Soluble microneedle patch for in-situ drug delivery of trabecular meshwork tissue as well as preparation method and application of soluble microneedle patch

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to a soluble microneedle patch for in-situ drug delivery of trabecular meshwork tissue and a preparation method and application of the soluble microneedle patch. The soluble microneedle patch comprises a fan-ring-shaped backing and a microneedle array arranged on the fan-ring-shaped backing; the micro-needle and the fan-ring-shaped backing are both prepared from polyvinyl alcohol (PVA), the PVA concentration for preparing the micro-needle and the fan-ring-shaped backing is 5%-25%, and the PVA concentration is obtained by weighing 0.5 g-2. 5 g of PVA powder and dissolving the PVA powder in 10 mL of pure water or PBS. The microneedle patch is suitable for delivery of various types of drugs, is expected to be used for treatment of various eye diseases including glaucoma, ocular hypertension, cataract, uveitis, conjunctivitis, xerophthalmia and the like, and has important clinical application value and commercial value.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a soluble microneedle patch for in-situ drug delivery in trabecular meshwork tissue, its preparation method, and its application. Background Technology

[0002] Glaucoma is a chronic neurodegenerative disease of the eye, characterized by optic disc cupping, progressive degeneration of retinal ganglion cells and optic nerve axons, accompanied by irreversible visual field defects and vision loss, making it the leading cause of irreversible blindness worldwide. It is predicted that by 2040, the number of glaucoma patients globally will reach 112 million, placing a huge burden on countries and societies with related treatment costs. Abnormal trabecular meshwork cell function leading to impaired aqueous humor outflow is a major risk factor for elevated intraocular pressure and the development and progression of glaucoma. The trabecular meshwork is located within the iridocorneal angle, and its unique physical spatial distribution makes drug delivery extremely difficult. Current methods for drug delivery to the trabecular meshwork include eye drops, anterior chamber injection, and surgical implants. Among these, eye drops are currently the most widely used method for glaucoma treatment, but their drug bioavailability is extremely low (<5%). Increasing the frequency of eye drop use, such as once a day or even multiple times a day, is intended to improve treatment effectiveness, but the resulting poor patient compliance often leads to treatment failure. Compared to eye drops, anterior chamber injection and surgical implants have higher drug bioavailability, but they have many drawbacks, such as being highly dependent on the operator's skill and expertise, being prone to causing intraocular complications, and having low patient psychological acceptance, making them difficult to become the most mainstream drug delivery method for trabecular meshwork tissue.

[0003] Microneedle patches are a novel drug delivery method consisting of an array of micron-sized microneedles connected to a substrate. They enable the direct release of sufficient drug to the target site, maximizing drug efficacy. Due to their painless, non-invasive, and easy-to-use advantages, microneedle patches have attracted considerable research attention regarding their drug delivery function in ocular tissues. Types of microneedle patches include soluble microneedles, solid microneedles, hollow microneedles, and coated microneedles. Soluble microneedles, made from water-soluble materials, offer advantages such as good safety and high drug loading capacity. Polyvinyl alcohol (PVA) is a commonly used matrix material approved by the FDA for the preparation of soluble microneedles, and soluble microneedles prepared from PVA exhibit both good biocompatibility and mechanical properties. However, there is currently no microneedle patch designed specifically for the unique physical spatial distribution of the trabecular meshwork. Existing microneedle patches cannot adapt to the location characteristics of the trabecular meshwork, making it difficult to achieve efficient and safe in-situ drug delivery to the trabecular meshwork. Therefore, there is an urgent need to develop a soluble microneedle patch specifically for in-situ drug delivery to the trabecular meshwork to fill this technological gap. Summary of the Invention

[0004] The purpose of this invention is to provide a soluble microneedle patch for in-situ drug delivery in trabecular meshwork tissue, its preparation method and application. This microneedle patch is suitable for the delivery of various types of drugs and is expected to be used for the treatment of various eye diseases, including glaucoma, ocular hypertension, cataracts, uveitis, conjunctivitis, dry eye syndrome, etc., and has important clinical application value and commercial value.

