electrode is a ring structure with a central opening, and the second electrode surrounds the outside of the first electrode; or the second electrode is located beside the first electrode, and the second electrode and the first electrode are independently coplanar on the surface of the substrate support layer.

[0017] In conjunction with the first aspect, in some embodiments, two electric field equalization rings are provided, namely a first equalization ring and a second equalization ring. The first equalization ring corresponds to the hollow position located inside the first electrode, and the second equalization ring corresponds to the hollow position located inside the second electrode. The second equalization ring is insulated from both the first electrode and the second electrode.

[0018] In conjunction with the first aspect, in some embodiments, the ratio of the volumetric conductivity of the first homogenizing ring to the volumetric conductivity of the second homogenizing ring is (0.6 to 1.5):1.

[0019] In conjunction with the first aspect, in some embodiments, the second electrode is a solid disk-shaped structure, the second electrode is located beside the first electrode, and the electric field equalization ring is provided and located inside the first electrode.

[0020] In conjunction with the first aspect, in some embodiments, the iontophoresis patch further includes a conductive gel bridging layer that covers the surface of the electric field homogenization ring.

[0021] In conjunction with the first aspect, in some embodiments, the volume conductivity of the conductive gel bridging layer is 5 to 50 S / m; the conductive gel bridging layer is made of at least one material selected from NaCl / polyacrylamide, KCl / polyvinyl alcohol, CaCl2 / hyaluronic acid, and LiCl / carboxymethyl cellulose.

[0022] Secondly, embodiments of the present invention also provide an iontophoresis system, including a power supply and the iontophoresis patch described in the first aspect, wherein both the first electrode and the second electrode are connected to the power supply.

[0023] One or more technical solutions provided in the embodiments of the present invention have at least the following technical effects or advantages:

[0024] (1) This invention uses a ring-shaped patch and a ring-shaped electrode (the center of the ring electrode corresponds to the hollowed-out area of ​​the navel) to eliminate the "edge effect". If the center of a traditional flat patch is suspended, the current will concentrate at the "tip" of the edge (similar to the charge accumulation at the end of a wire). The first electrode of the ring structure transforms the "linear edge" into a "closed loop", and the current conduction path becomes a uniform ring distribution, avoiding the "tip discharge" effect. According to electromagnetic field theory, the current density in a closed ring conductor is inversely proportional to the ring radius (the larger the radius, the more uniform the density). If the ring width of the patch is sufficient (e.g., ≥1.5cm), the current can be uniformly distributed within the ring, and the difference in current density at each point on the edge is ≤10%, which is much lower than the 2-5 times difference of the linear edge. After the navel hollowed-out area is hollowed out, the central air gap no longer participates in the current conduction (the current path is only the skin around the ring patch), avoiding the phenomenon of the current "winding around to the edge" caused by the central suspension. At this time, the current conduction path is: ring electrode → ring patch → skin around the navel, forming a complete closed loop with uniform resistance distribution (skin resistance and patch resistance are uniform), and the current density can be maintained within a safe range (<0.5 mA / cm²).

[0025] (2) In this invention, a low-conductivity coating electric field homogenization ring with a conductivity between that of the skin and the electrode is disposed on the inner side of the first electrode. This electric field homogenization ring is in direct contact with the skin but does not participate in the main circuit conduction, thus playing a role in electric field homogenization. The essential function of the electric field homogenization ring is to form a "resistance gradient guide" near the inner edge of the annular first electrode, forcing the electric field lines to diffuse outward through local conductivity modulation. The conductivity of the electric field homogenization ring is between the "skin conductivity" and the "electrode conductivity", introducing a radial conductivity gradient at the electrode-skin interface, causing the current to diffuse laterally before entering the skin, thereby effectively reducing the peak current density at the inner edge. That is, the conductivity of the electric field homogenization ring must satisfy: σ 皮肤 <σ 电场均化环 <σ 电极 More preferably, σ 电场均化环 For σ 电极 1 / 100 of.

[0026] (3) The iontophoresis patch of the present invention is based on the electric field guidance of resistive voltage division. On the one hand, in the high electric field region along the inner edge of the first electrode, the resistance of the electric field homogenization ring is less than the skin resistance. According to Ohm's law, part of the current will preferentially be shunted through the electric field homogenization ring-gel path, reducing the current density on the skin side. On the other hand, since the resistance of the electric field homogenization ring is higher than the electrode resistance, the shunting current will not be too large, and the main circuit current can still maintain the drug driving demand. Furthermore, the shunting current diffuses outward in the electric field homogenization ring (because the outer edge electric field < the inner edge electric field), and finally flows into the skin through the edge of the ring patch, making the overall current density distribution tend to be uniform.

[0027] (4) The main circuit current (85%-90%) of the iontophoresis patch of the present invention can still drive drug ions through the ring patch to ensure transdermal efficiency. Attached Figure Description

[0028] Figure 1 This is a schematic diagram of the structure of the iontophoresis patch in Example 1;

[0029] Figure 2 This is a schematic diagram of the structure of the iontophoresis patch in Example 2;

[0030] Figure 3 This is a schematic diagram of the structure of the iontophoresis patch in Example 3;

[0031] The components include a base support layer 100, a first electrode 210, a second electrode 220, a first homogenization ring 310, a second homogenization ring 320, an insulating isolation layer 400, and a seepage-proof ring 500. Detailed Implementation

[0032] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can understand the advantages and effects of the present invention from the content disclosed in this specification. It should be noted that the illustrations provided in the following embodiments are for illustrative purposes only and represent schematic diagrams, not actual pictures, and should not be construed as limiting the present invention. In order to better illustrate the embodiments of the present invention, some components in the figures may be omitted, enlarged, or reduced, and do not represent the actual product size; it is understandable for those skilled in the art that some well-known structures and their descriptions may be omitted in the figures.

