A methotrexate delivery microneedle chip and a preparation method and use thereof

Abstract

The present application relates to the technical field of medicine, and particularly relates to a methotrexate delivery microneedle chip and a preparation method and use thereof. The methotrexate delivery microneedle chip comprises a substrate and a plurality of needle bodies arranged in an array on the substrate; the methotrexate delivery microneedle chip is formed by casting forming of a composition comprising methotrexate, a film-forming material and a solute, wherein the concentration of methotrexate in the composition is 10-25 mg / mL. The present application is aimed at refractory inflammatory skin diseases (especially nail psoriasis) in clinic, and a fully biodegradable methotrexate (MTX) drug-loaded transdermal micro delivery chip is developed by using micro / nano and biomaterial technologies. The MTX drug-loaded micro delivery chip can realize microneedle array transdermal delivery, chip subcutaneous fixed-point drug release, subcutaneous controllable residence and slow release, and the whole chip can achieve conformal fitting wear with the skin.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a methotrexate delivery microneedle chip, its preparation method, and its uses. Background Technology

[0002] Psoriasis is a chronic inflammatory skin disease with a global prevalence of approximately 0.5-3%, and a prevalence of 0.47% in my country according to a 2010 epidemiological survey. Psoriasis not only affects the skin but also frequently affects the fingernails and toenails. The prevalence of nail involvement in psoriasis patients ranges from 10% to 80.1%, with a lifetime incidence of over 80%. The different clinical manifestations of nail psoriasis depend on the different parts of the nail affected, generally divided into nail matrix involvement or nail bed involvement, and both can also occur simultaneously. Nail matrix involvement manifests as nail pitting, leukonychia, erythema lunulae, nail thickening, and brittleness, while nail bed involvement manifests as oil droplet-like changes, onycholysis, subungual hyperkeratosis, and linear hemorrhages.

[0003] Due to the unique physiological and anatomical structure of the nails (dense nail plate structure, strong drug penetration barrier), the treatment cycle is relatively long, and traditional topical medications are difficult to effectively reach the nail matrix and nail bed. There is currently no corresponding expert consensus or treatment guidelines for this condition. Commonly used local treatments include topical corticosteroids, vitamin D3 derivatives, retinoids, and calcineurin inhibitors, but these are limited by the nail plate barrier, resulting in low drug penetration efficiency, limited efficacy, and a high incidence of adverse reactions.

[0004] For patients with nail matrix involvement, clinical guidelines recommend intradermal injection of corticosteroids at the proximal nail fold. However, this injection therapy has significant drawbacks: it requires professional personnel to perform the procedure, and can cause acute or chronic pain at the injection site, short-term sensory abnormalities, hematoma formation, and nail plate loss. While systemic therapies such as oral or injectable methotrexate (MTX) have some efficacy, they carry systemic adverse reactions such as hepatotoxicity and bone marrow suppression, and require frequent administration, leading to poor patient compliance. Topical MTX formulations are also limited by the nail plate barrier, making it difficult to achieve ideal efficacy. Therefore, there is an urgent need for a novel drug delivery method that can achieve targeted drug delivery to the nail matrix, is minimally invasive and painless, and is easy to administer.

[0005] In the field of microneedle transdermal drug delivery technology, researchers have conducted extensive work. Zhen Gu et al. achieved controlled-response release of insulin microneedles in vivo, Matthew J. Mistilis et al. achieved stable loading of influenza vaccines into microneedles, and Wei Li et al. successfully loaded contraceptive drugs into microneedles. Regarding psoriasis treatment, studies have applied methotrexate-loaded microneedles to animal models of psoriasis. Du et al. (2019) demonstrated in a mouse model of psoriasis that MTX microneedle patches could reduce erythema and skin thickness, showing superiority over oral administration at the same MTX dose. Other studies have used hyaluronic acid-soluble microneedles loaded with glucocorticoids for the treatment of nail psoriasis, preliminarily confirming the feasibility of microneedle technology in the treatment of nail psoriasis.

