Microneedle drug delivery device and manufacturing process thereof

Abstract

The present disclosure relates to the technical field of drug delivery technology, in particular a microneedle drug delivery device and a manufacturing process thereof. The device comprises a substrate, a microneedle array, and a liquid-absorbing swelling material, wherein the substrate supports the microneedle array and the liquid-absorbing swelling material is enclosed within the substrate to form a sandwich structure. The device utilizes a mild water absorption-expansion mechanism and the natural peristaltic behavior of the gastrointestinal tract to insert microneedles into the intestinal wall, thereby achieving drug delivery. The device overcomes physical physiological barriers to the oral administration and absorption of biologics, thereby improving their oral bioavailability.All materials used are biodegradable soft materials, thus ensuring a high level of safety.

Description

TECHNICAL AREA

[0001] The present disclosure relates to the technical field of drug delivery technology, in particular a microneedle drug delivery device and a manufacturing process thereof. STATE OF THE ART

[0002] Oral administration has long been a preferred method of drug delivery due to its simplicity and high patient compliance. However, this approach is unsuitable for biological macromolecular drugs such as polypeptides, proteins, nucleic acids, and antibodies. Currently, injectable delivery methods, including intramuscular and intravenous injections, remain the primary route of administration for such biomolecular drugs. Nevertheless, problems such as pain, skin infections, allergic reactions, and poor patient compliance persist. Therefore, the development of novel delivery methods to replace injections remains an important avenue for pharmaceutical innovation. Liraglutide, a hypoglycemic agent used in diabetes intervention therapy, serves as an example.Since it currently requires daily injections, it causes significant inconvenience and discomfort for patients. Novo Nordisk® has developed semaglutide, which offers similar efficacy but requires only once-weekly injections. However, the problems associated with injection administration persist, particularly for patients with chronic conditions requiring long-term monitoring and repeated dosing. Therefore, the oral administration of biologics is of great medical importance.

[0003] However, biologics have low bioavailability when administered orally, which is due to three primary physiological barriers encountered during drug administration. First, after oral administration, drugs must pass through the acidic environment of the gastrointestinal tract and the physicochemical barriers formed by various digestive enzymes. Biologics such as polypeptides, proteins, and nucleic acids are prone to denaturation, inactivation, or degradation, which impairs the drug's efficacy. Furthermore, the mucus layer in the gastrointestinal tract represents another barrier to drug absorption. The mucus layer is a dynamic gel network composed of mucins and highly glycosylated glycoproteins.Through electrostatic interactions and its molecular network, it blocks the penetration of pathogens, but simultaneously inhibits the absorption and utilization of most macromolecule drugs. The final barrier is the poor absorption of the small intestinal epithelial cells: due to their large molecular size and the lack of corresponding receptors, biological macromolecules generally cannot enter the bloodstream via either transcellular or paracellular transport.

[0004] Given the challenges mentioned above in the oral administration of biologics, pharmacists are exploring various solutions. These include pH regulators, enzyme inhibitors, permeation enhancers, and cell-penetrating peptides to protect the macromolecules from degradation and promote their absorption. For example, permeation enhancers are essentially surfactants that temporarily damage the epithelial cells of the small intestine to increase drug absorption. The oral semaglutide tablet developed by Novo Nordisk® in 2019 uses sodium 8-(2-hydroxybenzamido)octanoate (salcaprozate sodium), a typical permeation enhancer. This forms a stable complex with semaglutide via non-covalent interactions, effectively increasing the lipophilicity of the drug and thus promoting uptake by the epithelial cells.While the use of various functional components can improve the stability and absorption of the active ingredient, these methods typically achieve a bioavailability of only about 1% due to biocompatibility limitations. Furthermore, differences in chemical structure, hydrophilicity / lipophilicity, and degradation rates among various drugs result in a lack of universality among adjuvant types and formulations, leading to lengthy development times. Novel oral delivery technologies such as intestinal patches, gastrointestinal hydrogels, or externally controlled delivery devices only partially overcome these three physiological barriers and also exhibit complex handling and low biocompatibility. Further technological advancements are needed, and currently, there are few effective and universally applicable technologies for the oral administration of biologics.