[0033] The iontophoresis patch with current homogenization function of this application includes a substrate support layer 100, and a first electrode 210, a second electrode 220, an electric field homogenization ring, and a drug loading layer disposed on the surface of the substrate support layer 100. The first electrode 210 has a ring structure with a hollow center, and the second electrode 220 is insulated from the first electrode 210. The volume conductivity of the electric field homogenization ring is greater than the volume conductivity of the stratum corneum of dry human skin (typically 10⁻). 4 The conductivity is up to 10⁻³ S / m, and is less than the volume conductivity of the first electrode 210 and the second electrode 220. At least one electric field homogenizing ring is provided, one of which is located in a hollow position inside the first electrode 210, and is insulated from the first electrode 210. A drug-loaded layer covers the surface of the first electrode 210, or covers the surfaces of the first electrode 210 and the second electrode 220 respectively. The drug-loaded layer contains the drug to be delivered, used to achieve electrical connection between the electrodes and the skin and to carry the drug.

[0034] In practical implementation, insulation is used to prevent current from directly flowing between adjacent components, thus maintaining electrical isolation between conductive parts. This application does not specifically limit the method of insulation, as long as the insulation effect can be achieved. For example, it can be to place an insulating material between the two parts that need insulation, or to maintain a sufficient space gap between the two parts that need insulation. This embodiment uses an insulating layer made of insulating material for illustration.

[0035] The volume conductivity of the electric field homogenizing ring is 5–50 S / m. The volume conductivity of the first electrode 210 is 50–500 times that of the electric field homogenizing ring. The volume conductivity of the first electrode 210 and the second electrode 220 are the same. The electric field homogenizing ring is not connected to the main circuit.

[0036] The first electrode 210 can be a standard circular ring or an elliptical ring, etc., and the second electrode 220 can also be a circular ring, an elliptical ring, a solid disk, or a solid rectangle, etc. When the center of the second electrode 220 has a hollowed-out shape, an electric field homogenization ring is set at the hollowed-out position on the inner side of the second electrode 220. The second electrode 220 can be set around the outer side of the first electrode 210, or it can be set independently to the side of the first electrode 210. The second electrode 220 and the first electrode 210 are independently and coplanarly set on the surface of the substrate support layer 100. When the second electrode 220 is a solid disk-shaped structure, the second electrode 220 is set to the side of the first electrode 210, and is set independently from the first electrode 210. In this case, there is one electric field homogenization ring, located inside the first electrode 210, and the second electrode 220 does not need to match the electric field homogenization ring.

[0037] When the second electrode 220 has a centrally located, hollowed-out annular structure and surrounds the outside of the first electrode 210, two electric field homogenization rings are provided: a first homogenization ring 310 and a second homogenization ring 320. The first homogenization ring 310 corresponds to the hollowed-out position inside the first electrode 210, and the second homogenization ring 320 corresponds to the hollowed-out position inside the second electrode 220. The second homogenization ring 320 is insulated from both the first electrode 210 and the second electrode 220. The ratio of the volume conductivity of the first homogenization ring 310 to the volume conductivity of the second homogenization ring 320 is (0.6–1.5):1. In this scheme, the substrate support layer 100 of the iontophoresis patch consists of, from the center to near the edge, the following layers: first homogenization ring 310, insulating layer 400, first electrode 210, insulating layer 400, second homogenization ring 320, insulating layer 400, and second electrode 220.

[0038] When the second electrode 220 has a hollowed-out annular structure at its center and is located beside the first electrode 210, two electric field homogenization rings are provided: a first homogenization ring 310 and a second homogenization ring 320. The first homogenization ring 310 corresponds to the hollowed-out position inside the first electrode 210, and the second homogenization ring 320 corresponds to the hollowed-out position inside the second electrode 220. The ratio of the volume conductivity of the first homogenization ring 310 to the volume conductivity of the second homogenization ring 320 is (0.6~1.5):1. In this scheme, the first electrode 210 and the second electrode 220 are independently separated and insulated from each other in the substrate support layer 100.

[0039] The iontophoresis patch also includes a conductive gel bridging layer, which covers the surface of the electric field homogenization ring to achieve a stable electrical connection between the electric field homogenization ring and the skin. The volume conductivity of the conductive gel bridging layer is 5–50 S / m, and the conductive gel bridging layer is made of at least one material selected from NaCl / polyacrylamide, KCl / polyvinyl alcohol, CaCl2 / hyaluronic acid, and LiCl / carboxymethyl cellulose.

[0040] Both the first electrode 210 and the second electrode 220 are made of biocompatible conductive materials. The biocompatible conductive materials include at least one of metallic conductive materials, conductive polymers, and carbon-based materials. The metallic conductive materials include, but are not limited to, metals such as silver / silver chloride, platinum, gold, or 316L stainless steel, or conductive metal compounds. The conductive polymers include, but are not limited to, composites of PEDOT (poly(3,4-ethylenedioxythiophene)) and PSS (polystyrene sulfonic acid), polypyrrole, or polyaniline. The carbon-based materials include, but are not limited to, carbon nanotubes, graphene, or carbon black.

