Microneedle patch device for delivering medicine

Abstract

The invention discloses a microneedle patch device for delivering drugs. The microneedle patch device comprises a printed circuit board, a flexible substrate and a microneedle patch which are sequentially stacked, and the printed circuit board is electrically connected with the microneedle patch. The microneedle patch comprises an electrothermal film and microneedles; the microneedles are arranged on the electrothermal film according to an array; the microneedle comprises a core material and a thermal response layer wrapping the core material. The material of the thermal response layer comprises at least one of polycaprolactone, lauric acid and fatty alcohol; the core material comprises a polymer and a functional material loaded in the polymer. According to the microneedle patch, the microneedle can be heated through the electric heating film, so that the thermal response layer in the microneedle is liquefied, the functional material loaded in the microneedle is released, and the release rate can be adjusted by adjusting the heating temperature of the electric heating film, so that the controlled release function is realized.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine, and in particular relates to a microneedle patch device for delivering drugs. Background Art

[0002] In order to achieve precise and personalized treatment in effective drug therapy, it is crucial to give the right drug to the right patient at the right dose and optimal time. The speed of drug administration is crucial to ensure therapeutic efficacy and minimize adverse reactions. Different drugs require specific administration methods and release rates. For example, epinephrine, used to treat acute anaphylactic shock, should be administered quickly by subcutaneous injection (SC) to obtain immediate effects. However, in chronic disease treatment, for example, IFN-γ, a pleiotropic cytokine used in tumor treatment, may cause cytokine storm if overdosed in a short period of time. Therefore, precise control of drug administration dynamics to stay within the therapeutic window is crucial to maximize drug efficacy and minimize side effects.

[0003] As a promising transdermal drug delivery technology, microneedles (MNs) have been widely developed in the fields of vaccine delivery, anti-tumor therapy, diabetes management, and wound healing. Currently, most studies using microneedles for transdermal drug delivery mainly use functional materials that respond to endogenous stimulation signals, allowing the drug to be passively released when the microneedles degrade. The versatility of microneedle delivery systems guided by this idea as a universal transdermal delivery platform is often limited. Their delivery capabilities are relatively simple, which may limit their applicability in different therapeutic contexts. Therefore, it is necessary to develop new universal transdermal delivery platforms. Summary of the invention

[0004] In order to overcome at least one technical problem existing in the above-mentioned prior art, one of the objectives of the present invention is to provide a microneedle patch.

[0005] A second object of the present invention is to provide a method for preparing a microneedle patch.

[0006] A third object of the present invention is to provide a microneedle patch device.

[0007] A fourth object of the present invention is to provide the use of the above-mentioned microneedle patch and / or the above-mentioned microneedle patch device in a transdermal delivery device.

[0008] In order to achieve the above object, the technical solution adopted by the present invention is:

[0009] The first aspect of the present invention provides a microneedle patch, comprising an electrothermal film and microneedles; the microneedles are arranged in an array on the electrothermal film (i.e., forming a microneedle array); the microneedles include a core material and a thermal response layer coated on the outside of the core material; the material of the thermal response layer includes at least one of polycaprolactone, lauric acid, and fatty alcohol; the core material includes a polymer and a functional material loaded in the polymer; the functional material includes a drug, a nutrient, an active ingredient, or a cosmetic ingredient.

[0010] The present invention does not limit the types of drugs, and all currently commercially available drugs can be loaded using the microneedle patch of the present invention. In some embodiments of the present invention, the drug includes at least one of an anesthetic drug, an anti-inflammatory drug, a diabetes drug, an anti-tumor drug, an analgesic drug, and a blood pressure lowering drug.

[0011] In some embodiments of the present invention, the functional material includes at least one of adrenaline, doxorubicin, chicken ovalbumin, interferon, serum response factor, temozolomide, bovine serum albumin, insulin, SRF, TMZ, BSA, insulin, IFN-γ, PROTAC drugs for degrading BRD4 protein, and ovalbumin.

[0012] The present invention does not limit the types of nutrients, and all nutrients currently available on the market can be loaded using the microneedle patch of the present invention. In some embodiments of the present invention, the nutrients include at least one of vitamins, calcium, iron, zinc, selenium, protein, glucose, potassium, and sodium.

[0013] The present invention does not limit the types of cosmetic ingredients, and all cosmetic ingredients currently available on the market can be loaded using the microneedle patch of the present invention. In some embodiments of the present invention, the cosmetic ingredients include at least one of whitening ingredients, anti-aging ingredients, and firming ingredients.

[0014] In some embodiments of the present invention, the electric heating film is a liquid metal electric heating film. The basic principle of heat generation by the electric heating film is the Joule heat principle.