[0005] The objective of this invention is achieved through the following technical solution: This invention provides a soluble microneedle patch for in-situ drug delivery in trabecular meshwork tissue. The soluble microneedle patch includes a fan-shaped backing and microneedles arranged in an array on the fan-shaped backing. Both the microneedles and the fan-shaped backing are made of polyvinyl alcohol.

[0006] Furthermore, the PVA concentration of the microneedles and the fan-shaped backing is 5%-25%, which is obtained by dissolving 0.5g-2.5g of PVA powder in 10mL of pure water or PBS.

[0007] Furthermore, the array contains 11 microneedles; the actual dimensions of the microneedles are: height 745.6±18.49μm, bottom diameter 356.3±11.59μm, needle body spacing 493.1±20.02μm, and needle tip diameter 11.28±1.93μm.

[0008] This invention also provides a method for preparing the soluble microneedle patch for in-situ drug delivery in trabecular meshwork tissue, comprising the following steps: (1) Positive mold preparation: The fan-shaped microneedle patch structure of the size described in claim 1 is designed by three-dimensional drawing software, and the corresponding size of polymer material positive mold is prepared by 3D printing technology; (2) Preparation of negative mold: Polydimethylsiloxane and curing agent are mixed at a preset volume ratio, and after centrifugation to remove bubbles, the mixture is injected into the positive mold described in step (1), centrifuged again to remove bubbles, and then heated at a preset temperature for a preset time to cure. After cooling to room temperature, the PDMS negative mold is obtained. (3) Preparation of microneedle patch: PVA matrix liquid of the concentration described in claim 2 is poured into the PDMS negative mold groove of step (2) according to a preset volume. After centrifugation, the operation is repeated a preset number of times. Then, it is dried at a preset temperature for a preset time and placed in a preset temperature environment. Finally, the soluble microneedle patch is separated from the negative mold.

[0009] Furthermore, the three-dimensional drawing software mentioned in step (1) is 3DMax, and the polymer material is polymer resin.

[0010] Furthermore, in step (2), the preset volume ratio is 10:1, the centrifugation speed is 3500 rpm and the time is 5 minutes, the preset temperature is 85℃, and the preset time is 2 hours.

[0011] Furthermore, in step (3), the preset volume is 2 μL, the centrifugation speed is 4000 rpm and the time is 15 minutes, the preset number of times is 3, the preset drying temperature is 37°C and the preset time is 15 minutes, the preset temperature environment is a 4°C refrigerator, and the placement method is overnight.

[0012] The present invention also provides the application of the soluble microneedle patch for in-situ drug delivery in trabecular meshwork tissue in the preparation of drugs for in-situ drug delivery in trabecular meshwork tissue.

[0013] Furthermore, the application includes the preparation of a drug for treating an eye disease selected from at least one of glaucoma, ocular hypertension, cataracts, uveitis, conjunctivitis, and dry eye syndrome.

[0014] Furthermore, the types of drugs that the microneedle patch can load include at least one of hydrophilic drugs and nucleic acid / liposome complexes.

[0015] The beneficial effects of this invention are as follows: The microneedle patch designed and prepared in this invention has the following advantages: (1) The ring-fan design effectively avoids the central corneal region and the limbal stem cell region, ensuring the transparency of the pupil optical zone and minimizing pain as much as possible (corneal nerves gradually decrease from the center of the cornea outwards). (2) The appropriate microneedle length design ensures efficient drug delivery while avoiding damage to the corneal endothelial cell layer caused by penetrating the entire corneal layer (corneal endothelial cells have almost no self-regeneration function). (3) It contains only PVA, which has been approved by the FDA. The raw materials are simple and safe, and the preparation process is simple, which is conducive to large-scale mass production. (4) The treatment procedure is simple. The microneedle patch is applied to the corneal edge area and gently pressed for 2 minutes. It can be used once and then discarded, which effectively improves patient compliance. (5) The microneedle patch has good biosafety, and its minimally invasive and painless characteristics effectively reduce the psychological barriers to patients caused by methods such as ocular injection and surgical implantation. (6) The microneedle patch has good mechanical properties and can effectively break the physical barrier of the corneal epithelium; (7) This microneedle patch can efficiently deliver different types of drugs, such as hydrophilic drugs and nucleic acid / liposome drugs, into the trabecular meshwork tissue, significantly improving the bioavailability of the trabecular meshwork tissue; (8) This microneedle patch can be used to open up a new in-situ drug delivery technology for trabecular meshwork tissue, and can be further used for drug delivery in anterior segment tissues, including cornea, conjunctiva, sclera, anterior chamber, iris, ciliary body, lens, etc.