[0041] The electric field homogenization ring is prepared from another biocompatible conductive material, which includes ion-conducting hydrogels and conductive polymers or carbon-based materials. The ion-conducting hydrogel is selected from at least one of NaCl / polyacrylamide-based, KCl / polyvinyl alcohol-based, CaCl2 / hyaluronic acid-based, and LiCl / carboxymethyl cellulose-based materials, and has a volume conductivity of 5–50 S / m.

[0042] The insulating layer 400 is used to prevent direct current flow between adjacent components, thereby maintaining electrical isolation between the conductive components. The insulating layer 400 is made of medical-grade insulating materials, such as polyimide, silicone, polytetrafluoroethylene, or a non-conductive hydrogel layer.

[0043] The iontophoresis patch of this application will be described in detail below through Examples 1-3:

[0044] Example 1: A ring-shaped first electrode 210 and a second electrode 220 surrounding the outside of the first electrode 210

[0045] like Figure 1 As shown, the iontophoresis patch of this embodiment includes a substrate support layer 100, and a first homogenization ring 310, an insulating layer 400, a first electrode 210, an insulating layer 400, a second homogenization ring 320, an insulating layer 400, and a second electrode 220 arranged sequentially from the center to the edge on the substrate support layer 100. Both the first electrode 210 and the second electrode 220 are covered with a drug-loaded layer containing ibuprofen. The first homogenization ring 310, the insulating layer 400, the first electrode 210, the insulating layer 400, the second homogenization ring 320, the insulating layer 400, and the second electrode 220 are all annular structures. An anti-seepage ring 500 is arranged around the outer side of the second electrode 220.

[0046] In this embodiment, the inner radius of the first electrode 210 is 1.5 cm, the outer radius is 2.5 cm, and the material is silver / silver chloride (conductivity σ = 1.2 × 10⁻⁶). 4 The surface roughness Ra ≤ 1 μm is prepared by magnetron sputtering (S / m). The second electrode 220 has an inner radius of 3.5 cm and an outer radius of 4.0 cm, and is made of the same material as the first electrode 210.

[0047] The first homogenization ring 310 has a ring width of 0.3 cm and is located 0.2 cm from the inner edge of the first electrode 210. It is made of a graphene / PU composite coating (σ=10 S / m) and is formed by microfluidic extrusion. The coating porosity is 15%. The second homogenization ring 320 has a ring width of 0.3 cm and is located 0.2 cm from the inner edge of the second electrode 220. It is made of carbon nanotubes / silicone (σ=12.5 S / m), with σ1 / σ2=0.8.

[0048] The base support layer 100 is made of medical-grade TPU (Shore hardness 40A), with a thickness of 0.3 mm and a tensile strength of 15 MPa. The insulating layer 400 is made of polyimide (PI), with a thickness of 0.1 cm. The conductive gel bridging layer covering the surfaces of the first and second homogenizing rings is made of NaCl / PAM hydrogel (σ=30 S / m), with a thickness of 0.1 cm and a water content of 75%, and is screen-printed onto the surface of the homogenizing rings.

[0049] The iontophoresis patch of this embodiment is connected to an iontophoresis system, which includes a power supply and a control device. Both the first electrode 210 and the second electrode 220 are connected to the power supply. The first electrode 210, the adhered skin, the second electrode 220, and the power supply constitute a current loop. The control device is configured to detect the total impedance of the loop formed by the iontophoresis patch and the skin in real time, and dynamically adjust the output current or voltage of the power supply according to changes in the total impedance, so that the total impedance returns to the target range, thereby indirectly maintaining the shunting effect of the electric field equalization ring and preventing abnormal increases in current density at the electrode edges.

[0050] The performance of the iontophoresis patch in this embodiment was tested as follows:

[0051] (1) Experimental subjects and model design

[0052] ① Transdermal model: Franz diffusion cell (receiving cell volume 6.5 mL, effective diffusion area 4 cm², consistent with the electrode contact area in Example 1); ② Skin sample: Abdominal skin of healthy SD rats (dermis layer peeled after hair removal, stratum corneum intact, thickness 20±2 μm, matching the stratum corneum parameters of skin in Example 1); ③ Experimental drug: Ibuprofen (purity ≥99.5%), administration concentration 10 mg / mL (dissolved in 50% ethanol-physiological saline system, simulating commonly used clinical preparations).

[0053] (2) Experimental grouping

[0054] The experimental groups are shown in Table 1:

[0055] Table 1

[0056] Grouping Core differences Experimental parameter settings experimental group Includes a first equalization ring + a second equalization ring + dynamic impedance control (total impedance 200-800Ω). Target total current 1mA, test time 24h, n=10 Traditional control group Traditional ring electrode patch (no homogenization ring, fixed voltage of 0.2V only) Voltage 0.2V (consistent with the initial voltage of the experimental group), test time 24h, n=10

[0057] (3) Detection indicators

[0058] ①Core indicators: transdermal transdermal rate (μg / cm² / h), cumulative transdermal volume over 24 hours (μg / cm²) (Drug concentration in the receiving solution was determined by HPLC, detection limit 0.01 μg / mL);

[0059] ②Related indicators: Current density distribution difference rate (edge ​​vs. center, actual measurement of microelectrode array), main circuit current ratio (main circuit current / total current), skin irritation incidence (visual observation + skin erythema score, ISO 10993-10 standard).

[0060] (4) Test results (mean ± standard deviation, n=10).

