Hydrothermal-responsive microneedle patch and its preparation method and application

Abstract

The present invention belongs to the technical field of microneedles, and specifically discloses a hydrothermal-responsive microneedle patch, a preparation method thereof, and an application thereof. The hydrothermal-responsive microneedle patch includes a microneedle array for loading drugs, having a microneedle body disposed on the puncture drug delivery surface of the microneedle array; and a hydrothermal material layer that generates heat upon contact with water, disposed on the bottom surface of the microneedle array. The preparation method of the hydrothermal-responsive microneedle patch includes the following steps: S1. Loading the acting drug: adding the acting drug into the PDMS mold; S2. Constructing the microneedle array: adding a polycaprolactone / dichloromethane solution into the PDMS mold loaded with the acting drug to obtain the microneedle array; S3. Constructing the hydrothermal-responsive microneedle: disposing the hydrothermal material at the bottom of the microneedle array to form the hydrothermal-responsive microneedle. The present invention utilizes the minimally invasive microneedle technology and combines the hydrothermal reaction to construct a self-regulating intelligent release microneedle patch capable of penetrating the epidermis to contact the subcutaneous tissue, realizing the local high-efficiency release of anticancer drugs, and can be effectively applied to the treatment of superficial tumors.

Description

Technical Field

[0001] The present invention belongs to the technical field of microneedles, and particularly relates to a hydrothermal-responsive microneedle patch and its preparation method and application. Background Art

[0002] Cancer is the most common life-threatening disease and a major cause of death. Taking the treatment of superficial tumor malignant melanoma as an example, melanoma originates from melanocytes, usually occurs in the bottom layer of the epidermis, and is the most dangerous type of skin cancer, with high metastasis and lethality. In addition to surgical resection, clinical treatment options also include conventional chemotherapy and radiotherapy, as well as emerging biotherapy and immunotherapy.

[0003] Paclitaxel is a natural anti-cancer drug isolated and purified from the bark of Taxus chinensis, and has a unique mechanism of action that promotes the polymerization of cellular microtubulin, coagulates it into bundles, and prevents its depolymerization. It has been widely used in the clinical treatment of cancers such as breast cancer, ovarian cancer, and lung cancer.

[0004] Traditional drug delivery methods such as oral administration and intravenous injection of chemotherapy drugs have systemic toxicity. Importantly, chemotherapy drugs kill cancer cells while reducing the patient's immunity, and have limitations such as large side effects and premature drug degradation. Transdermal drug delivery provides a promising alternative for the treatment of melanoma, maximizing the therapeutic efficacy and minimizing adverse reactions. The advantages of transdermal drug delivery include convenient self-administration, appropriate long-term treatment, avoidance of the first-pass effect, and improved patient compliance. For skin diseases, topical application is more effective, with a high therapeutic concentration and the lowest systemic toxicity, aiming to deliver drugs to the skin for local treatment or for systemic treatment through the skin.

[0005] However, as the first line of defense of the human body, the stratum corneum is the outermost layer of the skin, mainly responsible for resisting the invasion of pathogens, and is the most important barrier that needs to be overcome for transdermal drug delivery. Microneedles can penetrate the epidermis and deliver a large amount of drugs to the dermis. Compared with traditional invasive injection and / or oral-based strategies, microneedles can achieve minimally invasive and painless local drug delivery for superficial tumors, and the transdermal patch can provide drugs in a good manner for a long time. For these reasons, traditional drug delivery methods are difficult to meet the requirements of minimally invasive, local, painless, and efficient drug delivery. Summary of the Invention

[0006] Aiming at the above problems, the present invention provides a hydrothermal-responsive microneedle patch and its preparation method and application, mainly solving the problems that the existing microneedles have poor drug delivery effects, cannot achieve efficient local drug release, and cannot perform local control on the microneedle patch.

[0007] To solve the above problems, the present invention adopts the following technical solutions:

[0008] The hydrothermal-responsive microneedle patch includes

[0009] A microneedle array for loading drugs, having

[0010] Microneedle bodies disposed on the puncture drug delivery surface of the microneedle array;

[0011] A hydrothermal material layer that generates heat when encountering water, disposed on the bottom surface of the microneedle array.