[0016] (9) This microneedle patch is suitable for the delivery of various types of drugs and is expected to be used to treat a variety of eye diseases, including glaucoma, ocular hypertension, cataracts, uveitis, conjunctivitis, dry eye, etc. This invention has important clinical application value and commercial value. Attached Figure Description

[0017] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0018] Figure 1 This is a schematic diagram showing the dimensions of the fan-shaped soluble microneedle patch in this invention; Figure 2 This is a stereomicroscope image of the microneedle patch morphology taken in the open field in Embodiment 1 of the present invention; Figure 3 This is a scanning microscope image of the microneedle patch morphology and its specific dimensions as shown in Embodiment 1 of the present invention. Figure 4 This is a mechanical property test diagram of the microneedle patch in Embodiment 1 of the present invention; Figure 5 This is a microscopic field image and a statistical diagram of the puncture depth of the anterior chamber tissue after microneedle patch puncture in Embodiment 1 of the present invention.

[0019] Figure 6 This is a diagram showing the degree of dissolution of the cornea at different time points after the microneedle patch punctures the cornea in Embodiment 1 of the present invention; Figure 7 These are fluorescence microscopy and scanning electron microscopy images of the microneedle patch loaded with nucleic acid / liposome complex and hydrophilic small molecule drug in Example 1 of the present invention; Figure 8 This is a confocal microscope image showing the expression of functional proteins in the trabecular meshwork tissue after puncture of a microneedle patch loaded with a nucleic acid / liposome complex in Example 1 of this invention. Figure 9 This is a UPLC-MS-MS image showing the drug content in the trabecular meshwork and aqueous humor after puncture of the microneedle patch loaded with hydrophilic small molecule drugs in Example 1 of the present invention. Figure 10 This is a graph showing the safety of the rat's eye and changes in body weight after microneedle patch puncture in Example 1 of the present invention. Detailed Implementation

[0020] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0021] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0022] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0023] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0024] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0025] The preferred embodiments of the present invention will now be described in detail with reference to the accompanying drawings: Example 1 I. Preparation of Materials and Equipment 1. Core Materials Matrix materials: polyvinyl alcohol (PVA, FDA approved grade), polydimethylsiloxane (PDMS) and matching curing agent; Solvents: pure water, phosphate buffered saline (PBS); Drugs and markers: fluorescent molecule C6, Nmnat1-GFP plasmid, cationic liposomes, fluorescent molecule Cy3, hydrophilic small molecule drug NAM; Animal samples: SPF-grade SD rats (for in vivo testing, in accordance with animal ethics guidelines); Anesthetic: 1% sodium pentobarbital solution.

[0026] 2. Key Equipment Design software: 3D drawing software 3DMax (used for microneedle patch structure design). Preparation equipment: 3D printer (for printing positive molds using polymer resin material), constant temperature heating stage (for curing at 85℃), centrifuge (3500rpm / 4000rpm), oven (for drying at 37℃); Testing equipment: texture analyzer (mechanical property testing), stereomicroscope (morphological observation and demolding operation), scanning electron microscope (SEM, for precise measurement of microneedle size), confocal fluorescence microscope (for drug delivery effect observation), ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS, for drug concentration quantification), and slit lamp (for ocular safety observation).

[0027] II. Preparation steps of soluble microneedle patches 1. Preparation of a positive mold for a fan-shaped microneedle patch To avoid the central corneal region, ensure the transparency of the pupillary optical zone, and minimize pain (corneal nerves radiate outwards from the center of the cornea, gradually decreasing in number), while also avoiding penetration of the full corneal layer that could damage the corneal endothelial cell layer (corneal endothelial cells have almost no self-regenerative function) and avoiding damage to limbal stem cells, a fan-shaped microneedle patch structure was designed using 3DMax: it contains 11 conical microneedles, each with a height of 800μm, a base diameter of 400μm, and a center-to-center spacing of 600μm; the fan-shaped backing has a height of 500μm, an inner arc of 2.4mm, an outer arc of 3.1mm, and a difference in inner and outer radii of 1.4mm.