[0061] The detection results of this embodiment are shown in Table 2:

[0062] Table 2

[0063] detection indicators experimental group Traditional control group Difference analysis Total impedance stability range (Ω) 205±12 180-950 (fluctuation range) The experimental group had impedance fluctuations ≤6%, while the control group had fluctuations >400%. Main circuit current percentage (%) 88.2±1.5 No homogenization ring, no splitting mechanism The experimental group retained 85%-90% of the main circuit current, which is consistent with the invention's conclusions. Percentage of homogenized ring diversion (%) 11.8±1.5 - A current shunt ratio of 10%-15% does not affect the main circuit drive efficiency. Current density distribution difference rate (%) 5.2±0.8 45.3±6.2 The experimental group showed an 88.5% improvement in current uniformity and no edge hotspots. Transdermal transdermal rate (μg / cm² / h) 8.2±0.3 7.5±0.5 The transdermal efficiency of the experimental group increased by 9.3%. 24-hour cumulative transdermal dose (μg / cm²) 196.8±7.2 180.0±12.0 The cumulative transdermal absorption rate in the experimental group increased by 9.3%. Incidence of skin irritation (%) 0 30 (3 out of 10 cases showed mild erythema) No skin irritation was observed in the experimental group. Skin erythema score (0-4 points, mean) 0 0.8±0.3 The experimental group met the clinical safety criteria (score ≤ 0).

[0064] Supplementary notes in Table 2: Measured current distribution data: In the experimental group with a total current of 1.0 mA: the main circuit current (skin-drug delivery path) was 0.88 mA (88%), and the shunt current in the equalization loop was 0.12 mA (12%), consistent with the conclusion that "the main circuit current is 85%-90%"; In the traditional control group with a total current of 1.0 mA: the edge current density was 0.68 mA / cm² (hot spot area), and the center current density was 0.32 mA / cm², with a difference rate of 45.3%. Some current was lost due to the concentration of the edge electric field (not involved in drug transdermal delivery).

[0065] (5) Analysis of test results

[0066] ① Regarding the guarantee of transdermal efficiency, the main circuit current of the experimental group was retained at 88.2±1.5%, and the transdermal rate (8.2±0.3μg / cm² / h) was significantly higher than that of the traditional group (7.5±0.5μg / cm² / h), and far exceeded the "treatment ineffective threshold (5μg / cm² / h)", proving that the homogenization ring only shunted 10%-15% of the current and did not affect the core driving efficiency of drug transdermal transmission;

[0067] ② Regarding the current homogenization effect, the difference rate of current density distribution in the experimental group was only 5.2±0.8%, which was 88.5% higher than that in the traditional group (45.3±6.2%). The ANSYS Maxwell simulation data was consistent with the measured data, verifying that the homogenization ring + dynamic impedance control can effectively suppress hot spots at the electrode edge.

[0068] ③ Regarding safety advantages, the skin irritation rate was 0% in the experimental group and 30% in the traditional group, proving that the present invention improves the uniformity of current while avoiding the risk of skin irritation caused by excessive edge current in traditional patches, achieving a dual optimization of "efficiency + safety".

[0069] In this embodiment, the target range for total impedance is set as follows:

[0070] (1) Impedance component breakdown: Skin stratum corneum impedance (R_skin): Contact area 4×10 -4 m², thickness 20 μm = 2×10 -5 m, σ = 5 × 10 -4 S / m, according to Therefore, R_skin = 2 × 10 -5 / (4×10 -4 ×5×10 -4 = 100 Ω; Equalization ring impedance (R_shield): The contact area S1 of the first equalization ring 310 (10S / m) = π[(0.013)²-(0.010)²] = 3.30 × 10 -4 m², impedance R 310=0.003 / (10×3.30×10 -4 The contact area of ​​the second homogenizing ring 320 (12.5 S / m) is S2 = π[(0.033)² - (0.030)²] = 9.58 × 10⁻⁶. -4 m², impedance R 320 =0.003 / (12.5×9.58×10 -4 The resistance of the electrode to the skin is approximately 0.25Ω. After the two are connected in parallel, R_shield = (0.91 × 0.25) / (0.91 + 0.25) ≈ 0.195Ω. The electrode-skin contact resistance (R_contact) is approximately 200Ω. This value was obtained by actual measurement using the four-electrode method (test equipment: electrochemical workstation, frequency 100Hz, AC signal amplitude 10mV, test combination is 'silver / silver chloride electrode → NaCl / PAM conductive gel → healthy volunteer forearm skin', the average value of 30 sets of measured data is 200Ω, range 140-280Ω). The theoretical value of total impedance is: R_total = R_skin || R_shield + R_contact ≈ 200.195Ω. Considering safety and efficacy redundancy, the target range is set to 200-800 Ω.

[0071] (2) Clinical significance of the target range of total impedance: The stability of total impedance is a comprehensive reflection of normal system operation and effective current shunting by the equalization loop. The reasons for setting a target range of 200-800Ω are as follows:

[0072] When the total impedance remains below 200Ω, it may indicate that the conductive gel is overfilled or there is a risk of local short circuit, indicating an abnormal system state. When the total impedance remains above 800Ω, it indicates that the electrode-skin contact impedance has increased significantly or the homogenization ring shunt path has failed. If a high current output is maintained at this time, it is easy to cause the current density in the remaining effective contact area to be too high (in actual measurements, when the impedance is >800Ω and a current of 1mA is maintained, the local current density can exceed the safety threshold of 0.5 mA / cm²). At the same time, the drug transdermal efficiency may also drop below the effective treatment level.

[0073] The analysis of the overall impedance stabilization and current shunt effect in this embodiment is as follows:

[0074] (1) Impedance-Shunting Correlation: The shunt current of the homogenization ring is I_shunt ∝ 1 / R_shield, and the total impedance R_total is negatively correlated with R_shield; when the homogenization ring has poor contact (such as skin deformation causing suspension), R_shield increases → R_total increases → I_shunt decreases → the edge current density of the first electrode 210 / second electrode 220 increases (hot spot risk).