[0012] In some embodiments, the hydrothermal material layer includes several hydrothermal material layer petals, and the several hydrothermal material layer petals are disposed on the bottom surface of the microneedle array;

[0013] The microneedle array includes several microneedle working areas, and at least one hydrothermal material layer petal is provided in any one of the microneedle working areas.

[0014] In some embodiments, there is a gap between any two adjacent hydrothermal material layer petals,

[0015] The microneedle array includes several microneedle array petals, and there is a gap between any two adjacent microneedle array petals;

[0016] Any one hydrothermal material layer petal is only connected to one microneedle array petal.

[0017] In some embodiments, a hydrothermal material protection layer is provided on the activation surface of the hydrothermal material layer.

[0018] In some embodiments, the selection of the material of the hydrothermal material protection layer includes sucrose; the selection of the material of the hydrothermal material layer includes calcium oxide.

[0019] A method for preparing a hydrothermal-responsive microneedle patch, comprising the following steps

[0020] S1. Loading the acting drug: adding the acting drug into a PDMS mold, applying a vacuum, centrifuging, and drying;

[0021] S2. Constructing the microneedle array: adding a polycaprolactone / dichloromethane solution into the PDMS mold loaded with the acting drug, applying a vacuum, centrifuging, and drying to obtain the microneedle array;

[0022] S3. Constructing the hydrothermal-responsive microneedle: disposing the hydrothermal material at the bottom of the microneedle array to form the hydrothermal-responsive microneedle.

[0023] In some embodiments, the selection of the material of the hydrothermal material includes calcium oxide.

[0024] In some embodiments, it further includes the following steps

[0025] S4. Constructing multi-round hydrothermal-responsive microneedles:

[0026] The hydrothermal-responsive microneedles are segmented into several hydrothermal-responsive microneedle petals, with a spacing gap between any two adjacent hydrothermal-responsive microneedle petals, and a hydrothermal material protective layer is provided on the activation surface of any one hydrothermal-responsive microneedle petal to form multi-round hydrothermal-responsive microneedles; or

[0027] Several hydrothermal-responsive microneedles with a hydrothermal material protective layer provided on the activation surface are assembled, and there is a spacing gap between any two adjacent hydrothermal-responsive microneedles to form multi-round hydrothermal-responsive microneedles.

[0028] In some embodiments, the selection of the hydrothermal material protective layer material includes sucrose;

[0029] The acting drug includes an anti-tumor drug, and the anti-tumor drug includes paclitaxel.

[0030] Use of any of the aforementioned hydrothermal-responsive microneedle patches in the preparation of products for treating deep melanoma or breast cancer.

[0031] The beneficial effects of the present invention are as follows:

[0032] By using the minimally invasive microneedle technology and combining with the hydrothermal reaction, a self-regulating intelligent release microneedle patch capable of penetrating the epidermis to contact the subcutaneous tissue is constructed, realizing the local high-efficiency release of anti-cancer drugs, and can be effectively applied to the treatment of superficial tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 Practical pictures of the 3D printed microneedle resin mold and polycaprolactone microneedles;

[0034] Figure 2 Practical pictures of the microneedles of the product of the present invention, its assembled hydrothermal materials, and being uniformly wrapped by sucrose;

[0035] Figure 3 Scanning electron microscope photos before and after the melting change during the hydrothermal reaction of the microneedle structure;

[0036] Figure 4 Process of drug release and temperature change during the experiment of multi-round hydrothermal-responsive microneedles (HRMAM);

[0037] Figure 5 Process of drug release of multi-round hydrothermal-responsive microneedles (HRMAM);

[0038] Figure 6 Safety evaluation (CCK8) of the drug stability and efficacy of the microneedle material;

[0039] Figure 7 Comparison of in vivo anti-tumor effects as described in Example 6;

[0040] Figure 8It is a schematic structural diagram of a hydrothermal-responsive microneedle patch;

[0041] Figure 9 It is a schematic structural diagram of a multi-lobe morphology of a hydrothermal-responsive microneedle patch;

[0042] Figure 10 It is another schematic structural diagram of a multi-lobe morphology of a hydrothermal-responsive microneedle patch.