[0028] Using 3D printing technology and polymer resin as raw material, a fan-shaped microneedle patch positive mold with the same design size was printed, which was then used for subsequent preparation of the negative mold.

[0029] 2. Preparation of PDMS negative mold Mix PDMS and curing agent at a volume ratio of 10:1, place in a centrifuge tube and centrifuge at 3500 rpm for 5 minutes to remove air bubbles from the mixture; Slowly inject the defoamed PDMS mixture into the male mold, and centrifuge again at 3500 rpm for 5 minutes to ensure that the mixture completely fills the microneedle grooves of the male mold and avoids air bubble residue. Place the positive mold containing PDMS on an 85℃ constant temperature heating table and heat it for 2 hours to cure. After the male mold and PDMS have cooled to room temperature, the PDMS is gently peeled off to obtain a fan-shaped microneedle patch female mold that complements the structure of the male mold, for later use.

[0030] 3. Preparation of fan-shaped soluble microneedle patches Preparation of PVA matrix solution: Weigh 0.5g, 1g, 1.5g, 2g and 2.5g of PVA powder respectively, add 10mL of pure water or PBS to each, and heat and stir in a 60℃ constant temperature water bath for 2 hours until PVA is completely dissolved to obtain PVA matrix solutions with concentrations of 5%, 10%, 15%, 20% and 25%. Casting and centrifugation: Use a pipette to draw 2 μL of PVA matrix solution and cast it evenly into the microneedle grooves of the PDMS negative mold. Centrifuge at 4000 rpm for 15 minutes to ensure that the matrix solution fully fills the grooves. Repeat this step 3 times to ensure that the grooves are completely filled. Drying and demolding: The cast negative mold was placed in a 37°C oven to dry for 15 minutes, and then transferred to a 4°C refrigerator overnight; the next day, the microneedle patch was separated from the PDMS negative mold by sterile forceps under a stereomicroscope to obtain a complete fan-shaped soluble microneedle patch. Morphology verification: The overall morphology of the patch was observed using a stereomicroscope. Figure 2 As shown, a miniature fan-shaped microneedle patch was successfully obtained, on which 11 fully formed conical microneedles were arranged. Furthermore, the actual dimensions of the microneedles were obtained by scanning electron microscopy (SEM) imaging and measurement: microneedle height approximately 745.6 ± 18.49 μm, base diameter 356.3 ± 11.59 μm, needle spacing 493.1 ± 20.02 μm, and tip diameter 11.28 ± 1.93 μm. Figure 3 ).

[0031] III. Core Performance Testing of Microneedle Patches 1. Mechanical performance testing Place the microneedle patch with the tip facing upwards on the stainless steel platform of the texture analyzer, and select a cylindrical probe with a diameter of 1 cm. Set the texture analyzer parameters: constant speed 0.1 mm / s, apply external force vertically to the microneedle patch, preset termination pressure distance 500 μm; Results: PVA microneedle patches with concentrations of 5%-20% did not break during the entire pressure application process (e.g. Figure 4 As shown in the figure, it has sufficient mechanical strength to break the corneal epithelial barrier.

[0032] 2. Corneal barrier breaking ability test SD rats were anesthetized by intraperitoneal injection of 1% sodium pentobarbital solution. Microneedle patches were then applied to the corneal limbus of the rats and removed after gentle pressure with the thumb for 2 minutes. The rat eyeballs were dissected, corneal tissue sections were prepared, and the puncture effect and puncture depth were observed under a microscope. Results: The puncture depth of the 20% PVA microneedle patch reached 67.91±7.98 μm, which is greater than the thickness of the corneal epithelium in rats (38.4±1.2 μm), enabling drug delivery to the corneal stroma (e.g., Figure 5 (As shown in the image); existing studies have shown that once the drug enters the corneal stroma, it can rapidly diffuse into the anterior chamber, which is beneficial for drug absorption by the trabecular meshwork. Furthermore, this microneedle patch does not penetrate the corneal endothelium, demonstrating good safety.