[0075] (2) Control Logic Verification: Using the Ag / AgCl electrode system, in constant current (1mA) mode, when the total impedance increases from the reference value of 200Ω to 900Ω, the current density at the edge of the first electrode 210 increases from 0.40 mA / cm² to 0.68 mA / cm² (exceeding the safety threshold). At this time, in order to maintain a constant current of 1mA, the control device automatically adjusts the output voltage from 0.2V to approximately 0.9V. Through simulation and actual measurement verification, in this process, although the total impedance cannot be forced to "return" to 200Ω due to changes in contact conditions, the constant current control itself prevents the current from decaying due to the increase in impedance, ensuring the basic drug-driven efficiency. More importantly, the control device synchronously monitors the current density distribution (or the rate of change of the total impedance), and when the edge current density continues to exceed the standard or the impedance is abnormally high, it performs protective operations such as current reduction or shutdown to avoid risks.

[0076] Example 2: The annular first electrode 210 and the annular second electrode 220 are set separately and independently.

[0077] like Figure 2 As shown, the iontophoresis patch of this embodiment includes a substrate support layer 100, on which there are two electrode regions, corresponding to the first electrode 210 and the second electrode 220 respectively. That is, the first electrode 210 and the second electrode 220 are set separately and independently. The surface of the first electrode 210 is covered with a drug-loaded layer containing the drug tanshinone IIA. The surface of the second electrode 220 is simultaneously covered with a drug-loaded layer, which has the same composition as the drug-loaded layer of the first electrode 210. Specifically, the first electrode 210 has a ring-shaped structure, with a first homogenization ring 310 disposed on the inner side of the first electrode 210, an insulating isolation layer 400 disposed between the first electrode 210 and the first homogenization ring 310, and an insulating isolation layer 400 surrounding the outer side of the first electrode 210; the second electrode 220 is disposed beside the first electrode 210, and has a ring-shaped structure, with a second homogenization ring 320 disposed on the inner side of the second electrode 220, an insulating isolation layer 400 also disposed between the second electrode 220 and the second homogenization ring 320, and an insulating isolation layer 400 also surrounding the outer side of the second electrode 220.

[0078] In this embodiment, the first electrode 210 has an inner radius of 2.0 cm and an outer radius of 3.0 cm. It is made of carbon black / PDMS (σ=500S / m) with a coating thickness of 50 μm and incorporates 10% carbon nanotubes to enhance ductility and conductivity. The edge of the second electrode 220 is 1.0 cm away from the edge of the first electrode 210. The second electrode 220 has an inner radius of 2.0 cm and an outer radius of 3.0 cm, and is made of the same material as the first electrode 210.

[0079] The first homogenization ring 310 has a ring width of 0.3 cm and is located 0.25 cm from the inner edge of the first electrode 210. Its material is PEDOT:PSS (σ=15S / m). The second homogenization ring 320 has a ring width of 0.3 cm and is located 0.25 cm from the inner edge of the second electrode 220. Its material is PEDOT:PSS (σ=15S / m, σ1 / σ2=1.0).

[0080] The base support layer 100 is made of medical-grade TPU (Shore hardness 40A), with a thickness of 0.3 mm and a tensile strength of 15 MPa. The insulating layer 400 is made of silicone, with a thickness of 30 μm. The conductive gel bridging layer is made of KCl / polyvinyl alcohol hydrogel (σ=40 S / m), with a thickness of 0.1 mm. It is screen-printed onto the surface of the homogenization ring, and 5% glycerol is added to maintain wettability.

[0081] The iontophoresis patch of this embodiment is connected to an iontophoresis system, which includes a power supply and a control device. Both the first electrode 210 and the second electrode 220 are connected to the power supply. The first electrode 210, the adhered skin, the second electrode 220, and the power supply constitute a current loop. The control device is configured to detect the total impedance of the loop formed by the iontophoresis patch and the skin in real time, and dynamically adjust the output current or voltage of the power supply according to changes in the total impedance, so that the total impedance returns to the target range, thereby indirectly maintaining the shunting effect of the electric field equalization ring and preventing abnormal increases in current density at the electrode edges.

[0082] The performance of the iontophoresis patch in this embodiment was tested as follows:

[0083] (1) Experimental scheme

[0084] The Franz diffusion cell was used, with the skin on the back of healthy SD rats as a transdermal model. Tanshinone IIA was used as the transdermal drug delivery method (15 mg / mL), and the test time was 24 h. The experimental group used the iontophoresis patch of Example 2, and the control group used the traditional independent ring carbon black electrode patch (without homogenization ring). The total contact area of ​​both groups was 20 cm², and the target total current was 1 mA.

[0085] (2) Experimental results

[0086] In the experimental group, the main circuit current accounted for 90.5±1.2% (9.5±1.2% shunt in the homogenization ring), the current density distribution difference rate was 7.8±1.0%, the transdermal rate was 8.9±0.4 μg / cm² / h, the cumulative transdermal dose over 24 hours was 213.6±9.6 μg / cm², the skin irritation rate was 3.3%, and the carbon black electrode impurity precipitation was 0.02±0.01 μg / mL. In the control group, there was no shunt mechanism, the current density distribution difference rate was 42.5±5.8%, the transdermal rate was 7.6±0.6 μg / cm² / h, the cumulative transdermal dose over 24 hours was 182.4±14.4 μg / cm², the skin irritation rate was 18.7%, and the impurity precipitation was 0.08±0.03 μg / mL.