[0015] In some embodiments of the present invention, the electrothermal film includes an electrospun film and a gallium-indium liquid metal circuit located on the electrospun film.

[0016] In some embodiments of the present invention, the electrothermal film is prepared by a preparation method comprising the following steps: electrospinning an electrospinning solution to prepare an electrospinning film; and then forming a gallium-indium alloy conductive circuit on the electrospinning film by screen printing.

[0017] In some embodiments of the present invention, the solute of the electrospinning solution includes at least one of styrene-butadiene-styrene block copolymer (SBS) and thermoplastic polyurethane (TPU).

[0018] In some embodiments of the present invention, the solvent of the electrospinning solution includes at least one of tetrahydrofuran (THF), N,N-dimethylformamide (DMF), acetone (AC), and hexafluoroisopropanol.

[0019] In some embodiments of the present invention, the mass percentage of the solute in the electrospinning solution is 5-15%.

[0020] In some embodiments of the present invention, in the electrospinning step, the voltage is 10-15 KV, the spinning distance is 12-18 cm, and the flow rate is 0.8-1.2 mL / min. In some embodiments of the present invention, the polymer includes polyvinyl alcohol.

[0021] In some embodiments of the present invention, the height of the microneedle is 700-1100 μm.

[0022] In some embodiments of the present invention, the length of the microneedle is 200 to 600 μm.

[0023] In some embodiments of the present invention, the width of the microneedle is 200-600 μm.

[0024] In some embodiments of the present invention, the number of the microneedles is 50 to 200.

[0025] The second aspect of the present invention provides a method for preparing the microneedle patch according to the first aspect of the present invention, comprising the following steps:

[0026] S1: mixing the polymer and the functional material and molding them using a microneedle female mold to obtain a core material;

[0027] S2: Compounding the core material and the electric heating film together, and then forming a thermal response layer on the core material to obtain the microneedle patch.

[0028] In some embodiments of the present invention, step S2 is: placing the electrothermal film on the core material, then pouring the polymer solution, taking it out from the microneedle negative mold after drying, and then forming a thermal response layer on the surface of the microneedle to obtain the microneedle patch.

[0029] The third aspect of the present invention provides a microneedle patch device, comprising a printed circuit board, a flexible substrate and the microneedle patch according to the first aspect of the present invention stacked in sequence; the printed circuit board is electrically connected to the microneedle patch.

[0030] In some embodiments of the present invention, the material of the flexible substrate includes polydimethylsiloxane (PDMS).

[0031] In some embodiments of the present invention, the printed circuit board includes an MCU chip and a wireless communication chip; the MCU chip and the wireless communication chip are electrically connected.

[0032] The present invention can communicate with terminals such as mobile phones and computers through wireless communication chips, use mobile phones or computers for remote control, and accurately control the heating temperature of the electric heating film through the MCU chip to achieve the timed and quantitative release of the functional components loaded in the microneedles by the microneedle patch. Specifically, the wireless communication chip is used to communicate with the printed circuit board, and the actual output power of the printed circuit board is modulated by sending different program instructions to control the heat generation of the electric heating film, so that the phase change material in the thermal response layer on the surface of the microneedle releases the functional material on demand under the drive of electric heat.

[0033] In some embodiments of the present invention, the MCU chip is Atemage328P.

[0034] In some embodiments of the present invention, the wireless communication chip is a Bluetooth chip; in some embodiments of the present invention, the wireless communication chip is an ECB01C Bluetooth chip, which is used to realize low-power Bluetooth communication with a smart terminal.

[0035] In some embodiments of the present invention, the printed circuit board further includes a voltage regulator and a field effect transistor; the voltage regulator, the field effect transistor, the MCU chip and the wireless communication chip are all electrically connected.

[0036] In some embodiments of the present invention, the printed circuit board is a flexible circuit board.

[0037] When the microneedle patch device in the present invention is used, it is necessary to point the needle tip of the microneedle toward the skin and then press it, so that the needle tip of the microneedle pierces the stratum corneum of the skin and forms a drug delivery channel on the skin surface. Subsequently, the user can send instructions to the wireless flexible control circuit through the APP of the smart terminal, and indirectly adjust the output power by controlling the PWM output of the printed circuit board to adjust the heat generation temperature of the electric heating film. The thermal response layer on the microneedle undergoes a phase transition after being heated, from a solid state to a liquid state, so that the functional materials loaded inside are released. The user can adjust the heat generation temperature of the electric heating film by adjusting different instructions, thereby indirectly adjusting the release rate of the functional materials. When the microneedle array is used up, a new microneedle array can be replaced again.

[0038] The fourth aspect of the present invention provides use of the microneedle patch described in the first aspect of the present invention and / or the microneedle patch device described in the third aspect of the present invention in a transdermal delivery device.