[0043] In the figure:

[0044] 100 Microneedle array, 110 Microneedle array lobe, 111 Microneedle body, 200 Hydrothermal material layer, 300 Microneedle protective layer, S1 First microneedle lobe, S2 Second microneedle lobe, S3 Third microneedle lobe. Detailed implementation

[0045] To facilitate the understanding of the technical solution of the present invention, the present invention will be further described below.

[0046] The first aspect Introduce the hydrothermal-responsive microneedle patch.

[0047] The hydrothermal-responsive microneedle patch, as Figure 8 shown in, includes

[0048] A microneedle array 100 for loading drugs, having

[0049] Microneedle bodies 111 disposed on the puncture drug delivery surface of the microneedle array 100;

[0050] A hydrothermal material layer 200 that generates heat when encountering water, disposed on the bottom surface of the microneedle array 100.

[0051] The bottom surface is the side away from the puncture drug delivery surface. The microneedle array 100 is generally a sheet-like structure. One side of it is provided with a number of microneedle bodies 111 for attaching to the skin or affected area, and the other side is the bottom surface for setting the hydrothermal material. The characteristic of the hydrothermal material is that it releases heat when encountering water (not limited to pure water, and other liquids that can contact the hydrothermal material to make it release heat are also acceptable). Common hydrothermal materials are some metal oxides and composite oxides. The hydrothermal material can be selected according to needs on the premise of not causing negative impacts on the human body and drug administration. Commonly used ones such as calcium oxide, etc., release heat when encountering water and the reaction is relatively mild, with almost no negative impact on the human body.

[0052] In the design of the needle model, the height of the microneedle body is 50 microns to 1 millimeter, the bottom diameter of the needle body is 50 microns to 1 millimeter, and the number of needle bodies is 1 - 500.

[0053] Such as Figure 10As shown, in the application scenario, in order to achieve the heating of the partitioned microneedle array 100, the hydrothermal material layer 200 can be divided into several independent working areas, and each working area can generate heat when encountering water alone. Among them, the hydrothermal material layer 200 includes several hydrothermal material layer petals, and the several hydrothermal material layer petals are arranged on the bottom surface of the microneedle array 100; by activating any one of the hydrothermal material layer petals, the corresponding part of the microneedle array 100 can be heated;

[0054] For the microneedle array 100, in order to avoid the influence of the heating of one hydrothermal material layer petal on the entire microneedle array 100, the microneedle array 100 can be divided into several working areas, and any one hydrothermal material layer petal only affects one working area (ignoring the influence of radiant heat on adjacent working areas). Thus, the microneedle array 100 includes several microneedle working areas, and at least one hydrothermal material layer petal is provided in any one of the microneedle working areas. Among them, the number of working areas is 3, and the drug loading amount of each working area is the same.

[0055] When multiple microneedle working areas are adopted, the microneedles can be made into multi-round hydrothermal response microneedles, and different microneedle working areas respond to drug administration in stages, which has a better therapeutic effect in more usage scenarios.

[0056] For different working areas, one way of partitioning can adopt an interval seam and is set separately.

[0057] As Figures 9-10 shown, there is an interval seam between any two adjacent hydrothermal material layer petals, and the microneedle array 100 includes several microneedle array petals 110, and there is an interval seam between any two adjacent microneedle array petals 110.

[0058] In order to achieve that one hydrothermal material layer petal only generates a thermal effect on one working area of the microneedle array 100, any one hydrothermal material layer petal is only connected to one microneedle array petal 110. Of course, multiple hydrothermal material layer petals can be provided on the same working area of the microneedle array 100, and thus the same microneedle array 100 working area can be activated in stages and multiple times to a certain extent.

