A transdermal drug delivery device and methods of making and using the same

Abstract

The application belongs to the technical field of new materials, and discloses a transdermal drug delivery device and a preparation method and use method thereof. The transdermal drug delivery device comprises a flexible patch and a power supply. The flexible patch comprises a flexible substrate and a liquid metal electrode. The liquid metal electrode is embedded in the flexible substrate, and the flexible patch is modified by extracellular matrix proteins. The power supply is connected with the flexible patch. The use method is as follows: a drug is coated on the surface of skin, the transdermal drug delivery device is covered on the skin surface coated with the drug, the power supply is turned on, and the transdermal drug delivery device realizes the penetration of the drug into the skin through iontophoresis. The device simply connects the flexible patch with the power supply, realizes the miniaturization and portability of iontophoresis therapy, does not harm the skin, is efficient and safe, and has high patient compliance.

Description

Technical Field

[0001] This invention belongs to the field of new materials technology, specifically relating to a transdermal drug delivery device and its preparation and usage methods. Background Technology

[0002] Transdermal drug delivery refers to the process by which drugs, through the skin, utilize their properties and physicochemical methods to allow them to penetrate the skin at a certain rate and enter the body to produce local or systemic therapeutic effects. Transdermal drug delivery is another important route of drug delivery besides oral and injection methods.

[0003] The barrier function of the various layers of the skin, especially the outermost layer (the stratum corneum), greatly hinders the transdermal delivery of topical preparations, making it difficult to achieve the desired transdermal rate and penetration volume for drug administration, which is a major challenge in the treatment of skin diseases. Therefore, developing novel transdermal drug delivery systems to improve drug permeability through the skin is of great significance.

[0004] To improve transdermal drug delivery and increase drug utilization, pharmaceutical, chemical, and physical methods have been used to promote transdermal drug absorption. Among these, iontophoresis, which uses weak currents to regulate skin permeability and accelerate drug movement, has become an effective strategy for promoting transdermal drug delivery in recent years. However, current iontophoresis equipment cannot be miniaturized or made portable, and the electrodes used are mostly rigid metal electrodes, which have significant mechanical differences from the skin. Summary of the Invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the present invention proposes a transdermal drug delivery device that is small in size, easy to carry, has good flexibility and conductivity, and can realize non-invasive, safe and efficient transdermal drug delivery.

[0006] The present invention also proposes a method for preparing the above-mentioned transdermal drug delivery device.

[0007] The present invention also proposes a method of using the above-described transdermal drug delivery device.

[0008] According to one aspect of the present invention, a transdermal drug delivery device is provided, comprising:

[0009] A flexible patch comprising a flexible substrate and a liquid metal electrode embedded in the flexible substrate; the flexible patch being modified with extracellular matrix proteins;

[0010] A power source, which is connected to the flexible patch.

[0011] According to a preferred embodiment of the present invention, at least the following beneficial effects are achieved:

[0012] The flexible patch of this invention uses a flexible material as a substrate, which is highly flexible and allows for conformal contact between the device and the skin. It uses liquid metal as an electrode, providing strong conductivity. This flexible patch endows the transdermal drug delivery device with iontophoresis (a physical process in which ion current diffuses directionally in a medium under the drive of an electric field, directly or indirectly constructing a method for actively transporting substances under the action of an electric field), which can promote drug transdermal delivery and improve the cure rate of skin diseases. Furthermore, this invention uses extracellular matrix proteins to modify the surface of the flexible patch, which can improve the biosafety and cell and tissue compatibility of the flexible patch.

[0013] Therefore, this device simply connects the flexible patch to a power source, enabling miniaturization and portability of iontophoresis therapy. It is also harmless to the skin, highly efficient and safe, resulting in high patient compliance.

[0014] In some embodiments of the present invention, the flexible substrate includes at least one of polydimethylsiloxane, polymethyl methacrylate, polycellulose acetate butyrate, polysilicate, poly(2-hydroxyethyl methacrylate), polyethylene terephthalate, or polyorthoester.