[0005] The microneedle drug delivery device for the gastrointestinal wall represents a promising, recently developed approach to oral drug administration. As a physical delivery system, microneedles can effectively penetrate the mucus layer and the epithelial barrier, delivering the drug directly into the tissue of the gastrointestinal wall, from where it is absorbed via the capillaries. This method is universally applicable and effective, regardless of the molecular weight of the administered drug. Furthermore, since the intestinal wall lacks pain receptors, the insertion of the microneedles is painless. Precise sizing of the microneedles can prevent intestinal perforation. Compared to other oral administration methods, this microneedle drug delivery device could therefore enable high drug utilization with a high level of safety.

[0006] Existing microneedle drug delivery technologies for the gastrointestinal wall often utilize springs, elastomers, or reactive chemicals. These rapidly release elastic potential energy or generate gases through rapid reactions to drive drug-loaded microneedles into the gastrointestinal wall. Furthermore, patent literature describes devices equipped with substances responsive to external fields, the application of which is controlled by magnetic or other external fields to trigger microneedle insertion. This physical insertion method ensures that macromolecules bypass the body's triple barriers, enter the bloodstream directly, and thereby improve the oral bioavailability of biologics. The aforementioned technologies face several challenges.First, poor biocompatibility results from the use of rigid materials such as springs, elastomers, or magnetosensitive substances as propulsion units; these materials are difficult to degrade and can pose risks if they remain in the gastrointestinal tract for extended periods or are retained there; furthermore, patient acceptance and compliance remain low; second, it is difficult to guarantee successful delivery rates with single-use rapid delivery methods, such as...Those with springs have difficulty ensuring consistent success rates when faced with the physiological variations that occur in different patients; thirdly, the retention efficacy of microneedles is overlooked. Existing microneedle drug delivery devices primarily focus on penetrating the epithelial cells of the gastrointestinal wall and neglect the retention effect of microneedles within the gastrointestinal wall. Microneedles can be dislodged from the gastrointestinal wall during peristalsis, thereby impairing the efficiency of drug delivery.

[0007] Therefore, there is an urgent need to develop an orally administered drug delivery device with high bioavailability. CONTENT OF THE PRESENT DISCLOSURE

[0008] The present disclosure aims to solve, at least to some extent, one of the technical problems in the related technology. To this end, one objective of the present disclosure is to provide a microneedle drug delivery device and a manufacturing method thereof. The microneedle drug delivery device provided by the present disclosure utilizes a mild water absorption expansion mechanism and the natural peristaltic behavior of the gastrointestinal tract to insert microneedles into the intestinal wall and thus achieve drug delivery. It is characterized by simple operation and a gentle drive mode, eliminating the need for external field control devices or rigid, non-degradable drive units, thereby ensuring a high level of safety.At the same time, it utilizes the mode of action of intestinal contraction forces to create a safe and effective area, thereby making the technical solution provided by the present disclosure more universally applicable.

[0009] For this purpose, the present disclosure provides, in one aspect, a microneedle drug delivery device. According to one embodiment of the microneedle drug delivery device of the present disclosure, the device comprises a substrate, a microneedle assembly, and a liquid-absorbing swelling material, wherein the substrate supports the microneedle assembly, the liquid-absorbing swelling material being enclosed in the substrate to form a sealed sandwich structure, the tips of the microneedles being loaded with the drug.

[0010] According to one embodiment of the present disclosure, the drug comprises at least one selected from biological macromolecule drugs and chemical small molecule drugs.

[0011] According to one embodiment of the present disclosure, the biological macromolecule drug comprises at least one selected from polypeptides, proteins, polysaccharides and nucleic acid drugs.