[0059] Any one of the microneedle array petals 110 is fan-shaped, and multiple microneedle array petals 110 form a circular structure. When fitting and protruding from the diseased part, the whole patch can form an arc-shaped curved surface, which can better wrap the diseased part.

[0060] A hydrothermal material protection layer 300 is provided on the activation surface of the hydrothermal material layer 200. The activation surface of the hydrothermal material layer 200 is generally the side away from the microneedle array 100, and the activation surface is used to contact water. In order to avoid the reaction of the hydrothermal material layer 200 with water vapor in the air during storage and cause heat release failure, the exposed surface of the hydrothermal material layer 200 can be wrapped by the protection layer to isolate it from water vapor in the air as much as possible.

[0061] The selection of the material for the hydrothermal material protective layer 300 includes sucrose. Using molten sucrose to wrap the exposed surface (activation surface) of the hydrothermal material layer 200 can achieve the protection of the hydrothermal material protective layer 300. In some other requirements, a material that can isolate and protect the hydrothermal material protective layer 300 and is easily soluble in water can be used.

[0062] The selection of the material for the hydrothermal material layer 200 includes calcium oxide. Granular calcium oxide particles can be used for the calcium oxide, and the calcium oxide particles are evenly attached to the bottom surface of the microneedle array 100. The loading mass of calcium oxide is 1 mg to 10 mg.

[0063] The microneedle array 100 is loaded with a therapeutic drug. When each microneedle array 100 is used (after being segmented or before being assembled), the drug concentration is 50 μg / ml to 2 mg / ml, and the loading amount of the antibody in the microneedles is 1 μg to 5 mg. The drug can be an anti-tumor drug such as paclitaxel.

[0064] The microneedle array 100 can be made of a high molecular polymer. The high molecular polymer solution during preparation can be at least a polycaprolactone / dichloromethane solution, and the polymers used include but are not limited to polymers such as polycaprolactone. Biocompatible polymers are mostly used for the high molecular polymer.

[0065] The second aspect Introduce the preparation method of the hydrothermal-responsive microneedle patch.

[0066] The preparation method of the hydrothermal-responsive microneedle patch mainly includes the following steps

[0067] S1. Loading the therapeutic drug: Add the therapeutic drug into the PDMS mold, apply vacuum, centrifuge, and dry.

[0068] S2. Constructing the microneedle array: Add the high molecular polymer solution into the PDMS mold loaded with the therapeutic drug, apply vacuum, centrifuge, and dry to obtain the microneedle array.

[0069] S3. Constructing the hydrothermal-responsive microneedles: Set the hydrothermal material at the bottom of the microneedle array to form the hydrothermal-responsive microneedles.

[0070] Among them, the selection of the hydrothermal material includes calcium oxide.

[0071] In order to prepare multi-round hydrothermal-responsive microneedles, the following steps are further included

[0072] S4. Constructing multi-round hydrothermal-responsive microneedles:

[0073] The hydrothermal-responsive microneedles are divided into several hydrothermal-responsive microneedle petals, and there is a spacing gap between any two adjacent hydrothermal-responsive microneedle petals. A hydrothermal material protective layer is provided on the activation surface of any one hydrothermal-responsive microneedle petal to form multi-round hydrothermal-responsive microneedles. In this preparation method, during the first three steps of preparing the microneedles, a relatively large microneedle is prepared, and then the microneedle is separated into several independent working blocks, and each working block can work independently. In one case, the number of divided working blocks is 3, and the drug content of each working block is the same (whether the content is the same refers to the clinical standard, and there may be a certain error).

[0074] Or,

[0075] Several hydrothermal-responsive microneedles with hydrothermal material protective layers provided on their activation surfaces are assembled, and there is a spacing gap between any two adjacent hydrothermal-responsive microneedles to form multi-round hydrothermal-responsive microneedles. In this preparation method, during the first three steps of preparing the microneedles, a single microneedle working petal is prepared, and then multiple prepared microneedle petals are assembled to form a large microneedle patch. In one case, the number of single-prepared working petals is 3, and the drug content of each working petal is the same (whether the content is the same refers to the clinical standard, and there may be a certain error).