[0033] 3. Solubility test SD rats were anesthetized by intraperitoneal injection of 1% sodium pentobarbital solution. Microneedle patches were applied to the corneal margin and removed after pressing for 0.5 minutes, 1 minute, and 2 minutes respectively. The dissolution state of the microneedle patch was observed using a stereomicroscope; Results: The needle tip completely dissolved after 0.5 minutes of pressure, the needle body partially dissolved after 1 minute, and the needle body completely dissolved after 2 minutes (e.g., Figure 6 As shown in the figure, it can be rapidly dissolved in the eye to achieve drug release.

[0034] IV. Verification of Drug Loading and In-situ Drug Delivery Efficacy 1. Feasibility verification of combined drug delivery Preparation of nucleic acid / liposome complex: The fluorescent molecule C6 was mixed with the Nmnat1-GFP plasmid and encapsulated into cationic liposomes by thin film dispersion to form nucleic acid / liposome complex (C6 / Nmnat1-LNPs). Preparation of hydrophilic drug system: The hydrophilic fluorescent molecule Cy3 is mixed with a hydrophilic NAM small molecule drug (Cy3 / NAM) to indicate the hydrophilic small molecule drug; Preparation of drug-loaded patches: C6 / Nmnat1-LNPs and Cy3 / NAM were mixed with 20% PVA matrix solution to prepare a combined drug-loaded microneedle patch; Results: Observation under a fluorescence microscope showed that... Figure 7 As shown in Figure A, the fan-shaped soluble microneedle patch can effectively combine a nucleic acid / liposome complex with a hydrophilic small molecule drug. Nmnat1-GFP plasmid, NAM small molecule drug, and 20% PVA were mixed to prepare single-drug-loaded and combined-drug-loaded microneedle patches, respectively. Figure 7 As shown in B, loading nucleic acid / liposome complexes and hydrophilic small molecule drugs did not disrupt the intact morphology of the microneedles.

[0035] 2. Validation of in-situ drug delivery in trabecular meshwork (1) Nucleic acid / liposome complex drug delivery Anesthetize SD rats, apply microneedle patches carrying nucleic acid / liposome complex (Nmnat1-LNPs) to the corneal edge, press for 2 minutes and then remove; Dissect the eyeball, prepare frozen sections, mount with coverslips, and observe under a confocal fluorescence microscope; Results: Fluorescent signals of Nmnat1-GFP protein were clearly observed in the trabecular meshwork (TM) region (e.g., Figure 8 As shown in the figure, this indicates that the microneedle patch successfully delivered the nucleic acid / liposome complex into the trabecular meshwork tissue in situ.

[0036] (2) Hydrophilic small molecule drug delivery Group testing: The “NAM-loaded microneedle patch group” and the “microneedle backing (BP) group” were set up and applied to the edge of the rat cornea, respectively. After pressing for 2 minutes, they were removed. Drug quantification: One hour later, the trabecular meshwork tissue and aqueous humor of rats were separated, and the NAM concentration was detected by UPLC-MS-MS; Results: Compared with the backing group, the microneedle patch group showed a 7.5-fold increase in NAM concentration in the trabecular mesh structure and a 105-fold increase in NAM concentration in the aqueous humor (e.g., ...). Figure 9 As shown in the figure, its efficient drug delivery capability is confirmed.

[0037] V. Animal safety assessment Ocular safety observation: SD rats were anesthetized with 1% sodium pentobarbital solution. Microneedle patches were applied to the corneal rim area of ​​the rats. After gently pressing with the thumb for 2 minutes, the microneedle patches were removed. The rats were observed for ocular surface edema, inflammation, neovascularization, corneal defects and other indicators using a slit lamp. Result: As Figure 10 As shown in AB, the rat cornea was transparent, without edema, inflammation, or neovascularization. Immediately after the microneedle patch was inserted, 11 fan-shaped array-like punctate defects were generated. Most of the defects healed after 6 hours, and the cornea returned to its intact state after 24 hours, indicating that this microneedle patch has good ocular safety in animals.