[0012] According to one embodiment of the present disclosure, the microneedles contained in the microneedle arrangement have a monolayer conical shape or a barbed structure, wherein the number of microneedles is from 1 to 1000.

[0013] According to one embodiment of the present disclosure, the barbed structure comprises at least one structure selected from a jaw-like, turret-like or spike-like configuration.

[0014] According to one embodiment of the present disclosure, the microneedles contained in the microneedle arrangement have a length of 30 to 5000 µm, a base dimension of 10 to 5000 µm and a tip dimension of 1 to 300 µm, wherein the base dimension is greater than or equal to the tip dimension.

[0015] According to one embodiment of the present disclosure, the substrate is a flexible, stretchable substrate, wherein the material for producing the substrate comprises at least one selected from sodium alginate, chitosan, cellulose and polyvinyl alcohol.

[0016] According to one embodiment of the present disclosure, the substrate surface has a microporous structure.

[0017] According to one embodiment of the present disclosure, the micropore diameter is 10 to 1000 µm.

[0018] According to one embodiment of the present disclosure, the micropore diameter is 80 to 500 µm.

[0019] According to one embodiment of the present disclosure, the micropore density is 0.01 to 1000 per mm². 2 .

[0020] According to one embodiment of the present disclosure, the liquid-absorbing swelling material comprises at least one selected from hydrogels, water-absorbing rubbers and water-absorbing resins.

[0021] According to one embodiment of the present disclosure, the liquid-absorbing swelling material is selected from water-absorbing polymeric resins.

[0022] According to one embodiment of the present disclosure, the particle size of the water-absorbing polymeric resin is 0.01 to 20 mm.

[0023] According to one embodiment of the present disclosure, the particle size of the water-absorbing polymeric resin is 0.5 to 5 mm.

[0024] According to one embodiment of the present disclosure, the microneedle drug delivery device further comprises a controllable release device, wherein the controllable release device encapsulates the substrate, the microneedle arrangement and the liquid-absorbing swelling material.

[0025] According to one embodiment of the present disclosure, the controllable release device has an enteric coating.

[0026] According to one embodiment of the present disclosure, the dimensions of the microneedle drug delivery device in source equilibrium do not exceed the inner diameter of the patient's intestinal lumen.

[0027] In another aspect, the present disclosure provides a method for manufacturing the above microneedle drug delivery device, comprising the following steps: (1) Production of a microneedle array; (2) Preparation of a substrate, application of the microneedle array obtained in step (1) to the substrate surface to obtain a substrate microneedle array; (3) Producing a liquid-absorbing swelling material, wherein the liquid-absorbing swelling material is arranged within the substrate of the substrate-microneedle arrangement obtained in step (2) to form a sealed sandwich structure.

[0028] According to one embodiment of the present disclosure, the method for producing the microneedle assembly in step (1) comprises at least one method selected from 3D printing, photolithography, soft photolithography, thermoplastic extrusion stretching, laser cutting and casting.

[0029] According to one embodiment of the present disclosure, the method for producing the microneedle assembly in step (1) comprises: mixing the drug product and the polymer solution 1, filling the tip position of the mold, performing photocrosslinking to obtain the microneedle assembly; wherein the polymer comprises at least one selected from methacrylated gelatin, methacrylated dextran, methacrylated sodium alginate, methacrylated hyaluronic acid, polyethylene glycol diacrylate and polyethylene glycol.

[0030] According to one embodiment of the present disclosure, the process for producing the substrate in step (2) comprises at least one process selected from spin coating, doctor blade coating, photopolymerization, chemical crosslinking, physical crosslinking and freeze-thaw cycles.

[0031] According to one embodiment of the present disclosure, the method for applying the microneedle arrangement to the substrate surface in step (2) comprises at least one method selected from photochemical crosslinking, chemical crosslinking and physical bonding.