[0006] However, existing microneedle technology research has the following obvious limitations: (1) Existing studies on MTX microneedle treatment of psoriasis all use the skin surface (including animal model skin or psoriasis lesion skin) as the drug administration target; however, the treatment target of nail psoriasis is the nail matrix and nail bed, while the skin surface and proximal nail fold have significant differences in anatomical structure, stratum corneum thickness, drug penetration characteristics, etc. The research conclusions of skin surface drug administration cannot be directly extrapolated to the proximal nail fold drug administration scenario.

[0007] (2) Existing studies have focused on the improvement of skin psoriasis plaques, while the pathological changes of nail psoriasis are located in the nail matrix and nail bed. Its treatment endpoints and efficacy evaluation systems (such as mNAPSI score) are completely different from those of skin psoriasis (such as PASI score). The special physiological and anatomical structure of the nail plate makes drug delivery more difficult and the treatment cycle longer.

[0008] (3) There are currently no systematic research reports on microneedle chip parameters (such as needle tip height, base flexibility, drug administration time, pressure intensity, etc.) specifically designed for the anatomical characteristics of the proximal nailfold, and there is also a lack of clinical efficacy data on MTX microneedles administered via the proximal nailfold route. Summary of the Invention

[0009] The purpose of this invention is to provide a methotrexate delivery microneedle chip, its preparation method, and its applications. The technical problem to be solved by this invention is not limited to the described technical subject matter; other technical subjects not mentioned herein will be clearly understood by those skilled in the art through the following description.

[0010] Transdermal drug delivery systems are a method of drug delivery through the skin surface using physical or chemical methods. This approach can increase the depth of local drug action, bypass the metabolism of drugs by liver and gastrointestinal enzymes, avoid the first-pass effect, reduce the amount of drug used, maintain constant blood drug concentrations or physiological effects, and prolong the duration of action. Furthermore, it offers advantages such as convenient administration, high patient compliance, easy removal, and reduced side effects, thus attracting increasing attention. Among these technologies, microneedle-chip drug delivery technology based on Micro-Electro-Mechanical Systems (MEMS) is the latest transdermal drug delivery technology and is currently a cutting-edge research focus internationally. It has attracted researchers' attention for the delivery of large molecule drugs such as insulin and vaccines, and is a humane, minimally invasive, painless, precise, efficient, and safe microdevice.

[0011] This invention targets clinically refractory inflammatory skin diseases. Utilizing micro / nano and biomaterial technologies, it systematically develops a fully biodegradable methotrexate (MTX) transdermal drug delivery chip, exploring its precise drug delivery, micro / nano-structured transdermal delivery, and clinical applications in skin disease treatment. This MTX drug delivery chip enables transdermal delivery via a microneedle array, targeted drug release under the skin, controlled subcutaneous residence and sustained release, and a conformal fit to the skin. The MTX drug delivery chip technology developed in this invention features high efficiency, painlessness, ease of use, and strong patient compliance. Small doses can be used for precise local treatment, potentially leading to a complete cure for patients with long-term, refractory, and topically resistant mild to moderate psoriasis rashes. Low doses avoid the first-pass effect in the liver and do not cause gastrointestinal reactions, hepatotoxicity, or bone marrow suppression, thus providing a high-quality and efficient treatment option for patients with moderate to severe psoriasis.

[0012] In a first aspect, the present invention provides a methotrexate delivery microneedle chip, comprising: a substrate and a plurality of needles arranged in an array on the substrate; the methotrexate delivery microneedle chip is formed by casting of a composition comprising methotrexate, a film-forming substance and a solute, wherein the concentration of methotrexate in the composition is 10-25 mg / mL.

[0013] In one embodiment, the needle body is a square pyramid; the ratio of the base length of the needle body to its original height is 8-24:21-37.

[0014] Specifically, the ratio of the bottom side length of the needle body to its original height is 1:0.875 to 4.625; preferably 16:29 (i.e. 1:1.8125).

[0015] In another embodiment, the original height of the needle body is 525–925 μm, the bottom side length is 200–600 μm, and the distance between the centers of two adjacent needle bodies is 600–1000 μm.