[0039] The beneficial effects of the present invention are as follows: the microneedle patch of the present invention can heat the microneedles through the electric heating film, so that the thermal responsive layer in the microneedles changes from solid to liquefied, and the functional materials loaded in the microneedles are released, and the release rate can be adjusted by adjusting the heating temperature of the electric heating film, thereby realizing the controlled release function.

[0040] The microneedle patch device of the present invention integrates both the printed circuit board and the microneedle patch on a flexible substrate, has high flexibility and is wearable, and the release rate of the functional materials loaded in the microneedles is adjustable, thereby improving the controlled release performance of the device. When used for drug delivery, it can be effectively used for systemic transdermal administration and local administration, and can better adapt to the release rate requirements of different drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 Schematic diagram of the structure of the microneedle patch device for drug delivery in Example 1.

[0042] Figure 2 Schematic diagram of the operating principle of the flexible printed circuit board in Example 1.

[0043] Figure 3 This is the circuit design schematic diagram of the atmega328p processor in Example 1.

[0044] Figure 4 This is a partial circuit design schematic diagram of the flexible printed circuit board in Example 1.

[0045] Figure 5 This is a partial circuit design schematic diagram of the flexible printed circuit board in Example 1.

[0046] Figure 6 Schematic diagram of the circuit layout of the flexible printed circuit board in Example 1.

[0047] Figure 7 Schematic diagram of the preparation process of the microneedle patch device for drug delivery in Example 1.

[0048] Figure 8 This is an optical micrograph of the microneedle array in Example 1.

[0049] Fig. 9 This is a temperature curve test diagram of the liquid metal electric heating film in Example 1 under different applied voltages.

[0050] Fig.10 This is a test diagram of the temperature response curve of the liquid metal electric heating film in Example 1 under a pulse voltage.

[0051] Fig.11These are tissue imaging images of the microneedle patch device in Example 1 with fast release and slow release.

[0052] Fig.12 These are small animal images of the microneedle patch device in Example 1 under different release modes.

[0053] Fig.13 This is a model drug release test diagram of the microneedle patch device in Example 1 under different release modes.

[0054] Fig.14 This is a test graph of the release curve of the microneedle patch device in Example 1 under different voltage driving conditions.

[0055] Fig.15 This is a test graph of the response release curve of the microneedle patch device in Example 1 under a thermal drive cycle.

[0056] Fig.16 This is a test diagram of the cumulative release performance of the microneedle patch device in Example 1 tested using the Franz diffusion method.

[0057] Fig.17 This is a test chart of the cumulative release performance of the microneedle patch device in Example 4 when delivering multiple drugs.

[0058] Fig.18 Schematic diagram of the process of the microneedle patch device in Example 2 during animal experiments.

[0059] Fig.19 Graph showing the behavioral scores and temperature test results of the microneedle patch device in Example 2 during animal experiments.

[0060] Fig. 20 This is a test chart of the blood histamine concentration and the degree of decrease in maximum body temperature when the microneedle patch device in Example 2 was used in an animal experiment.

[0061] Fig.21 This is a test graph of the tumor growth curve when the microneedle patch device in Examples 3 and Examples 5-6 is used to treat mouse melanoma.

[0062] Fig. 22 This is a graph showing the tumor weight test of the microneedle patch device in Examples 3 and 5-6 when treating mouse melanoma. DETAILED DESCRIPTION

[0063] The specific implementation of the present invention is further described in detail below in conjunction with the accompanying drawings and examples, but the implementation and protection of the present invention are not limited thereto. It should be noted that if there are processes that are not particularly described in detail below, they can be implemented or understood by those skilled in the art with reference to the prior art. The reagents or instruments used that do not indicate the manufacturer are all conventional products that can be purchased commercially.