[0032] According to one embodiment of the present disclosure, the method for producing the substrate in step (2) comprises: introducing the polymer solution 2 into a mold and performing photocrosslinking with the microneedle arrangement obtained in step (1), demolding to obtain a substrate-microneedle arrangement; wherein the polymer comprises at least one selected from a group consisting of a polymer with photocrosslinkable groups, a polymer monomer molecule with photocrosslinkable groups, and a composite of a polymer without photocrosslinkable groups and a polymer with photocrosslinkable groups.

[0033] According to one embodiment of the present disclosure, the polymer with photocrosslinkable groups comprises at least one selected from methacrylated gelatin, methacrylated chitosan, poly(ethylene glycol) F 127 acrylate and poly(ethylene glycol) acrylate; wherein the polymer without photocrosslinkable groups comprises at least one selected from polyvinyl alcohol, sodium alginate, chitosan and cellulose; wherein the polymer monomer molecule with photocrosslinkable groups comprises at least one selected from acrylamide, acrylic acid, N,N-methyleneacrylamide and methyl acrylate.

[0034] According to one embodiment of the present disclosure, step (3) particularly comprises: producing a water-absorbing resin based on a natural polymer; introducing the water-absorbing resin based on a natural polymer into the interior of the substrate of the substrate microneedle assembly produced in step (2) to form a sealed sandwich structure, thereby obtaining the microneedle drug delivery device.

[0035] According to one embodiment of the present disclosure, the drug comprises at least one selected from biological macromolecule drugs and chemical small molecule drugs.

[0036] According to one embodiment of the present disclosure, the biological macromolecule drug comprises at least one selected from polypeptides, proteins, antibodies, polysaccharides and nucleic acid drugs.

[0037] According to one embodiment of the present disclosure, the photocrosslinking process in step (1) comprises the following: Mixing the drug, polymer solution 1 and photoinitiator 1 to form a photocrosslinking solution, which is then dripped onto the needle tip position of the mold; ensuring that the photocrosslinking solution completely fills the needle tip position by ultrasonic movement, centrifugation or vacuum extraction, and performing crosslinking.

[0038] According to one embodiment of the present disclosure, the photoinitiator 1 comprises at least one selected from benzoin and its derivatives, benzoyl compounds, alkylphenones, acylphosphine oxides and benzophenones.

[0039] According to one embodiment of the present disclosure, the photocrosslinking process in step (2) comprises: mixing the polymer solution 2 and the photoinitiator 2, introducing the mixture into the mold and performing UV crosslinking under an ice water bath.

[0040] According to one embodiment of the present disclosure, the photoinitiator 2 comprises at least one selected from benzoic acid and its derivatives, phenyl derivatives, alkylbenzophenones, acylphosphine oxides and diphenylbenzophenones.

[0041] According to one embodiment of the present disclosure, step (2) further comprises performing a freeze-thaw cycle treatment after photocrosslinking.

[0042] According to one embodiment of the present disclosure, in step (3) the water-absorbing resin based on a natural polymer is filled into the cavity formed in the substrate and bonded using a biological adhesive or by hot pressing.

[0043] According to one embodiment of the present disclosure, the raw materials for the production of the liquid-absorbing swelling material in step (3) comprise a water-absorbing polymer and a crosslinking agent.

[0044] According to one embodiment of the present disclosure, the water-absorbing polymer comprises at least one selected from sodium carboxymethylcellulose, carboxymethyl chitosan, sodium carboxymethyl alginate and hyaluronic acid; wherein the crosslinking agent comprises at least one selected from citric acid, 1-ethyl-(3-dimethylaminopropyl) carbodiimide, glutaraldehyde and genipin.

[0045] In another aspect, the present disclosure provides an application of the aforementioned microneedle drug delivery device in the manufacture of a drug, wherein the drug is administered orally.

[0046] In another aspect, the present disclosure provides a medicinal product comprising the aforementioned microneedle drug delivery device and a pharmaceutical active ingredient.

[0047] In a further aspect, the present disclosure provides a method for the manufacture of a medicinal product, wherein a pharmaceutical active ingredient is introduced into the aforementioned microneedle drug delivery device or the microneedles of a microneedle drug delivery device manufactured according to the aforementioned method.