[0016] Specifically, the theoretical height of the needle body is 800μm, the original height is 725μm, the bottom side length is 400μm, and the distance between the centers of two adjacent needle bodies is 800μm.

[0017] In this invention, the original height is the height of the needle body after it has been formed on the substrate and is not subjected to external force; the actual height in the working state is the effective insertion height of the needle body when it is pressed into the skin. Therefore, in one embodiment, the needle body deforms in the working state of inserting into the skin, so that the ratio of its actual height (i.e., transdermal depth) in the working state to the original height of the needle body is 4-12:21-37.

[0018] Specifically, the ratio of the actual height (i.e., transdermal depth) of the needle body in the working state to the original height of the needle body is 1:1.75 to 9.25; preferably 8:29 (i.e. 1:3.625).

[0019] In another embodiment, the actual height (i.e., transdermal depth) of the needle body in the working state is 100-300 μm, preferably 200 μm.

[0020] In one embodiment, the film-forming substance includes, but is not limited to, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, and sodium alginate; preferably, polyvinyl alcohol has a relative molecular mass of 30–70 kDa.

[0021] In another embodiment, the methotrexate delivery microneedle chip is removed after being inserted into the skin, and the skin recovers to normal within 40–60 minutes.

[0022] In one embodiment, the methotrexate delivery microneedle chip has a storage stability of ≥20 days at room temperature.

[0023] In another embodiment, when stored at room temperature for the same period of time, the retention rate of methotrexate in the methotrexate delivery microneedle chip is significantly higher than that of methotrexate solution.

[0024] In a second aspect, the present invention provides a method for preparing the above-mentioned methotrexate delivery microneedle chip, wherein an aqueous solution of the film-forming substance is added to the methotrexate to form a methotrexate-film-forming substance aqueous solution, which is then cast and cured.

[0025] In one embodiment, the film-forming substance is polyvinyl alcohol with a relative molecular mass of 30–70 kDa.

[0026] In another embodiment, the aqueous solution of the film-forming substance has a mass fraction of 8-12%, preferably 10%.

[0027] In one embodiment, the specific operation of the casting and curing is as follows: the methotrexate-film-forming substance aqueous solution is poured into the microneedle mold, defoamed, and dried and cured at room temperature.

[0028] Specifically, the degassing operation is as follows: evacuate for 5-15 minutes to remove air bubbles, with a vacuum pressure of 0.05-0.10 MPa. Preferably, the vacuum pressure is 0.08 MPa and the evacuation time is 10 minutes.

[0029] In another embodiment, the concentration of methotrexate in the aqueous solution of the film-forming substance is 10-25 mg / mL, preferably 16.67 mg / mL.

[0030] In a third aspect, the present invention provides a pharmaceutical formulation comprising: the above-described methotrexate delivery microneedle chip and pharmaceutically acceptable excipients.

[0031] In one embodiment, the dosage form of the product includes, but is not limited to, patches and sustained-release formulations.

[0032] In a fourth aspect, the present invention provides the use of the above-described methotrexate delivery microneedle chip, or the above-described pharmaceutical preparation, in the preparation of products for treating chronic inflammatory skin diseases.

[0033] In one embodiment, the chronic inflammatory skin disease is at least one of nail psoriasis and atopic dermatitis.

[0034] In another embodiment, the product includes, but is not limited to, drugs, medical devices, drug-device combinations, etc.

[0035] In a fifth aspect, a method for treating chronic inflammatory skin diseases involves administering an effective amount of the aforementioned methotrexate delivery microneedle chip or the aforementioned product to a patient with a chronic inflammatory skin disease.

[0036] In one implementation, the effective amount is the dose used to treat chronic inflammatory skin diseases in patients with such diseases.

[0037] In another implementation, the patient is a mammal, such as a primate.

[0038] In one embodiment, the chronic inflammatory skin disease is at least one of nail psoriasis and atopic dermatitis.

[0039] Compared with existing technologies, the present invention has the following advantages: (1) Construct a novel fully degradable MTX drug delivery microchip technology to introduce a novel transdermal delivery method for MTX drugs in clinical practice.