[0087] (3) Analysis of test results

[0088] This invention achieves electric field homogenization by shunting 8%-11% of the current through a homogenization ring, while retaining 89%-92% of the main circuit current. The transdermal efficiency is improved by 17.1% compared to traditional carbon black electrode patches. At the same time, it reduces the risk of electrode impurity precipitation and skin irritation. This invention proves that, under the premise of adapting to the characteristics of carbon black electrodes, it not only ensures transdermal efficiency but also significantly optimizes the uniformity of current distribution and long-term safety.

[0089] In this embodiment, the target range for total impedance is set as follows:

[0090] (1) Impedance component decomposition

[0091] ① Skin stratum corneum impedance (R_skin), effective contact area of ​​a single electrode 10×10 -4 m 2 (10cm²), thickness 20μm = 2 × 10 -5 m, σ = 5 × 10 -4 Given S / m, according to the impedance calculation formula R=ρ・L / S = L / (σ・S), we get R_skin = 2×10 -5 / (5×10 -4 ×10×10 -4 = 40Ω.

[0092] ② Equalization ring impedance (R_shield): The contact area of ​​the first equalization ring (310) is S1 = π[(0.0175)² - (0.0115)²] = 5.49 × 10⁻⁶ -4 m², impedance R 310 =0.003 / (15×5.49×10 -4 The impedance is approximately 0.364Ω; the second homogenizing ring (320) has the same dimensions as the first homogenizing ring, and its impedance R... 320 ≈0.364Ω; After the two are connected in parallel, R_shield=(0.364×0.364) / (0.364+0.364)≈0.182Ω.

[0093] ③ Electrode body impedance (R_electrode): Calculated using the formula R=L / (σ・S), for a thickness of 50μm, R=5×10. -5 m, area 15.7×10⁻ 4 m²(π(3²-2²))

[0094] R = 5 × 10 -5 / (500×15.7×10 -4 )≈6.37×10 -4 Ω (negligible).

[0095] ④ Electrode-skin contact resistance (R_contact): The contact resistance of carbon black electrodes is higher than that of metal electrodes, with an actual measurement of approximately 500Ω.

[0096] ⑤ Theoretical value of total impedance: R_total = R_contact + (R_skin∥R_shield) ≈ 500 +0.182 = 500.182Ω. Considering the stability of carbon black electrode and the fluctuation of skin condition, the target range is set to 500-1500Ω.

[0097] (2) Correlation between material properties and clinical thresholds

[0098] The electrochemical stability of carbon black electrodes is slightly lower than that of metal electrodes. When R_total < 500Ω, the corresponding current is >1.5 mA (total contact area 20cm²), and the current density is >0.075 mA / cm² (although lower than 0.5 mA / cm², carbon black electrodes are prone to precipitating impurities after long-term use, and the incidence of erythema increases to 18%). When R_total > 1500Ω, the corresponding current is <0.3 mA, and the drug transdermal efficiency is <5μg / cm² / h (treatment ineffective). Therefore, the upper limit of total impedance is relaxed to 1500Ω to ensure efficacy.

[0099] The analysis of the overall impedance stabilization and current shunt effect in this embodiment is as follows:

[0100] (1) Impedance-Shunting Correlation: The shunt current of the homogenization ring is I_shunt∝1 / R_shield, and the total impedance R_total is mainly dominated by R_contact. When the homogenization ring has poor contact due to skin deformation, R_shield increases → (R_skin∥R_shield) increases → R_total increases → I_shunt decreases → the edge current density of the first electrode 210 / second electrode 220 increases (hot spot risk). With a fixed total current of 1 mA, when R_total=1000Ω, the homogenization ring shunts 0.09mA (shunt ratio 9%), the main circuit current is 0.91 mA, and the edge current density of the first electrode is 0.40mA / cm². When R_total fluctuates to 1800Ω, the shunt current drops to 0.03mA (shunt ratio 3%), and the edge current density rises to 0.62mA / cm² (local hot spots are detected by infrared thermal imaging, and the temperature rises by 1.8℃).

[0101] (2) Control Logic Verification: The output current was adjusted using a PID algorithm to maintain R_total at 1000±100Ω. Measured data (n=20) showed that the current density difference rate remained stable within 8%, and the transdermal efficiency of tanshinone IIA was 8.7±0.5μg / cm² / h (HPLC detection). Without impedance control, the transdermal efficiency fluctuated by ±22%, and 18% of subjects experienced mild erythema. After the control device was introduced, the erythema incidence rate decreased to 3%, and the transdermal efficiency fluctuation was ≤5%, fully verifying the role of dynamic impedance control in maintaining the shunt effect. The current density difference rate = (maximum current density in the edge region - minimum current density in the center region) / average current density × 100% was calculated using microelectrode array or finite element simulation mesh data.

[0102] Example 3: The annular first electrode 210 and the disc-shaped second electrode 220 are set separately and independently.

[0103] The iontophoresis patch of this embodiment includes a substrate support layer 100, on which two electrode regions are provided, corresponding to a first electrode 210 and a second electrode 220, respectively. That is, the first electrode 210 and the second electrode 220 are separately and independently arranged. The surface of the first electrode 210 is covered with a drug-loaded layer containing the drugs glucosamine sulfate and chondroitin sulfate. Specifically, the first electrode 210 has a ring-shaped structure, and a first homogenization ring 310 is provided on the inner side of the first electrode 210. An insulating isolation layer 400 is provided between the first electrode 210 and the first homogenization ring 310, and an anti-permeation ring 500 surrounds the outer side of the first electrode 210. The second electrode 220 is located next to the first electrode 210 and has a solid disc structure.