[0076] "Multi-round drug delivery" is a concept of multiple drug deliveries. For example, the number of drug delivery times and doses for different drugs acting on the treatment of different diseases are not fixed, and the drug delivery rounds can be determined according to specific experimental requirements. Thus, different numbers of hydrothermal-responsive microneedle sheets are set. Generally, one drug delivery behavior is regarded as one round.

[0077] The selection of the hydrothermal material protective layer material includes sucrose or other materials that can wrap the hydrothermal material layer and do not activate the hydrothermal material.

[0078] The acting drugs include anti-tumor drugs, and the anti-tumor drugs include paclitaxel. When using anti-tumor drugs, it is possible to more effectively administer drugs to superficial tumors and improve the treatment effect. For example, drugs can be specifically administered to melanoma. The drug concentration is 50 micrograms per milliliter to 2 milligrams per milliliter, and the loading amount of antibodies in the microneedles is 1 microgram to 5 milligrams.

[0079] The polymer solution is a polycaprolactone / dichloromethane solution, and the polymers used include but are not limited to polymers such as polycaprolactone. Biocompatible polymers are more commonly used for the polymer.

[0080] Regarding some conditions in the preparation process, specifically,

[0081] The pressure of the vacuum is 1 - 5 kPa, the centrifugation speed is 1000 - 3000 revolutions per minute, the number of repetitions of the operation is 1 - 20 times, the polymer concentration is 1% - 20%, the pressure of the vacuum is 1 - 5 kPa, the number of repetitions is 1 - 5 times, the centrifugation speed is 1000 - 3000 revolutions per minute, the drying temperature is 20 degrees Celsius to 40 degrees Celsius, and the drying time is 3 - 72 hours.

[0082] The third aspect Introduce the application of the hydrothermal-responsive microneedle patch.

[0083] The application of the hydrothermal-responsive microneedle patch in the preparation of products for treating deep melanoma or breast cancer. During use, the acting drug (such as paclitaxel) is loaded on the drug application surface of the hydrothermal-responsive microneedle patch.

[0084] A more specific application method can be as follows: First, add the paclitaxel DMSO solution into the microneedle mold, apply vacuum, and centrifuge to make the drug solution flow into the mold voids. Then, add the polycaprolactone / dichloromethane solution into PDMS to prepare a microneedle patch loaded with the drug.

[0085] When using the hydrothermal-responsive microneedle patch, multiple microneedle response working flaps can be combined to form a multi-round hydrothermal-responsive microneedle patch.

[0086] The fourth aspect Make a further introduction in combination with some specific research projects.

[0087] Example 1 Loading of Paclitaxel Drug

[0088] Use software such as solidworks to design the microneedle matrix, and use a small 3D printer to print out the mold with orange resin. Use a commercial PDMS kit to construct a microneedle mold with cavities. After fixing in a 3.5 mm cell culture dish, add 100 μL of 0.4 mg / mL paclitaxel DMSO solution, apply vacuum at about 2.5 KPa atmospheric pressure for 10 minutes, and centrifuge using a horizontal rotor centrifuge (2000 revolutions per minute, 20 minutes). After the liquid flows into the mold voids, supplement the drug solution and apply vacuum again for 10 minutes. The above process is repeated 3 times.

[0089] Example 2 Construction of the Microneedle Matrix

[0090] After loading the paclitaxel drug, prepare a 10% polycaprolactone / dichloromethane solution, add about 1 mL to PDMS in portions, centrifuge for 20 minutes (2000 revolutions per minute), and place it under a 2.5 KPa vacuum condition for 10 minutes. Dry in a fume hood for 24 hours. After complete drying, carefully peel the microneedles from the mold to obtain the final microneedle matrix (as Figure 1 shown).

[0091] Example 3 Structure of Multi-Round Hydrothermal Response Microneedles (HRMAM)

[0092] Select three fan-shaped microneedles, carefully and evenly disperse the hydrothermal substance at the bottom of the microneedle matrix, then carefully wrap the ends of the microneedle bases with molten sucrose, and place them in a storage box for low-temperature storage (as Figure 2 shown).