[0040] (2) Achieve flexible integrated packaging of microneedle drug-carrying chips, and truly realize portable and wearable precision drug delivery technology.

[0041] (3) The first application of MTX drug delivery chip to treat nail psoriasis and atopic dermatitis, and close monitoring of patients, provides new clinical evidence for topical medication for chronic inflammatory skin diseases.

[0042] (4) The efficacy of MTX drug delivery chip administration and mometasone furoate cream in the treatment of atopic dermatitis was observed and compared to provide a reliable, efficient and accurate treatment basis for clinical practice. Attached Figure Description

[0043] Figure 1 Bright-field image of microneedle fabrication using a methotrexate PVA solution with a concentration of 16.67 mg / mL.

[0044] Figure 2 Bright-field photographs of the dissolution process of methotrexate microneedles in gel; where a is the original gel, b is the gel into which the microneedles are inserted, c is the gel after the microneedles are removed, and d is a magnified view of the microneedle pores in c.

[0045] Figure 3 Images of normal skin before microneedle insertion; where a is a bright field photograph and b is an HE-stained section.

[0046] Figure 4 Images are taken after microneedles are inserted into the skin; a is a bright-field photograph, and b is a HE-stained section.

[0047] Figure 5 This shows the recovery of mouse skin within 60 minutes after microneedle chip removal.

[0048] Figure 6 This study compares the stability of methotrexate in microneedle loading versus solution loading.

[0049] Figure 7 This describes the fabrication process for microneedle chips.

[0050] Figure 8 The study investigated the improvement of nail condition in patients with psoriasis on the nails after 24 weeks of treatment (twice a week with topical MTX patches). The table shows the following: 1 represents the baseline nail condition; 2 represents the nail condition during MTX microneedling treatment; 3 represents the nail condition after 4 weeks of treatment (Visit 1); 4 represents the nail condition after 8 weeks of treatment (Visit 2); 5 represents the nail condition after 12 weeks of treatment (Visit 3); 6 represents the nail condition after 16 weeks of treatment (Visit 4); 7 represents the nail condition after 20 weeks of treatment (Visit 5); and 8 represents the nail condition after 24 weeks of treatment (Visit 6).

[0051] Figure 9 The curve of mNAPSI score over time is shown.

[0052] Figure 10 The curve shows the change of the mNAPSI score of the parent material over time.

[0053] Figure 11 The curve showing the change of the mNAPSI score of the nail bed over time.

[0054] Figure 12 The efficacy of MTX microneedling in treating atopic dermatitis was evaluated. Group A was the blank microneedling group, group B was the MTX microneedling treatment group, group C was the mometasone furoate cream topical treatment group, and group D was the blank control group. 1 represents the baseline atopic dermatitis rash; 2 represents the effect of MTX microneedling and blank microneedling on the rash; 3 represents the rash appearance in each group after 1 week of treatment (visit 1); 4 represents the rash appearance in each group after 2 weeks of treatment (visit 2); 5 represents the rash appearance in each group after 3 weeks of treatment (visit 3); 6 represents the rash appearance in each group after 4 weeks of treatment (visit 4); 7 represents the rash appearance in each group after 5 weeks of treatment (visit 5); 8 represents the rash appearance in each group after 6 weeks of treatment (visit 6); 9 represents the rash appearance in each group after 7 weeks of treatment (visit 7); and 10 represents the rash appearance in each group after 8 weeks of treatment (visit 8).

[0055] Figure 13 The change in the target rash score (TPSS) from baseline to the last visit (week 8 visit) for atopic dermatitis was studied. Group A was the blank microneedling group, Group B was the MTX microneedling treatment group, Group C was the mometasone furoate cream topical treatment group, and Group D was the blank control group.