[0048] Compared to the prior art, the present disclosure has the following advantages: (1) compared to existing pharmaceutical techniques, the present disclosure overcomes physical physiological barriers to the oral administration and absorption of biologics, thereby improving their oral bioavailability; (2) In comparison to existing gastrointestinal delivery devices, the present disclosure avoids the use of non-degradable rigid objects such as springs, elastomers or magnetosensitive particles as a drive module for the drug delivery device, and all materials used are biodegradable soft materials, thus preventing prolonged residence time in the human body or obstruction of the digestive tract, and this ensures a high level of safety and good patient compliance; (3) The present disclosure avoids the one-way trigger administration modes and externally controlled administration modes; instead, it utilizes the volume effect of the expanded device and the natural peristaltic contraction forces of the intestine to drive the microneedles into the intestinal wall and complete the administration. This approach is simple, natural, and uses a gentle propulsion mechanism. (4) the present disclosure improves the retention effect of the microneedles in the intestinal wall tissue by means of microneedle structures with barbs, thereby preventing the microneedles inserted into the intestinal wall from slipping during intestinal peristalsis; (5) the present disclosure allows the drug release rates to be adjusted by modifying the degree of crosslinking, while the source equilibrium volume is adjusted by

[0049] The regulation of the filler content in liquid-absorbing swelling materials and the mechanical strength of flexible, extensible substrates is controlled, providing convenient controllability. Simultaneously, the present disclosure focuses on utilizing normal intestinal contraction movements to drive drug-loaded microneedles into the intestinal wall. It establishes a safe and effective range for the source equilibrium volume based on the action pattern of intestinal contraction forces, thereby improving the universality of the device provided prior to the present disclosure.

[0050] Further aspects and advantages of the present disclosure are partly provided in the following description, partly evident from the following description, or understandable through the practical application of the present disclosure. BRIEF DESCRIPTION OF THE DRAWING

[0051] The above and / or additional aspects and advantages of the present disclosure will become obvious and easily understandable from the description of the embodiments in conjunction with the following drawings. Fig. Figures 1-7 each show an external view of a microneedle drug delivery device manufactured according to the present disclosure. Fig. 1, Fig. 2 to Fig. Figure 3 shows an external view of a spherical, cylindrical and capsule-shaped microneedle drug delivery device manufactured according to the present disclosure; Fig. 4, Fig. 5 to Fig. Figure 6 shows an external view of a spherical, cylindrical and capsule-shaped microneedle drug delivery device manufactured according to the present disclosure, after water absorption and expansion; Fig. Figure 7 shows a longitudinal section view of a capsule-shaped microneedle drug delivery device manufactured according to the present disclosure before and after water absorption and expansion; Fig. Figure 8 shows a form for manufacturing the microneedle assembly according to the present disclosure; Fig. Figure 9 shows a flowchart for the fabrication of the substrate microneedle arrangement in embodiment 1 of the present disclosure; wherein Figure a shows a flowchart for the fabrication of the substrate with a conical microneedle arrangement; wherein Figure b shows a flowchart for the fabrication of the substrate with a pine-like or tower-like microneedle arrangement; Fig. Figure 10 shows an external view of a microneedle drug delivery device in embodiment 2 of the present disclosure, which is loaded into a commercially available capsule shell; Fig. Figure 11 shows a diagram of the pressure exerted by the intestinal tract on sensors of different sizes in embodiment 3 of the present disclosure; Fig. Figure 12 shows a diagram of the results for pressure and force exerted by the intestinal tract on the microneedles in embodiment 3 of the present disclosure; Fig. 13 and Fig. Figure 14 shows the blood glucose-lowering effect of the insulin-loaded microneedle drug delivery device in embodiment 4 of the present disclosure in an experimental mini-pig; Fig. Figure 15 shows the drug release efficiency of the insulin-loaded microneedle drug delivery device in embodiment 4 of the present disclosure; Fig. Figure 16 shows a comparison of the area under the pharmacokinetic curve for insulin administered via intestinal administration, subcutaneous injection, intestinal administration using a conical microneedle drug delivery device, and intestinal administration using a tower-shaped microneedle drug delivery device in embodiment 4 of the present disclosure; Fig. Figure 17 shows gastrointestinal endoscopy images of the small intestine during administration with a microneedle drug delivery device in embodiment 5 of the present disclosure; Fig. Figure 18 shows histological sections of the small intestine of experimental mini-pigs, in vivo and ex vivo, together with a blind control group, after activation of the microneedle drug delivery device in the embodiment of the present disclosure. DETAILED DESCRIPTION