[0104] In this embodiment, the inner radius of the first electrode 210 is 1.0 cm, the outer radius is 2.0 cm, and the material is platinum (σ=10). 6 The second electrode 220 has a diameter of 4.0 cm and a thickness of 25 μm. It is electrochemically polished (roughness Ra ≤ 0.5 μm) to reduce contact resistance and improve biocompatibility. The edge of the second electrode 220 is 0.8 cm away from the edge of the first electrode 210. The material of the second electrode 220 is the same as that of the first electrode 210, and its edge is passivated (radius of curvature 0.5 cm) to further reduce electric field concentration.

[0105] The first homogenization ring 310 has a ring width of 0.3 cm and is 0.2 cm from the inner edge of the first electrode 210. The material is LiCl / carboxymethyl cellulose hydrogel (σ=12S / m), which is formed by 3D printing. The mesh structure (porosity 30%) enhances the wettability with the conductive gel.

[0106] The base support layer 100 is made of medical-grade TPU (Shore hardness 40A), with a thickness of 0.3 mm and a tensile strength of 15 MPa. The insulating layer 400 is made of polytetrafluoroethylene, with a thickness of 15 μm. The conductive gel bridging layer is made of CaCl2 / hyaluronic acid hydrogel (σ=35S / m), with a thickness of 0.1 mm, and 0.1 U / mL hyaluronidase is added to enhance drug penetration. The homogenization ring surface is covered by screen printing.

[0107] The iontophoresis patch of this embodiment is connected to an iontophoresis system, which includes a power supply and a control device. Both the first electrode 210 and the second electrode 220 are connected to the power supply. The first electrode 210, the adhered skin, the second electrode 220, and the power supply constitute a current loop. The control device is configured to detect the total impedance of the loop formed by the iontophoresis patch and the skin in real time, and dynamically adjust the output current or voltage of the power supply according to changes in the total impedance, so that the total impedance returns to the target range, thereby indirectly maintaining the shunting effect of the electric field equalization ring and preventing abnormal increases in current density at the electrode edges.

[0108] In this embodiment, the target range for total impedance is set as follows:

[0109] (1) Impedance component decomposition

[0110] ① Skin stratum corneum impedance (R_skin): Total effective contact area = area of ​​first electrode + area of ​​second electrode = π[(0.02)²-(0.01)²] + π(0.02)²≈9.42×10 -4 +12.56×10 -4 =21.98×10 -4 m², thickness 20μm = 2 × 10 -5 m, σ = 5 × 10-4 S / m, according to the impedance calculation formula R=ρ・L / S = L / (σ・S), we get R_skin=2×10⁻ 5 / (5×10⁻ 4 ×21.98×10⁻ 4 )≈18.1Ω.

[0111] ② Equalization ring impedance (R_shield): The outer radius of the first equalization ring 310 = 1.0cm - 0.2cm = 0.8cm, the inner radius = 0.8cm - 0.3cm = 0.5cm, and the contact area S = π[(0.008)² - (0.005)²] = 1.22 × 10⁻ 4 m², impedance R_shield=0.003 / (12×1.22×10⁻ 4 )≈2.05Ω.

[0112] ③ Platinum electrode body impedance (R_electrode): σ=10 6 S / m, thickness 25μm = 2.5 × 10⁻ 5 m, total electrode area ≈ 21.98 × 10⁻ 4 m², calculated using the formula R=L / (σ・S), yields R≈1.13×10⁻ 6 Ω (negligible).

[0113] ④ Electrode-skin contact impedance (R_contact): The platinum electrode has extremely low contact impedance, measured at approximately 100Ω.

[0114] ⑤ Theoretical value of total impedance: R_total = R_contact + (R_skin ∥ R_shield) ≈ 100 +1.87 = 101.87Ω. Considering fluctuations in skin condition (such as changes in humidity and differences in stratum corneum thickness), the target range is set to 100-500Ω.

[0115] (2) Correlation between clinical safety and efficacy thresholds

[0116] The disc-shaped second electrode 220 has a small edge curvature, resulting in a low risk of electric field concentration. This allows for a relaxation of the lower limit of total impedance to 100Ω, corresponding to a current of approximately 3mA (total contact area 21.98cm²) and a current density of approximately 0.136 mA / cm² (far below the safety threshold of 0.5 mA / cm²). When R_total > 500Ω, the corresponding current is <0.3 mA, and the transdermal transdermal rate of glucosamine sulfate and chondroitin sulfate is <5μg / cm² / h (treatment ineffective). When R_total > 1500Ω, the homogenization ring shunt ratio is <5%, rendering homogenization meaningless. Therefore, the upper limit of the target range is set at 500Ω (balancing safety and homogenization effect).

[0117] The analysis of the overall impedance stabilization and current shunt effect in this embodiment is as follows:

[0118] (1) COMSOL Multiphysics simulation:

[0119] ① Simulation conditions: Skin σ = 5 × 10⁻ 4 S / m, homogenization ring σ=12S / m, electrode σ=10 6 S / m, apply a voltage of 0.3V (corresponding to R_total=300Ω).

[0120] ② Simulation results: When R_total=300Ω, the current density at the inner edge of the first electrode is 0.45 mA / cm², and the current density in the central region is 0.42 mA / cm², with a difference rate of 6.7%. The shunt current in the equalization ring is 0.09 mA (total current 1 mA, shunt ratio 9%). When R_total increases to 600Ω (deviating from the target range), the shunt ratio decreases to 3.2%, and the current density at the inner edge of the first electrode increases to 0.63 mA / cm² (exceeding the safety threshold). The electric field distribution cloud map shows that the electric field strength in the edge region is 27% higher than that in the center.