[0093] Example 4 Process of Drug Release from Multi-Round Hydrothermal Response Microneedles (HRMAM) by Hydrothermal Response Insert the three-sided fan-shaped microneedle patch into the hydrogel, use a 1.5 ml pipette to drop a drop of ddH2O onto the bottom of one fan-shaped microneedle base. Wait until the temperature of one fan-shaped microneedle drops to room temperature, then repeat dropping water onto the next fan-shaped microneedle to trigger the hydrothermal response, and use a handheld thermal imager to record the temperature change process (as Figures 3-5 shown). Based on the temperature stimulus, the fluorescence of the fan-shaped patch will weaken, corresponding to drug release. The fluorescence of the fan-shaped patch without temperature stimulus does not weaken, and there is no drug release. The quantitative graph of drug release shows the drug release rate in response to temperature for three minutes.

[0094] Example 5 Safety Evaluation of the Stability and Efficacy of Microneedle Materials on Drugs

[0095] Release the paclitaxel drug carried in the prepared microneedle patch into DMSO solvent, co-incubate with tumor cells for 24 hours, and compare the cell viability with the paclitaxel drug before being carried by the microneedle to conduct the safety evaluation of the drug efficacy (as Figure 6 shown).

[0096] Example 6 In Vivo Antitumor Effect of Multi-Round Hydrothermal Response Microneedles (HRMAM)

[0097] Forty-eight Balb / c mice (6 weeks old, female, weighing 18 - 20 g) were randomly divided into six groups of eight mice each seven days after inoculating 800,000 4T1 triple-negative breast cancer cells in the second mammary pad. All mice had free access to food and water. The animal room was set with a 12-hour day-night cycle, and the room temperature was maintained at (22 ± 2) °C. The first group of mice in Group I received no treatment (control group); in the second group of mice in Group II, the HRMAM patch prepared in Example 2 (with a paclitaxel content of 120 micrograms) was pressed on the tumor surface without hydrothermal response treatment; in the third group of mice in Group III, paclitaxel (100 micrograms) was injected into the tail vein; in the fourth group of mice in Group IV, paclitaxel (100 micrograms) was injected into the tumor; in the fifth group of mice in Group V, the prepared HRMAM patch (with a paclitaxel content of 0) was pressed on the tumor surface and hydrothermal response was given; in the sixth group of mice in Group VI, the HRMAM patch prepared in Example 3 (with a paclitaxel content of 120 micrograms) was pressed on the tumor surface, and the mice were fixed with medical tape for the patch. Thereafter, the body weight and tumor size changes were measured every two days, and the drug was administered once a week for a total of three times. The results proved (asFigure 7 As shown in the figure, the microneedle patch prepared in Example 3 can delay tumor growth for a longer time compared with the conventional drug administration method, and the combination of multiple rounds of drug administration and hydrothermal response further significantly improves the effect.

[0098] In vivo antitumor effect of hydrothermally responsive microneedles (HRMAM) with different rounds in Example 7

[0099] Three groups of mice were respectively treated with a set dose (5 mg / kg) of DTX in single round (HRSAM), double round (HRDAM), and triple round (HRMAM). The drug dosage for each administration was 5 mg / kg, loaded in the same fan-shaped microneedle patches. The drug dosage in each patch was the same, the drug administration area was the same, and the drug release rate for each administration was basically the same. When performing tumor treatment, it is difficult to achieve better inhibitory effects by administering the drug four or five times. On the contrary, it may cause damage to normal tissue cells. The drug dosage for each administration was 5 mg / kg, loaded in the same fan-shaped microneedle patches. The drug dosage in each patch was the same, the drug administration area was the same, and the drug release rate for each administration was basically the same. One administration was to apply a fan-shaped patch with a total area of a and a total drug dosage of b; two administrations were to apply two fan-shaped patches with a total area of 2a and a total drug dosage of 2b, and so on. Therefore, the drug administration area for each administration calculated according to the drug administration area was the same, and the drug release efficiency was also certain, the same for single round and multiple rounds. (A) Individual tumor growth curves of B16F10 tumor-bearing mice after various treatments; (C) Tumors were taken from each group; (D) Tumor weights of each group on the 12th day; (E) Body weights of each group of mice. The results showed that the antitumor effect of HRMAM was significantly better than the other two groups, indicating that HRMAM was relatively the best. And the improvement amplitude of multiple rounds of drug administration compared with double rounds of drug administration was greater than the improvement amplitude of double rounds of drug administration compared with single round of drug administration.