[0052] The following section provides a more detailed explanation of exemplary embodiments of the present disclosure. These exemplary embodiments are merely illustrative, serve only to explain the present disclosure, and cannot be construed as limiting it.

[0053] Furthermore, “the first” and “the second” are used only to explain the objective and cannot be understood as indicating or implying relative importance or implicitly referring to the number of required technical features. Therefore, the features defined by “the first” and “the second” may explicitly or implicitly include at least one of the features. In the explanatory notes to this disclosure, “several” refers to at least two, such as two, three, etc., unless otherwise specified.

[0054] For a better understanding of the present disclosure, certain technical and scientific terms are defined below. Unless expressly defined otherwise herein, all other technical and scientific terms used herein have the meanings generally understood by those skilled in the field of the present disclosure.

[0055] In this document, the terms “comprehensive” or “inclusive” are open expressions, meaning that they encompass the content specified herein without excluding other aspects.

[0056] The term "peptide" refers to a compound formed from α-amino acids linked by peptide bonds and represents an intermediate in protein hydrolysis. A compound formed by the dehydration condensation of two amino acid molecules is called a dipeptide, with analogous terms applying to tripeptides, tetrapeptides, pentapeptides, etc.

[0057] The term "polypeptide" refers to a peptide consisting of three or more amino acid molecules. If the medicinal product encapsulated in the microneedle in the present disclosure is a polypeptide medicinal product, it includes, among others, antibody medicinal products.

[0058] The term "chemical small molecule drug" refers to a chemically synthesized small molecule drug, typically with a molecular weight below 1000.

[0059] The term “microneedle drug delivery device dimensions at source equilibrium” refers to the size that the microneedle drug delivery device reaches when the gradually decreasing expansion force and the progressively increasing substrate tension reach equilibrium during the expansion process of the microneedle drug delivery device.

[0060] The term “area under the pharmacokinetic curve (AUC)” refers to the average area under the plasma concentration-time curve of the drug, calculated using the trapezoidal rule over the entire sampling period.

[0061] According to a specific embodiment of the present disclosure, in one aspect the present disclosure provides a microneedle drug delivery device comprising a substrate, a microneedle arrangement and a liquid-absorbing swelling material, wherein the substrate carries the microneedle arrangement, wherein the liquid-absorbing swelling material is enclosed in the substrate to form a sealed sandwich structure, wherein the tips of the microneedles are loaded with the drug.