[0038] Systemic safety observation: Rat body weight was monitored for 14 consecutive days; Results: The use of microneedle patches did not affect the weight gain of rats, further demonstrating the animal safety of the microneedle patches (e.g., Figure 10 (As shown in C), there were no systemic adverse reactions.

[0039] In summary, in this embodiment, 20% PVA is the optimal matrix concentration: its mechanical strength meets the requirements for corneal puncture, its solubility is suitable for drug release within 2 minutes, and it does not damage the microneedle structure after drug loading; the fan-shaped design avoids the central optical zone of the cornea and limbal stem cells, minimizing pain and tissue damage; the operation only requires "adhesion and pressing for 2 minutes," without the need for professional medical intervention, which can significantly improve patient compliance. This embodiment demonstrates that this microneedle patch can achieve efficient in-situ drug delivery to the trabecular meshwork tissue, and has good safety and mass production feasibility, which can be further used for the treatment of eye diseases such as glaucoma and cataracts.

[0040] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A soluble microneedle patch for in-situ drug delivery in trabecular meshwork tissue, characterized in that, The soluble microneedle patch includes a fan-shaped backing and microneedles arranged in an array on the fan-shaped backing; both the microneedles and the fan-shaped backing are made of polyvinyl alcohol.

2. The soluble microneedle patch according to claim 1, characterized in that, The PVA concentration of the microneedles and the fan-shaped backing is 5%-25%, which is obtained by dissolving 0.5g-2.5g of PVA powder in 10mL of pure water or PBS.

3. The soluble microneedle patch according to claim 1, characterized in that, The array contains 11 microneedles; the actual dimensions of the microneedles are: height 745.6±18.49μm, bottom diameter 356.3±11.59μm, needle spacing 493.1±20.02μm, and needle tip diameter 11.28±1.93μm.

4. A method for preparing a soluble microneedle patch for in-situ drug delivery in trabecular meshwork tissue as described in any one of claims 1-3, characterized in that, Includes the following steps: (1) Positive mold preparation: The fan-shaped microneedle patch structure of the size described in claim 1 is designed by three-dimensional drawing software, and the corresponding size of polymer material positive mold is prepared by 3D printing technology; (2) Preparation of negative mold: Polydimethylsiloxane and curing agent are mixed at a preset volume ratio, and after centrifugation to remove bubbles, the mixture is injected into the positive mold described in step (1), centrifuged again to remove bubbles, and then heated at a preset temperature for a preset time to cure. After cooling to room temperature, the PDMS negative mold is obtained. (3) Preparation of microneedle patch: PVA matrix liquid of the concentration described in claim 2 is poured into the PDMS negative mold groove of step (2) according to a preset volume. After centrifugation, the operation is repeated a preset number of times. Then, it is dried at a preset temperature for a preset time and placed in a preset temperature environment. Finally, the soluble microneedle patch is separated from the negative mold.

5. The preparation method according to claim 4, characterized in that, The three-dimensional drawing software mentioned in step (1) is 3DMax, and the polymer material is polymer resin.

6. The preparation method according to claim 4, characterized in that, The preset volume ratio in step (2) is 10:1, the centrifugation speed for defoaming is 3500 rpm and the time is 5 minutes, the preset temperature is 85℃ and the preset time is 2 hours.

7. The preparation method according to claim 4, characterized in that, The preset volume in step (3) is 2 μL, the centrifugation speed is 4000 rpm and the time is 15 minutes, the preset number of times is 3, the preset drying temperature is 37℃ and the preset time is 15 minutes, the preset temperature environment is a 4℃ refrigerator, and the placement method is overnight.

8. The use of the soluble microneedle patch for in-situ drug delivery in trabecular meshwork tissue as described in any one of claims 1-4 in the preparation of drugs for in-situ drug delivery in trabecular meshwork tissue.

9. The application according to claim 8, characterized in that, The application includes the preparation of a drug for treating an eye disease selected from at least one of glaucoma, ocular hypertension, cataracts, uveitis, conjunctivitis, and dry eye syndrome.

10. The application according to claim 8, characterized in that, The microneedle patch can be loaded with at least one of the following drug types: hydrophilic drugs and nucleic acid / liposome complexes.

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