[0015] In some preferred embodiments of the present invention, the flexible substrate is selected from polydimethylsiloxane (PDMS).

[0016] In some embodiments of the present invention, the liquid metal electrode is made of at least one of gallium indium alloy, gallium indium tin alloy, or bismuth tin alloy.

[0017] In some preferred embodiments of the present invention, the liquid metal electrode is made of gallium indium alloy.

[0018] Gallium-indium alloy is a safe, low-melting-point liquid metal with ductility and good electrical conductivity.

[0019] In some embodiments of the present invention, the liquid metal electrode is prepared by screen printing.

[0020] In some embodiments of the present invention, the extracellular matrix protein includes at least one of collagen, fibronectin, or laminin.

[0021] By using the extracellular matrix protein to modify the surface of the flexible patch, the biosafety and cell and tissue compatibility of the flexible patch can be improved.

[0022] In some embodiments of the present invention, the power source is connected to the liquid metal electrode of the flexible patch.

[0023] In some preferred embodiments of the present invention, the power source is connected to the liquid metal electrode of the flexible patch via a wire.

[0024] In some embodiments of the present invention, the power source includes a flexible battery, a button battery, or an IoT battery.

[0025] In some preferred embodiments of the invention, the power source is a button cell battery.

[0026] According to a second aspect of the present invention, a method for preparing the transdermal drug delivery device is provided, specifically comprising the following steps:

[0027] S1: Fabricating a liquid metal electrode with a circuit pattern on a substrate;

[0028] S2: Cast the flexible material onto the liquid metal electrode described in step S1, so that the liquid metal electrode is embedded in the flexible substrate formed by the flexible material to form a flexible patch;

[0029] S3: Incubate the flexible patch described in step S2 with the extracellular matrix protein to complete the modification of the flexible patch by the extracellular matrix protein;

[0030] S4: Connect the power source to the flexible patch to form a transdermal drug delivery device.

[0031] In some embodiments of the present invention, the line width of the circuit pattern is 0.3 mm to 1 cm.

[0032] In some embodiments of the present invention, the method for preparing the liquid metal electrode includes screen printing, inkjet printing, or microfluidic technology.

[0033] In some preferred embodiments of the present invention, the liquid metal electrode is prepared by screen printing.

[0034] In some preferred embodiments of the present invention, step S1 requires the preparation of ink first.

[0035] In some preferred embodiments of the present invention, the ink is made from a gallium-indium alloy.

[0036] Specifically, the ink is prepared by mixing the gallium-indium alloy with a solvent containing a polymer compound and ultrasonicating the mixture at 4–25°C for 2–10 minutes.

[0037] Specifically, the solvent includes at least one of n-decyl alcohol, anhydrous ethanol, terpineol, N,N-dimethylformamide, chloroform, cyclohexanone, dichloromethane, or acetone.

[0038] Preferably, the solvent is n-decyl alcohol.

[0039] Specifically, the polymeric compound includes at least one of polyvinylpyrrolidone, polyvinyl alcohol, polyoxyethylene, polyacrylamide, polyurethane, polyacrylic acid, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, and polycaprolactone.

[0040] Preferably, the polymer compound is polyvinylpyrrolidone.

[0041] In some preferred embodiments of the present invention, the concentration of the ink is 0.1 to 5 mg / mL.

[0042] In some preferred embodiments of the present invention, the circuit pattern is drawn by screen printing with the ink to prepare the liquid metal electrode with the circuit pattern.

[0043] In some embodiments of the present invention, after the liquid metal electrode with the circuit pattern is prepared in step S1, the liquid metal electrode needs to be dried at room temperature for 6 to 12 hours, or dried at 80°C for 10 to 30 minutes, so that the solvent evaporates.

[0044] In some embodiments of the present invention, the substrate includes at least one of polyethylene terephthalate, glass, polyvinyl chloride, polymethyl methacrylate, or polydimethylsiloxane.