[0062] Due to the fluid-absorbing and expanding properties of the fluid-absorbing swelling material, the microneedles in the device remain in a horizontal position when the device is dry, thus resisting compression in the gastric tract. Upon contact with external digestive fluids or water entering the device, the fluid-absorbing swelling material absorbs water and expands, elongating the substrate. The microneedles then stand erect and penetrate the intestinal wall with the aid of intestinal peristalsis. This design reduces the effects of gastric peristalsis on the microneedles, preventing breakage or detachment of the microneedle assembly before it enters the intestinal tract. See Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6 to Fig. 7, wherein Fig. 1, Fig. 2 to Fig. 3 an external view of a microneedle drug delivery device provided by the present disclosure, and the shape of the device may be spherical, rectangular or capsule-shaped, without being limited to these shapes. Fig. 4, Fig. 5 to Fig. Figure 6 shows an external view of a microneedle drug delivery device provided by the present disclosure after expansion, and Fig. Figure 7 shows a longitudinal section view of a capsule-shaped microneedle drug delivery device before and after water absorption and expansion. Assuming that the frequency and amplitude of small bowel peristaltic contractions are constant, A larger volume of the microneedle drug delivery device will be subjected to a greater force. However, since the small intestinal tissue is flexible and can adapt to the shape of the device during contraction, the shape of the microneedle drug delivery device provided by the present disclosure is not limited to cylindrical, spherical, and capsule shapes. Assuming a uniform radial compressive force from the small intestinal wall, a higher apparent modulus of pressure and a higher apparent compressive strength of the device result in less deformation during peristaltic compression of the small intestine, thereby increasing the force exerted and facilitating penetration of the microneedle into the intestinal wall.Since the microneedle material encapsulating the drug does not substantially affect the drug itself, a microneedle drug delivery device provided by the present disclosure can encapsulate any desired drug.

[0063] According to a specific embodiment of the present disclosure, the drug comprises at least one selected from biological macromolecule drugs and chemical small molecule drugs.

[0064] According to a specific embodiment of the present disclosure, the biological macromolecule drug comprises at least one selected from polypeptides, proteins, polysaccharides, and nucleic acid drugs. The microneedle drug delivery device can encapsulate, but is not limited to, polypeptides, proteins, polysaccharides, and nucleic acid drugs.

[0065] According to a specific embodiment of the present disclosure, the microneedles contained in the microneedle arrangement have a monolayer conical shape or a barbed structure, wherein the number of microneedles is from 1 to 1000.

[0066] According to a specific embodiment of the present disclosure, the barbed structure comprises at least one structure selected from a jaw-like, turret-like or spike-like configuration.

[0067] Designing the microneedles with conical, pine-like, turret-like, or spike-like structures increases their release force after penetration of the intestinal wall. This improves the retention effect of the microneedles within the intestinal wall and thus the bioavailability of the drug.

[0068] According to a specific embodiment of the present disclosure, the microneedles contained in the microneedle arrangement have a length of 30 to 5000 µm, a base dimension of 10 to 5000 µm and a tip dimension of 1 to 300 µm, wherein the base dimension is greater than or equal to the tip dimension.

[0069] According to a specific embodiment of the present disclosure, the substrate is a flexible, expandable substrate, wherein the material for producing the substrate comprises at least one selected from sodium alginate, chitosan, cellulose, and polyvinyl alcohol. The flexible, expandable substrate can be subjected to tensile elongation. This property, in combination with the fluid-absorbing and expanding properties of the fluid-absorbing swelling material, enables the microneedle drug delivery device to undergo shape changes within the intestinal tract. When the microneedle drug delivery device is subjected to intestinal compression, assuming that the volume of the fluid-absorbing swelling material remains constant, the compressive force of the intestinal tract is primarily balanced by the tensile stress that arises as the flexible, expandable membrane continues to expand.Therefore, a flexible, stretchable membrane with high toughness and fatigue resistance is required to withstand the frequent contraction movements of the intestinal wall and thus maintain the integrity of the device in the initial phase.

[0070] According to a specific embodiment of the present disclosure, the substrate surface has a microporous structure. This microporous structure can be formed by methods such as needle or laser perforation and serves as water absorption channels to facilitate the penetration of external digestive fluids or water into the interior of the device.

[0071] According to a specific embodiment of the present disclosure, the micropore diameter is 10 to 1000 µm.

[0072] According to a specific embodiment of the present disclosure, the micropore diameter is 80 to 500 µm.

[0073] According to a specific embodiment of the present disclosure, the micropore density is 0.01 to 1000 per mm². 2 .

[0074] According to a specific embodiment of the present disclosure, the liquid-absorbing swelling material comprises at least one selected from hydrogels, water-absorbing rubbers and water-absorbing resins.