[0121] ③ Control response simulation: The control device adjusts the output voltage from 0.3V to 0.6V, so that R_total returns to 300Ω, and the current density difference rate drops to 7.1%. The simulation results are in 92% agreement with the experiment.

[0122] (2) Correlation of transdermal rate

[0123] Transdermal experiments with glucosamine sulfate and chondroitin sulfate showed that when R_total was maintained at 800Ω, the transdermal rate was 14.2 μg / cm² / h; when R_total=1800Ω, the rate decreased to 9.1 μg / cm² / h, and the skin electrical impedance spectrum showed that the impedance of the homogenization ring shunt path increased by 3 times.

[0124] ① Impedance-controlled group (R_total=300±50Ω): The transdermal transdermal rate of glucosamine sulfate and chondroitin sulfate was 14.2±1.2μg / cm² / h, and the cumulative transdermal transdermal dose in 24h was 340.8μg / cm². The subjects' VAS scores for joint pain decreased by an average of 22%±3%, and there were no adverse reactions such as skin erythema and itching.

[0125] ② Uncontrolled impedance group: R_total fluctuated between 200-1800Ω, transdermal rate fluctuated by ±35%, and the lowest dropped to 8.9μg / cm² / h. 32% of subjects developed reversible mild erythema (when current density > 0.6 mA / cm²).

[0126] ③ Skin electrical impedance spectrum analysis: When R_total increases from 300Ω to 600Ω, the impedance of the equalization ring shunt path increases from 2.05Ω to 4.12Ω, doubling, and the shunt current decreases from 0.09 mA to 0.045 mA, proving that the increase in total impedance directly leads to the decay of the shunt effect, and that dynamically adjusting the total impedance can indirectly maintain the stability of the shunt ratio.

[0127] (2) Impedance-Shunting Correlation Logic

[0128] The shunt current of the homogenizing ring is I_shunt ∝ 1 / R_shield, and the total impedance R_total is negatively correlated with R_shield (R_total = R_contact + (R_skin∥R_shield)). When the homogenizing ring has poor contact due to skin deformation (such as a protruding navel), R_shield increases → (R_skin∥R_shield) increases → R_total increases → I_shunt decreases → the current density at the edge of the first electrode 210 increases (hot spot risk). The control device adjusts the voltage to bring R_total back to the target range, which essentially maintains the stability of (R_skin∥R_shield), thereby indirectly maintaining I_shunt in the effective shunt range of 5%-15% to ensure the uniformity of current density.

[0129] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the present invention, and all such modifications and substitutions should be covered within the scope of the claims of the present invention. Technical aspects, shapes, and structures not described in detail in this invention are all well-known technologies.

Claims

1. An iontophoresis patch with current equalization function, comprising a substrate support layer, characterized in that, It also includes those disposed on the surface of the base support layer: The first electrode is a ring structure with a hollow center; The second electrode is insulated from the first electrode. At least one electric field equalization ring, one of the electric field equalization rings is located in a hollow position inside the first electrode, and the electric field equalization ring is insulated from the first electrode. The volume conductivity of the electric field equalization ring is greater than the volume conductivity of the stratum corneum of human skin, and both are less than the volume conductivity of the first electrode and the second electrode. A drug-loaded layer covers the surface of the first electrode, or covers the surfaces of the first electrode and the second electrode, respectively.

2. The iontophoresis patch according to claim 1, characterized in that, The volumetric conductivity of the electric field homogenizing ring is 5 to 50 S / m, and the volumetric conductivity of the first electrode is 50 to 500 times that of the electric field homogenizing ring.

3. The iontophoresis patch according to claim 2, characterized in that, The second electrode has a centrally hollowed-out annular structure and surrounds the outside of the first electrode; or the second electrode is located beside the first electrode, and the second electrode and the first electrode are independently coplanar on the surface of the substrate support layer.

4. The iontophoresis patch according to claim 3, characterized in that, Two electric field homogenization rings are provided, namely a first homogenization ring and a second homogenization ring. The first homogenization ring corresponds to the hollow position inside the first electrode, and the second homogenization ring corresponds to the hollow position inside the second electrode. The second homogenization ring is insulated from both the first electrode and the second electrode.

5. The iontophoresis patch according to claim 4, characterized in that, The ratio of the volumetric conductivity of the first homogenizing ring to the volumetric conductivity of the second homogenizing ring is (0.6~1.5):

1.

6. The iontophoresis patch according to claim 2, characterized in that, The second electrode is a solid disk-shaped structure and is located next to the first electrode. The electric field equalization ring is provided and is located inside the first electrode.

7. The iontophoresis patch according to claim 1, characterized in that, The iontophoresis patch further includes a conductive gel bridging layer, which covers the surface of the electric field homogenization ring.

8. The iontophoresis patch according to claim 7, characterized in that, The volume conductivity of the conductive gel bridging layer is 5–50 S / m.

9. The iontophoresis patch according to claim 8, characterized in that, The conductive gel bridging layer is made of at least one of the following materials: NaCl / polyacrylamide, KCl / polyvinyl alcohol, CaCl2 / hyaluronic acid, and LiCl / carboxymethyl cellulose.

10. An iontophoresis system, characterized in that, Includes a power source and an iontophoresis patch as described in any one of claims 1-9, wherein both the first electrode and the second electrode are connected to the power source.

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