[0064] Example 1

[0065] like Figure 1 As shown, this example provides a microneedle patch device for delivering drugs, including a flexible printed circuit board (i.e., a flexible circuit board), a flexible substrate (i.e., a flexible substrate, whose material is polydimethylsiloxane) and a microneedle patch, which are stacked in sequence. The microneedle patch and the flexible printed circuit board (i.e., FPCB) are electrically connected. In this example, the microneedle patch includes a liquid metal electric heating film and a microneedle array stacked in sequence. The microneedle array is formed by an array of at least two microneedles, and the microneedles are sequentially arranged with a thermal response layer and a core material from the outside to the inside; the material of the thermal response layer is polycaprolactone (PCL), and the material of the core material is a mixture of drugs and PVA. The drug in this example can be any drug that needs to be delivered. In order to study the performance of the microneedle patch device in this example, this example uses rhodamine B (fluorescent molecular dye) as a model drug. The liquid metal electric heating film is composed of an electrospun film and a gallium-indium liquid metal circuit located on the electrospun film. It is prepared by dissolving SBS in hexafluoroisopropanol to prepare an electrospinning solution with a mass percentage of 10%, and then electrospinning the electrospinning solution at a voltage of 12KV, a spinning distance of 15cm, and a flow rate of 1.0mL / min to obtain a BS electrospinning film as a substrate, and then printing conductive ink on the SBS electrospinning film by screen printing to form a liquid metal electric heating film. The conductive ink is made by ultrasonic treatment of a gallium-indium alloy in an organic solvent. Figure 2 As shown, the flexible printed circuit board includes a flexible chip based on atmega328p, the flexible chip based on atmega328p is arranged on a flexible substrate, and the flexible chip based on atmega328p is electrically connected to a power source (i.e., a lithium battery). The flexible chip based on atmega328p includes a low-dropout linear regulator (LDO), a metal oxide semiconductor field effect transistor (MOSFET), an ECB01C Bluetooth chip, and an atmega328p processor; the low-dropout linear regulator (LDO), the metal oxide semiconductor field effect transistor (MOSFET), the ECB01C Bluetooth chip, and the atmega328p processor are all electrically connected. The specific circuit principle design of the atmega328p processor is as follows Figure 3 As shown in the figure, some circuit principle design diagrams of flexible printed circuit boards are as follows Figures 4 to 6 As shown, the present invention integrates a MOSFET circuit (such as Figure 5 As shown below) to control the output power of the flexible printed circuit board.

[0066] The microneedle patch device of the present invention can control the PWM output of the flexible chip based on atmega328p through the low-power ECB01C Bluetooth chip through the instructions sent by the intelligent terminal to control the actual output power of the MOSFET circuit, so as to simulate different voltage outputs. The liquid metal electric heating film will produce different temperatures under different voltages. When the temperature reaches the response temperature of the thermal response layer, the thermal response layer of the outer layer of the microneedle will be converted from solid to liquid, and the drug will be released. The device can control the final heat generation temperature of the liquid metal electric heating film by controlling the sending of different instructions, thereby indirectly controlling the drug release rate of the microneedle array.

[0067] like Figure 7 As shown, the microneedle patch device for delivering drugs in this example is prepared by a preparation method comprising the following steps:

[0068] (1) 10 mL of PVA polymer solution was mixed with 0.02 g of drug rhodamine B to obtain a mixed solution; the polymer solution was a polyvinyl alcohol (PVA) aqueous solution with a mass percentage of 25 wt%.

[0069] (2) Take 0.3 mL of the mixed solution obtained in step (1) and add it to the microneedle array PDMS negative mold. Cover the negative mold with a matching PDMS cover, put it into a 50 mL centrifuge tube with a wooden stopper, and then put it into a centrifuge and centrifuge it at 4000 rpm for at least 10 min.

[0070] (3) Take out the PDMS negative mold containing the mixed solution in the centrifuge tube in step (2), put it into a 60° C. oven, and dry it overnight until it is completely dry. Do not take out the microneedles.

[0071] (4) The previously prepared liquid metal electric heating film is evenly spread on the back of the microneedle in the negative mold in step (3), led out with a lead wire, and then 1.5 mL of 25 wt% PVA solution is poured again. After drying, the microneedle is carefully removed from the negative mold.

[0072] (5) The thermal responsive material polycaprolactone (PCL) is sprayed on the microneedle component obtained in step (4) by a spraying process. PCL is prepared in advance as a dichloromethane solution with a mass percentage of 10 wt%, and the amount used is 0.5 mL. After the spraying is completed, wait for the solvent to evaporate completely to obtain a double-layer microneedle array with controlled release function.

[0073] (6) Connecting the leads of the microneedle patch obtained in step (5) to the output pads of the flexible printed circuit board by welding to complete the overall assembly of the device, thereby obtaining the microneedle patch device for drug delivery in this example.

[0074] The optical microscope image of the microneedle array in this example is tested using an optical microscope. Figure 8 As shown. Figure 8 It can be seen that a microneedle array with good morphology and appearance was successfully prepared in this example. A single microneedle was in the shape of a quadrangular pyramid. The size of the microneedles was measured under an optical microscope. The average height of the microneedles was 900 μm and the bottom side length was 400 μm.

[0075] Example 2

[0076] The microneedle patch device for drug delivery in this example is different from that in Example 1 only in that adrenaline is used in this example instead of rhodamine B in Example 1, and the mass percentage of adrenaline in the PVA solution is 0.01%.

[0077] Example 3

[0078] The microneedle patch device for drug delivery in this example is different from that in Example 1 only in that IFN-γ and PROTAC drugs for degrading BRD4 protein are used in this example instead of Rhodamine B in Example 1, and the mass percentages of IFN-γ and PROTAC drugs for degrading BRD4 protein in the PVA solution are both 0.01%.