[0100] Those skilled in the art can clearly understand that various modifications to the above embodiments can be made without departing from the general spirit and concept of the present invention. All of them fall within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims attached to the present invention.

Claims

1. Hydrothermal-responsive microneedle patch, characterized in that, Comprising a microneedle array (100) for loading drugs, having microneedle shafts (111) disposed on the puncture drug delivery surface of the microneedle array (100); a hydrothermal material layer (200) which generates heat upon contact with water, disposed on the bottom surface of the microneedle array (100); the hydrothermal material layer (200) comprises several hydrothermal material layer segments, and the several hydrothermal material layer segments are disposed on the bottom surface of the microneedle array (100); the microneedle array (100) comprises several microneedle working areas, and at least one hydrothermal material layer segment is provided in any one of the microneedle working areas; there is a spacing gap between any two adjacent hydrothermal material layer segments, the microneedle array (100) comprises several microneedle array segments (110), and there is a spacing gap between any two adjacent microneedle array segments (110), any one hydrothermal material layer segment is only connected to one microneedle array segment (110); any one of the microneedle array segments (110) is fan-shaped; a hydrothermal material protective layer (300) is provided on the activation surface of the hydrothermal material layer (200); the material selection of the hydrothermal material protective layer (300) includes sucrose; the material selection of the hydrothermal material layer (200) includes calcium oxide.

2. The preparation method of the hydrothermal response microneedle patch according to claim 1, characterized in that, Comprising the following steps S1. Loading the acting drug: adding the acting drug into a mold, applying vacuum, centrifuging, and drying; the vacuum pressure is 1 - 5 kPa, the centrifugation speed is 1000 - 3000 revolutions per minute, the number of repetitions of the operation is 1 - 20 times, the polymer concentration is 1% - 20%, the drying temperature is 20 °C to 40 °C, and the drying time is 3 - 72 hours; S2. Constructing the microneedle array: adding a polymer solution into the mold loaded with the acting drug, applying vacuum, centrifuging, and drying to obtain the microneedle array; S3. Constructing the hydrothermally responsive microneedle: disposing the hydrothermal material at the bottom of the microneedle array to form the hydrothermally responsive microneedle; S4. Constructing multi-round hydrothermally responsive microneedles: dividing the hydrothermally responsive microneedle into several hydrothermally responsive microneedle segments, with a spacing gap between any two adjacent hydrothermally responsive microneedle segments, and disposing a hydrothermal material protective layer on the activation surface of any one hydrothermally responsive microneedle segment to form multi-round hydrothermally responsive microneedles; or assembling several hydrothermally responsive microneedles with hydrothermal material protective layers disposed on their activation surfaces, and having a spacing gap between any two adjacent hydrothermally responsive microneedles to form multi-round hydrothermally responsive microneedles.

3. The preparation method of the hydrothermal response microneedle patch according to claim 2, characterized in that, The material selection of the hydrothermal material includes calcium oxide.

4. The preparation method of the hydrothermal response microneedle patch according to claim 2, wherein The material selection of the hydrothermal material protective layer includes sucrose; The acting drug includes an anti-tumor drug, and the anti-tumor drug includes paclitaxel; The polymer solution is at least a polycaprolactone / dichloromethane solution; The mold is a PDMS mold.

5. Use of the hydrothermally responsive microneedle patch according to any one of claims 1 - 4 in the preparation of a product for treating deep melanoma or breast cancer.

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