[0045] In some embodiments of the present invention, the flexible patch is incubated with the extracellular matrix protein for 6 to 12 hours.

[0046] In some preferred embodiments of the present invention, the flexible patch is incubated with the extracellular matrix protein for 6 hours.

[0047] In some embodiments of the present invention, during the incubation, the concentration of the extracellular matrix protein is 100–1000 μg / mL, and the pH of the extracellular matrix protein is 7.4–7.5.

[0048] In some preferred embodiments of the present invention, during the incubation, the concentration of the extracellular matrix protein is 100 μg / mL, and the pH of the extracellular matrix protein is 7.4.

[0049] In some embodiments of the present invention, the power supply in step S4 is connected to the flexible patch via a wire.

[0050] In some preferred embodiments of the present invention, the power source in step S4 is connected to the liquid metal electrode of the flexible patch via a wire.

[0051] According to a third aspect of the present invention, a method of using the transdermal drug delivery device is provided, comprising the following steps: applying a drug to a skin surface, covering the skin surface on which the drug is applied with the transdermal drug delivery device, turning on a power source, and allowing the drug to pass through the skin via iontophoresis. Attached Figure Description

[0052] The present invention will be further described below with reference to the accompanying drawings and embodiments, wherein:

[0053] Figure 1 This is a schematic diagram of the circuit pattern in Embodiment 1 of the present invention;

[0054] Figure 2 This is a scanning electron micrograph of the flexible patch prepared in Example 1 of the present invention; wherein, Figure 2 The middle image is an enlarged view of A, and the right image is an enlarged view of B;

[0055] Figure 3 These are photographs of the conductivity test of the transdermal drug delivery device in the experimental examples of this invention;

[0056] Figure 4 These are photographs illustrating the conformal contact test between the transdermal drug delivery device and the skin, as part of an experimental example of the present invention.

[0057] Figure 5 This is a fluorescence microscopy image of doxorubicin uptake by mouse skin melanoma cells in the experimental examples of this invention;

[0058] Figure 6 This is a fluorescence micrograph of doxorubicin penetrating pig skin tissue in an experimental example of the present invention; Hoechst33342 is used to characterize the cell nucleus.

[0059] Figure 7 This is a photograph of the effect of the transdermal drug delivery device on mouse skin in an experimental example of the present invention;

[0060] Figure 8 This is a live imaging image of doxorubicin penetrating mouse skin in an experimental example of the present invention. Detailed Implementation

[0061] The embodiments of the present invention are described in detail below. These embodiments are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0062] In the description of this invention, unless otherwise explicitly defined, terms such as incubation and printing should be interpreted broadly, and those skilled in the art can reasonably determine the specific meaning of the above terms in this invention in conjunction with the specific content of the technical solution.

[0063] In the description of this invention, references to terms such as "one embodiment," "some embodiments," etc., indicate that a specific structure, material, or feature described in connection with that embodiment is included in at least one embodiment of the invention. In this specification, illustrative expressions of the above terms do not necessarily refer to the same embodiment. Furthermore, the specific structures, materials, or features described may be combined in any suitable manner in one or more embodiments.

[0064] Unless otherwise specified, the experimental methods used in the examples are conventional methods; unless otherwise specified, the materials and reagents used are commercially available.

[0065] Example 1

[0066] This embodiment prepares a transdermal drug delivery device, the specific process of which is as follows:

[0067] (1) Design as follows Figure 1 The circuit pattern shown has a spacing of 1 mm between each pair of adjacent vertical lines and a line width of 1 mm; a corresponding screen printing plate is prepared based on the above circuit pattern.

[0068] The circuit pattern described above can also be set to other patterns, including but not limited to interdigitated electrodes and grid-shaped electrodes.

[0069] (2) The gallium-indium alloy was dissolved in n-decyl alcohol containing polyvinylpyrrolidone and ultrasonically broken up at 20% amplitude for 4 minutes to prepare a 3 mg / mL liquid metal ink with a core-shell structure. The prepared liquid metal ink was added to the screen plate containing the circuit pattern in step (1) and screen printed on the polyethylene terephthalate substrate to prepare a liquid metal electrode with the above circuit pattern.