[0079] Example 4

[0080] The microneedle patch device for drug delivery in this example is different from that in Example 1 only in that doxorubicin (DOX) and ovalbumin (OVA) are used instead of rhodamine B in Example 1, and the dosage of doxorubicin (DOX) and ovalbumin (OVA) is 50 μL, and the concentration in the mixed solution is 2 mg / mL.

[0081] Example 5

[0082] The microneedle patch device for drug delivery in this example is different from that in Example 1 only in that an equal amount of IFN-γ is used in this example to replace the rhodamine B in Example 1.

[0083] Example 6

[0084] The microneedle patch device for drug delivery in this example is different from that in Example 1 only in that this example uses an equal amount of PROTAC drug (i.e., PRO) for degrading BRD4 protein instead of Rhodamine B in Example 1.

[0085] Example 7

[0086] The microneedle patch device for drug delivery in this example is different from that in Example 1 only in that an equal amount of sorafenib (SRF) is used in this example to replace the rhodamine B in Example 1.

[0087] Example 8

[0088] The microneedle patch device for drug delivery in this example is different from that in Example 1 only in that an equal amount of temozolomide (TMZ) is used in this example to replace the rhodamine B in Example 1.

[0089] Example 9

[0090] The microneedle patch device for drug delivery in this example is different from that in Example 1 only in that an equal amount of bovine serum albumin (BSA) is used in this example to replace the rhodamine B in Example 1.

[0091] Example 10

[0092] The microneedle patch device for drug delivery in this example is different from that in Example 1 only in that an equal amount of insulin is used in this example to replace the rhodamine B in Example 1.

[0093] When the microneedle patch device for delivering drugs in Examples 1 to 6 of the present invention is used, the device is inserted into the specific location of the skin where the drug needs to be applied, and a command is sent to the device to start the device. During the electrical heating process, the microneedle array will begin to dissolve and release the drug.

[0094] Performance Test:

[0095] (1) Electrothermal effect and voltage responsiveness test

[0096] The electric heating performance of the liquid metal electric heating film used in the present invention under voltage drive was tested by using a thermal imager. The specific experimental method is: different voltages (0.5V, 0.75V, 1.0V, 1.25V, 1.5V) were applied to the liquid metal electric heating film, and the temperature change caused by the electric heating effect was tested by using a thermal imager to obtain the heat generation performance of the liquid metal electric heating film under different voltages. The test results are shown in FIG. Fig. 9 Then, the voltage responsiveness was tested by applying a pulse voltage (2.5V, 2min, 0V, 1min) and measuring the change in surface temperature. The specific test results are shown in Fig.10 As shown. Fig. 9 It can be seen that by applying different voltages (0.5V, 0.75V, 1.0V, 1.25V, 1.5V) to the liquid metal electric heating film, using a thermal imager to test the temperature change caused by the electric heating effect, the heat generation performance of the liquid metal electric heating film under different voltages can be obtained, and the final temperatures of the lowest 25°C and the highest 63°C can be obtained respectively. Fig.10It can be seen that by applying a pulse voltage (2.5V, 2min, 0V, 1min) and testing the change in its surface temperature to test its voltage responsiveness, the test results show that its temperature can be quickly switched between 25°C and 48°C, with good dynamic feedback and stability. Therefore, the liquid metal electric heating film used in the present invention has good electric heating effect and voltage responsiveness.

[0097] (2) Drug release performance test

[0098] The in vitro and tissue drug release performance of the microneedle patch device in Example 1 was tested. The specific experimental method was as follows: the needle tips of the microneedle array were inserted into the skin tissue and back taken from the back of nude mice, and "fast" and "slow" release rate instructions were sent using a smartphone, respectively. The fluorescent staining of the skin tissue was observed using a fluorescence confocal microscope at the corresponding time points. Visual analysis was performed using an in vitro imaging system (IVIS Spectrum, Perkin Elmer) to analyze the biodistribution of the dye on the back of living mice. The fluorescence emission intensities of the ex vivo tissue and the back of living mice under two different release modes were compared. Both groups of experiments were imaged at predetermined time points (30 seconds, 60 seconds, 120 seconds, 30 minutes, 60 minutes, and 120 minutes, of which 30 seconds, 60 seconds, and 120 seconds were all fast release groups, and 30 minutes, 60 minutes, and 120 minutes were all slow release groups). The specific test results are shown as follows. Fig.11 , Fig.12 and Fig.13 As shown, Fig.13 (a) shows the release test diagram when the test time is 30s, 60s and 120s. Fig.13 (b) is the release test diagram when the test time is 30min, 60min and 120min. Figure 11 to Figure 13 It can be seen that the device can release the functional components of the load under different release powers. When in use, it can be released as needed and in quantity according to different functional components.