[0056] Figure 14 The study examined the changes in target rash score (TPSS) over time and the differences between groups in atopic dermatitis (8th visit vs. baseline). Group A was the blank microneedling group, Group B was the MTX microneedling treatment group, Group C was the mometasone furoate cream topical treatment group, and Group D was the blank control group. Detailed Implementation

[0057] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0058] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0059] The methotrexate (MTX) used below has a relative molecular mass of 454 Da and was purchased from Pfizer Inc. (USA). The polyvinyl alcohol (PVA) used below has a relative molecular mass of 30-70 kDa and was purchased from Sigma-Aldrich (USA). Higher molecular weight PVA (30-70 kDa) can simultaneously meet the requirements of transdermal needle tip strength and substrate flexibility.

[0060] Example 1 First, prepare the PVA solution: Dissolve the PVA powder in ultrapure water to prepare a 10wt% homogeneous and stable solution, and store it at 4°C for later use. Then, add the PVA solution to the MTX powder to form a homogeneous and stable MTX-PVA solution.

[0061] In constructing microneedles, a film-forming solution containing mixed drugs is first poured in once, followed by a second pour of a pure film-forming solution. The mixture is then dried and solidified to form the microneedles. Figure 7 As shown. The specific operation is as follows: Pour the MTX-PVA solution into the microneedle mold, ensuring the mold is completely filled. Vacuum (approximately 0.08 MPa) for about 10 minutes to roughly remove air bubbles from the needle holes. If any solution is lost during the vacuuming process, add more solution to ensure the microneedle mold is always filled with MTX-PVA solution. Place in a clean bench and allow air circulation for about 20 hours for drying and curing at room temperature.

[0062] The parameters of the obtained microneedle chip are as follows: substrate size 1.5 × 1.5 cm. 2 The microneedle array contains 256 (16×16) microneedles, with a distance of 800 μm between the centers of two adjacent needles. Each microneedle is a square pyramid with a consistent structure and a sharp tip. The tip height is 725 μm (the theoretical height of the mold is 800 μm), and the base length is 400 μm.

[0063] To prevent direct contact between the fingers and the drug-containing microneedle chip, after the microneedle chip has completely solidified, PVA solution is added again until the microneedle mold is full, and then dried and solidified. Finally, it is demolded, stored in a petri dish, and sealed with sealing tape, then placed at room temperature for later use.

[0064] Example 2 Considering the required drug loading capacity and material strength in clinical practice, a PVA solution with an MTX concentration of 16.67 mg / mL was selected to prepare the drug delivery microneedle chip. The 16.67 mg / mL PVA solution was prepared as follows: 3 mL of PVA solution was added to 50 mg of methotrexate powder to form a 16.67 mg / mL solution, which was then cast into a microneedle. The chip exhibited good molding properties, and the microneedle tips possessed transdermal strength. Figure 1 As shown.

[0065] Example 3 To assess the solubility of the MTX drug delivery microneedle chip, the MTX drug delivery microneedle chip obtained in Example 2 was inserted into the gel with tweezers and removed after 60 seconds.

[0066] like Figure 2 This describes the dissolution process of the MTX drug delivery microneedle chip obtained in this embodiment within the gel. For example... Figure 2 As shown in Figure c, the residual yellow color on the gel after removing the microneedles indicates that the microneedles dissolved and released the drug.

[0067] A magnified view of the remaining pinholes, such as... Figure 2 As shown in Figure d, the pyramidal needle holes left by the microneedles are clearly visible. Comparing the microneedles removed after inserting the gel with the original microneedles, it can be seen that the needle tips have dissolved, indicating that the microneedle chip can successfully release the drug encapsulated within its needle tips.

[0068] Example 3 To evaluate the transdermal delivery of the microneedle chip in live mice, the inventors conducted a transdermal experiment using 8-week-old B6 mice. Before transdermal delivery, the mice were anesthetized with isoflurane gas for 5 minutes. Hair was removed from the back area of ​​the mice using a razor and depilatory cream. The MTX drug delivery microneedle chip obtained in Example 2 was pressed firmly onto the skin of the mouse's back using the thumb. The mice were then euthanized by cervical dislocation, and the skin area, along with the microneedles, was immersed in 4% cell fixative for preservation. HE-stained sections were then prepared, and the skin with the microneedles inserted (e.g., ...) was examined. Figure 4 (as shown) and normal skin (such as) Figure 3 (As shown) Compare and observe the transdermal depth of microneedles in vivo.