[0070] (3) The printed liquid metal electrode was dried at 80°C for 20 min until all the solvent evaporated. A polydimethylsiloxane (PDMS, purchased from Dow Corning, Sylgard 184) solution (PDMS to curing agent mass ratio 10:1) was then poured onto the liquid metal electrode and dried at 80°C for 20 min. After the PDMS cured, it was peeled off from the polyethylene terephthalate substrate. At this point, the liquid metal electrode was embedded in the PDMS, forming a flexible patch. The scanning electron micrograph of the flexible patch is shown below. Figure 2 As shown, the whole ( Figure 2 Looking at the left side, the liquid metal electrode is embedded in PDMS. After magnifying part A, the dark part is PDMS and the light part is the liquid metal electrode. Further magnification of part B of the liquid metal electrode shows that PDMS can be seen in some areas of the liquid metal electrode, further indicating that the liquid metal electrode is embedded in PDMS.

[0071] (4) The flexible patch was mixed with fibronectin and incubated for 6 hours to complete the surface modification of the flexible patch, so as to improve the biosafety and cell and tissue compatibility of the flexible patch.

[0072] (5) A button battery is provided as a power source. The button battery is placed in a package. The package is equipped with a switch to control the power supply. The button battery and the liquid metal electrode are connected by wires to form a transdermal drug delivery device.

[0073] Test case

[0074] This experimental example tested the performance of the transdermal drug delivery device prepared in the examples.

[0075] 1. Testing the conductivity of transdermal drug delivery devices

[0076] The LED light was placed in the liquid metal electrode of the flexible patch, and the transdermal drug delivery device was turned on to observe whether the LED light emitted light. The results were as follows: Figure 3 As shown. Figure 3 In this invention, the LED light located in the liquid metal electrode of the flexible patch can maintain a certain brightness, indicating that the liquid metal electrode has strong conductivity and its conductivity is not affected after being made into a flexible patch and transdermal drug delivery device.

[0077] 2. Testing of the conformal contact between the transdermal drug delivery device and the skin

[0078] The flexible patch of the transdermal drug delivery device prepared in Example 1 was placed on the hand, as shown in the photograph. Figure 4 As shown, the flexible patch (in which the PDMS is transparent) adheres tightly to the skin on the hand, indicating that the transdermal drug delivery device prepared in Example 1 has good conformal contact with the skin.

[0079] 3. Ion electroosmotic function test of transdermal drug delivery device

[0080] a. Transdermal drug delivery devices promote cellular drug uptake.

[0081] The flexible patch of the transdermal drug delivery device prepared in Example 1 was placed in a culture dish at a temperature of 7 × 10⁻⁶ cm⁻¹. 5 Mouse skin melanoma cells (B16F10 cells, derived from ATCC) were seeded at a density of [number] cells / mL and cultured in 1640g Gibco medium (GIBCO) at 37°C for 24 hours. After adhesion, doxorubicin (DOX, 5 μg / mL) was added, and the transdermal drug delivery device was opened in one group while not in the other. After 3 hours, the cells were fixed and stained with DAPI for 10 minutes. The uptake of doxorubicin by the cells was then observed under a laser confocal microscope. The results are as follows: Figure 5 As shown. Figure 5In the diagram, the top row of fluorescence is used to characterize doxorubicin, and the bottom row of fluorescence is used to characterize the cell nucleus. In cells that have not been treated by the transdermal drug delivery device, the fluorescence of doxorubicin is weaker, indicating that the amount of doxorubicin taken up is less. In contrast, in cells treated by the transdermal drug delivery device, the fluorescence of doxorubicin is stronger, indicating that the amount of doxorubicin taken up is greater. This means that the iontophoresis function of the flexible patch in the transdermal drug delivery device promotes the large-scale entry of doxorubicin into the cells.