[0099] (3) In vitro dissolution test

[0100] The in vitro dissolution performance of the microneedle patch device in Example 1 was further studied by controlling the release kinetics of the microneedle patch device (i.e., FBMP). The fluorescence intensity of the model drug Rhodamine B was characterized using a Tecan Infinite 200Pro microplate reader. The specific experimental method was as follows: the microneedle patch was fixed in a 12-well plate, 3 mL of PBS solution was added, and different voltages (0 V, 0.75 V, 1.5 V) were applied to the microneedle patch using a DC power supply. Samples were taken at relevant time points, and 200 μL was taken each time in a 96-well plate. After sampling, an equal amount of 200 μL of PBS solution was added to the 12-well plate. The molecular fluorescence intensity data of the model drug in the 96-well plate was read using an ELISA instrument. The specific test results are shown in the figure. Fig.14 Then, using the same method, a DC power supply was used to output a pulse voltage (the voltage change in one pulse cycle was: 1.25V, 2min first; then 0V, 1min) to test the thermal cycle response release data of the microneedle patch. The specific test results are shown in Fig.15 As shown. Fig.14 It can be seen that at 0V, the PCL electric heating layer (i.e., the outer layer) protects the core material PVA from being dissolved by water, and the cumulative release within 10 minutes is negligible. At 0.75V and 1.5V voltages, due to the thermal melting of the PCL phase change layer, the cumulative release rates within 10 minutes were 27±2.7% and 93±3.1%, respectively. Under these activation conditions, the increased temperature promotes release by accelerating molecular diffusion. Fig.15 It can be seen that through multiple thermal excitations and repeated application of voltage, a progressive release curve is obtained, and the controllable release of the model drug is achieved, including rapid release under electrical heating and slow release under off heating.

[0101] (4) Drug release capacity test

[0102] The drug controlled release ability of the microneedle patch device in Example 1 was tested in vitro by using FBMP and Franz diffusion method. The specific experimental method is as follows: First, the transdermal release ability of the microneedle patch device was tested by Franz diffusion method. The microneedle patch was inserted into the skin tissue taken from the back of nude mice and placed in a Franz diffusion cell. The diffusion cell was filled with PBS solution to collect the model drug molecules that penetrated the tissue. 200 μL of samples were taken at regular intervals, and then an equal amount of fresh PBS solution was added to the diffusion cell. The specific test results are shown in FIG. Fig.16 As shown; Fig.16 In the figure, (a) is a comparison test diagram of transdermal release efficiency under heating and natural conditions; (b) is a characterization curve diagram of concentration and intensity, which is the model drug standard curve required for the test process. This curve is measured in advance to calibrate the concentration of the sample solution taken at different time points; (c) is a schematic diagram of the structure of the test device using the Franz diffusion method. Fig.16 It can be seen that the cumulative release rate of the microneedle patch device in Example 1 in the heated state is higher than that in the natural state. This is because the PCL undergoes a phase change after being heated, begins to melt, and exposes the internal core material and begins to dissolve. The slow release rate and low cumulative release rate of the non-heating group are due to the fact that the PCL is not melted by heat, and the PCL layer sprayed on the outside of the PVA is not completely dense. In the in vitro release test, moisture can still penetrate into the microneedles through the small holes on the PCL layer, causing the PVA core layer to slowly begin to dissolve and release the model drug molecules. At the same time, heating also helps the rate of molecular diffusion, so the release rate and cumulative release rate of the heated group in Figure (c) are higher than those of the natural state group.

[0103] FBMP was used to test the in vitro release ability of the microneedle patch device in Example 4 and Examples 7 to 10, and to verify the ability of the device as a transdermal delivery platform for multiple drugs. The specific experimental method is to further study its in vitro dissolution performance by controlling the release kinetics of FBMP. That is, the drug dissolution solution of the microneedle patch was collected at different time points, and the concentration of drug molecules therein was determined, and the cumulative drug release curve was calculated. The fluorescence intensity of the model and other drugs was characterized by an enzyme marker, and the cumulative release rate curve was calculated after characterization. That is, the drug dissolution solution of the microneedle patch was collected at different time points, and the concentration of drug molecules therein was determined, and the cumulative drug release curve was calculated. The specific test results are as follows. Fig.17 As shown; Fig.17 In the figure, A is a cumulative release rate test chart of DOX, B is a cumulative release rate test chart of SRF, C is a cumulative release rate test chart of TMZ, D is a cumulative release rate test chart of OVA, E is a cumulative release rate test chart of BSA, and F is insulin. Fig.17 It can be seen that the microneedle patch device in the present invention can be used to deliver a variety of drugs and can achieve release patterns at different rates, and has the potential to become a universal multi-drug delivery platform.