[0069] like Figure 4 As shown in b, HE staining results revealed that the epidermis pierced by the microneedles was stretched and could indeed break through the epidermal layer to enter the dermis, with a transdermal depth of about 200 μm. This indicates that the microneedles can indeed successfully enter the subcutaneous layer to deliver drugs.

[0070] Example 4 To evaluate the recovery of mouse skin after microneedle removal, the inventors conducted a transdermal experiment using 8-week-old B6 mice. Before transdermal administration, mice were anesthetized with isoflurane gas for 5 minutes. Similarly, the hair on the back of the mice was removed with a razor and depilatory cream. The MTX drug delivery microneedle chip obtained in Example 2 was pressed firmly onto the skin on the back of the mice with the thumb and removed after 5 minutes. The condition of the mouse skin after microneedle removal was observed, and photos were taken at 0 min, 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, and 60 min after microneedle chip removal.

[0071] like Figure 5As shown, the mouse skin returned to normal about one hour after the microneedle chip was removed.

[0072] The experimental results from Examples 3 and 4 combined verify that microneedles have the dual advantages of being both transdermal and minimally invasive.

[0073] Example 5 To evaluate the drug storage stability of the MTX drug delivery microneedle chip obtained in Example 2 at room temperature, the inventors observed the microneedle chip after 20 days at room temperature, and took samples for testing at 0, 3, 5, 7, 10, 15, and 20 days. When testing the MTX concentration of the microneedle chip, the chip was dissolved in 1 mL of ultrapure water, and the concentration was tested using a methotrexate ELISA kit according to the instructions for use.

[0074] The inventors discovered that methotrexate has a higher retention rate in microneedle chips than in solution, such as... Figure 6 As shown, this demonstrates that methotrexate encapsulated in microneedle chips exhibits higher stability and is less prone to inactivation than when stored in solution, thereby reducing the storage and transportation requirements for the drug.

[0075] Example 6: Therapeutic effect of nail psoriasis This invention recruited 15 patients with nail psoriasis and applied the MTX drug delivery microneedle chip obtained in Example 2 twice a week (pressed onto the proximal nail fold for 15 minutes). The improvement of methotrexate microneedle treatment mNAPSI score from baseline and drug-related safety were evaluated using the modified nail psoriasis assessment scale (mNAPSI), thereby evaluating its efficacy in treating nail psoriasis.

[0076] Table 1. Baseline and visit scores for nail psoriasis, nail matrix, and nail bed mNAPS.

[0077] Note: 1. For comparisons between multiple visit time points (>2) of the same subject, the Friedman test was used because the outcome indicators did not conform to normality; 2. For comparisons between two visit time points of the same subject, the Wilcoxon Signed Rank test was used because the outcome indicators did not conform to normality; 3. Statistical significance was judged at the 0.05 level.

[0078] Table 2. Improvement of mNAPS scores for nail psoriasis, nail matrix, and nail bed compared to baseline during follow-up visits.

[0079] Note: 1. For comparisons between multiple visit time points (>2) of the same subject, Friedman's test was used for ordered categorical indicators; 2. Statistical significance was judged at the 0.05 level.

[0080] MTX microneedling treatment efficacy such as Figure 8 As shown in the figure. The changes in mNAPSI scores of the whole nail, nail matrix, and nail bed over time are respectively as follows. Figure 9 , Figure 10 , Figure 11 As shown.

[0081] After 12 weeks of treatment, the mNAPSI score of patients with A1 treated with MTX drug delivery microneedle chip was lower than the baseline level (P<0.05) (see Table 1), 26.67% of patients had moderate improvement in A1 compared with the baseline (improvement degree >50-75%), and 1 patient was clinically cured (6.67%) (see Table 2).

[0082] After 24 weeks of treatment, the mNAPSI score of patients with A1 treated with MTX drug delivery microneedle chip was lower than the baseline level (P<0.05) (see Table 1). 46.67% of patients showed moderate improvement in A1 compared to baseline (improvement >50-75%), 26.67% of patients showed significant improvement in A1 compared to baseline (improvement >75-99%), and 2 patients achieved clinical cure (13.33%) (see Table 2).