[0082] b. Transdermal drug delivery devices promote drug transdermal delivery.

[0083] Doxorubicin was evenly applied to two groups of pig skin (3cm x 3cm). The transdermal drug delivery device prepared in Example 1 was then attached to one group of pig skin coated with doxorubicin. The power was turned on, allowing the flexible patch to iontophoretically penetrate the skin. After complete action, excess doxorubicin was wiped off. The skin was then directly fixed and embedded in an OCT embedding machine. Sections (10μm thickness) were prepared using a cryostat. The sections were stained with Hoechst 33342 (Beyotime, C1022), and fluorescence imaging was performed under a laser confocal microscope to observe the transdermal thickness of the doxorubicin. The results are as follows: Figure 6 As shown. Figure 6 In the study, doxorubicin penetrated the skin to a shallow depth without the action of a transdermal drug delivery device. However, after the action of the transdermal drug delivery device, doxorubicin could penetrate deeper into the skin tissue. This indicates that the flexible patch in the transdermal drug delivery device can promote the transdermal penetration of doxorubicin through iontophoresis and increase the skin's uptake of doxorubicin.

[0084] In addition, two groups of mice were taken, and doxorubicin was evenly applied to the skin near the right hind limb of the mice (BALB / c nude). Then, the transdermal drug delivery device prepared in Example 1 was attached to the skin of one group of mice coated with doxorubicin. The switch was turned on to connect the power supply, so that the flexible patch could perform iontophoresis on the skin (e.g., Figure 7 (As shown), after complete treatment, the excess doxorubicin was wiped off. In vivo imaging of mice was performed using a Perkinelmer (IVIS imaging system) and its instructions to observe the transdermal effect of doxorubicin. The results are as follows: Figure 8 As shown. Figure 8 The results showed that the skin uptake of doxorubicin in mice treated with the transdermal drug delivery device was higher than that in mice not treated with the transdermal drug delivery device, indicating that the flexible patch in the transdermal drug delivery device can promote the transdermal absorption of doxorubicin through iontophoresis and increase the skin uptake of doxorubicin.

[0085] The embodiments of the present invention have been described in detail above. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof can be combined with each other unless otherwise specified.

Claims

1. A method for preparing a transdermal drug delivery device, characterized by, The method comprises the following steps: S1: preparing a liquid metal electrode with a circuit pattern on a substrate, the preparation method of the liquid metal electrode comprising screen printing, inkjet printing or micro-channel technology; S2: pouring a flexible material on the liquid metal electrode in step S1, embedding the liquid metal electrode in a flexible substrate formed by the flexible material to form a flexible patch; S3: incubating the flexible patch in step S2 with extracellular matrix proteins to complete the modification of the flexible patch by the extracellular matrix proteins; wherein the incubation time of the flexible patch with the extracellular matrix proteins is 6-12h, the concentration of the extracellular matrix proteins is 100-1000μg / mL when the incubation is performed, and the pH of the extracellular matrix proteins is 7.4-7.5; S4: connecting a power supply to the liquid metal electrode of the flexible patch through a wire, i.e. preparing a transdermal drug delivery device; The transdermal drug delivery device comprises: a flexible patch comprising a flexible substrate and a liquid metal electrode embedded in the flexible substrate; the flexible patch is modified by extracellular matrix proteins; the flexible substrate comprises at least one of polydimethylsiloxane, polymethyl methacrylate, cellulose acetate butyrate, polysilicate, poly(2-hydroxyethyl methacrylate), poly(ethylene terephthalate) or polyorthoester; a power supply connected to the liquid metal electrode of the flexible patch through a wire.

2. The method of claim 1, wherein, The material of the liquid metal electrode is selected from at least one of gallium-indium alloy, gallium-indium-tin alloy or bismuth-tin alloy.

3. The method of claim 1, wherein, The extracellular matrix proteins comprise at least one of collagen, fibronectin or laminin.

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