[0104] (5) Animal experiments

[0105] The effect of the microneedle patch device in Test Example 2 on the treatment of acute allergic shock in animals was tested. The animals used were: SPF-grade Balb / c female mice purchased from Hunan Silake Jingda Experimental Animal Co., Ltd. All animal experiments were carried out in accordance with the guidelines in the "Guide to the Care and Use of Laboratory Animals". The specific experimental method is: Balb / c mice were used as model animals to study the effect of using this device to deliver adrenaline to treat acute allergic shock. The method for constructing an acute allergic shock model in mice is as follows: 200 μL monoclonal mouse anti-dnp IgE antibody (D8406, clone SPE-7, Sigma Aldrich, MO) IgE solution (100 μg / mL) was injected intraperitoneally with 0.9% NaCl by mass percentage to sensitize mice (BALB / c), so that the mice obtained a total of 20 μg of IgE anti-dnp. After 24h, sensitized mice were intravenously injected with 100 μL of DNP-HAS solution (DNP-HAS solution 10 mg / mL, 0.9% NaCl). 100 μL of DNP-HAS solution was injected into the peritoneal cavity of sensitized mice to induce sensitization reactions. Fig.18 shown.

[0106] The mice were then treated with the microneedle patch device in Example 2, and their behavior and body temperature were recorded. The mice were characterized by physiological parameters and symptoms, including rectal temperature, movement score, respiratory rate or blood histamine level. The rectal temperature was measured in real time every 2 minutes with a rectal probe. The respiratory rate was measured by counting the number of breaths every 20 seconds and observing chest movement. Action score test: active reaction after provocation (score 3), slow reaction after initiation (score 2), no active reaction after initiation (score 1); death or complete lack of reaction (score 0). Blood histamine levels were measured by whole blood samples taken from mice and quantified by ELISA kit (Catalog number: IT6088, Geno Technology Inc., MO). All samples were stored at -80°C for later evaluation of histamine concentrations by ELISA kits.

[0107] After the acute shock model was successfully constructed, the groups were divided into the following groups: control group and treatment group; the on-demand delivery of epinephrine through the present device was tested to treat allergic reactions. About 10 minutes after the induction of the allergic reaction, the allergic mice received treatment. We used the microneedle patch device in Example 2 to administer epinephrine percutaneously. The microneedles were loaded with epinephrine, and the controlled delivery of epinephrine was tested in vitro. In order to verify the effectiveness of our device in treating acute allergic reactions, we used body temperature, behavioral scores, and serum histamine levels to track the dynamic progression and treatment response of allergic mice. After injection of the allergen DNP-HAS, the behavioral scores and body temperatures of the five mice decreased significantly, indicating that the induction of sensitization reactions was successful. Allergic mice received a burst delivery of epinephrine, and the red arrow indicates the burst delivery 10 minutes after the allergic reaction. Normal behavioral scores and body temperatures show the reversal of the allergic reaction. The behavioral scores and temperatures recorded for each mouse during the experiment are as follows: Fig.19 As shown. Fig.19 It can be seen that, in contrast, the allergic mice without any treatment could not return to normal, while the mice treated with the microneedle patch device of the present invention could return to normal. The ELISA kit was used to quantitatively measure the blood histamine level, as shown in the following example. Fig. 20 As shown in (a), compared with the blank group, the average histamine level after adrenaline treatment decreased from 891.98 to 140.24. The statistical results of the maximum body temperature decrease of the two groups of mice are shown in Fig. 20 As shown in (b), the average values ​​of the two groups were 3.4 and 14.48, respectively, which further proves that the microneedle patch device in Example 2 can quickly deliver epinephrine through the skin and effectively treat acute allergic reactions.