[0083] Example 7: Therapeutic effect of atopic dermatitis This invention recruited 15 patients with atopic dermatitis and completed a randomized controlled clinical observation. The treatment period was 8 weeks. Before each treatment, photos were taken and the target rash score (TPSS) was recorded.

[0084] Among them, Group A: blank microneedle group, treated with blank microneedles (without MTX, still prepared according to the method of Example 2) twice a week, with pressure applied to the rash for 15 minutes; Group B: MTX microneedle treatment group, treated with MTX microneedles (MTX drug delivery microneedle chip obtained in Example 2) twice a week, with pressure applied to the rash for 15 minutes; Group C: mometasone furoate cream applied topically once a day; Group D: blank control group.

[0085] Table 3. Differences in target rash score (TPSS) among different groups of atopic dermatitis.

[0086] Table 4. Number of cases with >50% improvement in Target Rash Score (TPSS) at the 8th visit for atopic dermatitis compared to baseline.

[0087] The efficacy of MTX microneedling treatment for atopic dermatitis is as follows: Figure 12As shown. Wilcoxon signed-rank test was used to compare the differences between the experimental and control groups. All statistical tests were considered to have a two-sided significance level of 0.05. The changes in the baseline TPSS score of the atopic dermatitis group from the initial TPSS score to the last visit (week 8 visit) are shown below. Figure 13 As shown.

[0088] Except for the control group, TPSS decreased to varying degrees in all groups after treatment. The degree of decrease in each group and the differences between groups are shown in Table 3. Figure 14 As shown in Table 4, the skin rash improved by more than 50% in group C, followed by group B, then group A, while the control group did not show a significant decrease. In group C, 15 patients (100%), in group B, 3 patients (20%), and in group A, 0 patients showed improvement after treatment.

[0089] The present invention has been described in detail above. Those skilled in the art will recognize that the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope, and without requiring unnecessary experiments. While specific embodiments have been provided, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including changes made using conventional techniques known in the art that depart from the scope disclosed herein.

Claims

1. A methotrexate delivery microneedle chip, characterized in that, include: A substrate and a plurality of needles arranged in an array on the substrate; The methotrexate delivery microneedle chip is formed by casting a composition comprising methotrexate, a film-forming substance and a solute, wherein the concentration of methotrexate in the composition is 10–25 mg / mL.

2. The methotrexate delivery microneedle chip according to claim 1, characterized in that, The needle body is a square pyramid shape; the ratio of the base length of the needle body to its original height is 8-24:21-37.

3. The methotrexate delivery microneedle chip according to claim 1, characterized in that, The ratio of the actual height of the needle in working condition to the original height of the needle is 4-12:21-37.

4. The methotrexate delivery microneedle chip according to claim 1, characterized in that, At room temperature, the methotrexate delivery microneedle chip exhibits storage stability of ≥20 days.

5. A method for preparing a methotrexate delivery microneedle chip as described in any one of claims 1-4, characterized in that, An aqueous solution of the film-forming substance is added to the methotrexate to form a methotrexate-film-forming substance aqueous solution, which is then cast and cured.

6. The preparation method according to claim 5, characterized in that, The specific operation of the casting and curing is as follows: the methotrexate-film-forming substance aqueous solution is poured into the microneedle mold, defoamed, and dried and cured at room temperature.

7. A pharmaceutical preparation, characterized in that, include: The methotrexate delivery microneedle chip and pharmaceutically acceptable excipients as described in any one of claims 1-4.

8. The pharmaceutical preparation according to claim 7, characterized in that, Its dosage form is selected from any of the following dosage forms: patch, sustained-release preparation.

9. The use of the methotrexate delivery microneedle chip according to any one of claims 1-4, or the pharmaceutical preparation according to any one of claims 7-8, in the preparation of a product for treating chronic inflammatory skin diseases.

10. The use according to claim 9, characterized in that, The chronic inflammatory skin disease mentioned is at least one of nail psoriasis and atopic dermatitis.

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