[0108] The effect of the microneedle patch device in Example 3 on the treatment of mouse melanoma was tested. The animals used in the test were: SPF-grade Balb / c female mice purchased from Hunan Silake Jingda Experimental Animal Co., Ltd. All animal experiments were conducted in accordance with the guidelines in the "Guide to the Care and Use of Laboratory Animals". Balb / c female mice were used as model animals to construct a tumor model. Melanoma tumor cells (B16F10) were subcutaneously inoculated in mice. After the tumor model was successfully established, the groups were divided into the following groups: (1) G1: PBS group; (2) G2: IFN-γ (IV) group, only IFN-γ was injected; (3) G3: IFN-γ (FBMP) group, IFN-γ drug was administered alone using the microneedle patch device in Example 5; (4) G4: PRO (FBMP) group, PRO drug was administered alone using the microneedle patch device in Example 6; (5) G5: IFN-γ + PRO (FBMP) group, two drugs were administered in combination using the microneedle patch device in Example 3. When the tumor volume reaches ≈100 mm 3At the same time, B16F10 tumor-bearing mice were randomly divided into 5 groups according to the above grouping method for treatment experiments, and treatment was performed once a day on the 1st, 3rd, and 7th days. Tumor volume and body weight were measured every other day. The tumor volume calculation formula is: V = L × W × W / 2 (L is the longest dimension; W is the shortest dimension). After treatment, the mice were killed, the solid tumors were removed, weighed, and recorded. The specific test results are as follows Fig.21 and Fig. 22 As shown. Fig.21 and Fig. 22 It can be seen that the tumor in group G1 grew rapidly, and the tumor growth in groups G2, G3, and G4 could be inhibited, but the therapeutic effect was not obvious; the tumor growth could not be effectively inhibited; the G5 group showed a strong tumor therapeutic effect, and had a significant inhibition on the tumor. The experimental results further illustrate the potential application value of the microneedle patch in the present invention in the combined delivery of drugs to treat tumors, and can provide research methods and ideas for the clinical treatment of tumors.

[0109] In summary, the microneedle patch device in the present invention can be connected to the instruction sending APP of the smart terminal through the ECB01C Bluetooth chip, so that the administration time and the dosage can be actively regulated by the smart terminal, and the remote control of the microneedle patch device can be realized, and the medication is convenient, and daily administration can be easily realized, and it can be effectively applied to systemic transdermal administration and topical administration. At the same time, because it has the characteristics of adjustable release rate, the controlled release ability of the microneedle patch device is improved, and the release rate requirements of different drugs can be better adapted, and it has the potential to become a universal intelligent transdermal drug delivery platform. In addition, the microneedle patch device in the present invention has the advantages of low cost and easy control, and the patient does not need to use expensive exogenous equipment, and has the characteristics of being portable. It can meet the needs of patients in terms of economy and practicality. The microneedle patch device in the present invention can overcome the problem that the current microneedle system has poor active controlled release ability and can only be developed for a single drug. At the same time, it can be used as a universal delivery platform for different kinds of drugs, and the release rate can be controlled, and the release rate can be regulated according to the release requirements of different drugs, and the drug can be delivered on demand actively.

[0110] The above is a detailed description of the embodiments of the present invention, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge of ordinary technicians in the relevant technical field without departing from the purpose of the present invention. In addition, the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

Claims

1. A microneedle patch, characterized in that: The invention comprises an electric heating film and microneedles; the microneedles are arranged in an array on the electric heating film; the microneedles comprise a core material and a thermal response layer coated on the outside of the core material; the material of the thermal response layer comprises at least one of polycaprolactone, lauric acid and fatty alcohol; the core material comprises a polymer and a functional material loaded in the polymer; The functional materials include medicines, nutritional ingredients, active ingredients or cosmetic ingredients.

2. The microneedle patch according to claim 1, characterized in that: The electric heating film is a liquid metal electric heating film; And / or, the polymer comprises polyvinyl alcohol.

3. The microneedle patch according to claim 1, characterized in that: The electric heating film comprises an electrostatic spinning film and a gallium-indium liquid metal conductive circuit located on the electrostatic spinning film.

4. The microneedle patch according to claim 1, characterized in that: The height of the microneedle is 700 to 1100 μm; and / or, the length of the microneedle is 200 to 600 μm; and / or, the width of the microneedle is 200 to 600 μm; And / or, the number of the microneedles is 50 to 200.

5. The method for preparing the microneedle patch according to any one of claims 1 to 4, characterized in that: The following steps are involved: S1: mixing the polymer and the functional material and molding them using a microneedle female mold to obtain a core material; S2: Compounding the core material and the electric heating film together, and then forming a thermal response layer on the core material to obtain the microneedle patch.

6. A microneedle patch device, characterized in that: The invention comprises a printed circuit board, a flexible substrate and the microneedle patch according to any one of claims 1 to 4 which are stacked in sequence; the printed circuit board is electrically connected to the microneedle patch.

7. The microneedle patch device according to claim 6, characterized in that: The printed circuit board comprises an MCU chip and a wireless communication chip; the MCU chip and the wireless communication chip are electrically connected.

8. The microneedle patch device according to claim 7, characterized in that: The MCU chip is Atemage328P; And / or, the wireless communication chip is a Bluetooth chip.

9. The microneedle patch device according to claim 7, characterized in that: The printed circuit board also includes a voltage stabilizer and a field effect transistor; the voltage stabilizer, the field effect transistor, the MCU chip and the wireless communication chip are all electrically connected.

10. Use of the microneedle patch according to any one of claims 1 to 4 and / or the microneedle patch device according to any one of claims 6 to 9 in a transdermal delivery device.

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