[0075] According to a specific embodiment of the present disclosure, the liquid-absorbing swelling material is selected from water-absorbing polymeric resins.

[0076] According to a specific embodiment of the present disclosure, the particle size of the water-absorbing polymeric resin is 0.1 to 20 mm.

[0077] According to a specific embodiment of the present disclosure, the particle size of the water-absorbing polymeric resin is 0.5 to 5 mm.

[0078] According to a specific embodiment of the present disclosure, the microneedle drug delivery device further comprises a controllable release device, wherein the controllable release device encapsulates the substrate, the microneedle arrangement and the liquid-absorbing swelling material.

[0079] According to a specific embodiment of the present disclosure, the controllable release device has an enteric coating.

[0080] The aforementioned enteric coating can be produced by a spray coating process or an immersion coating process. Specifically, the spray coating process involves preparing a 95% ethanol solution containing 6% Eudragit L-100, 0.6% triethyl citrate, and 1.25% talc. Using a spray gun with suitable air pressure and liquid output, micrometer-sized droplets are sprayed onto the controllable release device. After complete evaporation of the solvent, this process is repeated several times to form the enteric coating. The immersion coating process can be carried out by preparing an ethanol solution containing 7% Eudragit L-100, immersing the controllable release device in it, and repeating the process several times after complete evaporation of the solvent to form an enteric coating.

[0081] According to a specific embodiment of the present disclosure, the dimensions of the microneedle drug delivery device at source equilibrium do not exceed the inner diameter of the patient's intestinal lumen. This allows the device to deform axially under pressure, thus preventing intestinal obstruction. The dimensions of the device at source equilibrium are crucial for utilizing the radial compressive forces generated during small bowel peristalsis. If the radial compressive force from the small bowel wall is uniform, a higher apparent modulus of pressure and higher apparent compressive strength of the device result in less deformation during peristaltic compression of the small bowel, thereby increasing the force exerted and facilitating penetration of the microneedle into the intestinal wall.At the same time, the filling volume of the liquid-absorbing source material and the tensile properties of the substrate influence the dimensions of the device in source equilibrium.

[0082] The present disclosure provides, in another aspect, a method for manufacturing the above microneedle drug delivery device, comprising the following steps: (1) manufacturing a microneedle assembly; (2) manufacturing a substrate, applying the microneedle assembly obtained in step (1) to the substrate surface to obtain a substrate-microneedle assembly; (3) manufacturing a liquid-absorbing swelling material, wherein the liquid-absorbing swelling material is arranged within the substrate of the substrate-microneedle assembly obtained in step (2) to form a sealed sandwich structure.

[0083] According to a specific embodiment of the present disclosure, the method for producing the microneedle assembly in step (1) comprises at least one method selected from 3D printing, photolithography, soft photolithography, thermoplastic extrusion stretching, laser cutting and casting.

[0084] According to a specific embodiment of the present disclosure, the method for producing the microneedle assembly in step (1) comprises: mixing the drug product and the polymer solution 1, filling the tip position of the mold, performing photocrosslinking to obtain the microneedle assembly; wherein the polymer comprises at least one selected from methacrylated gelatin, methacrylated dextran, methacrylated sodium alginate, methacrylated hyaluronic acid, polyethylene glycol diacrylate and polyethylene glycol.

[0085] According to a specific embodiment of the present disclosure, the process for producing the substrate in step (2) comprises at least one process selected from spin coating, doctor blade coating, photopolymerization, chemical crosslinking, physical crosslinking and freeze-thaw cycles.

[0086] According to a specific embodiment of the present disclosure, the method for applying the microneedle arrangement to the substrate surface in step (2) comprises at least one method selected from photochemical crosslinking, chemical crosslinking and physical bonding.

[0087] According to a specific embodiment of the present disclosure, the method for producing the substrate in step (2) comprises: introducing the polymer solution 2 into a mold and performing photocrosslinking with the microneedle assembly obtained in step (1), demolding to obtain a substrate-microneedle assembly; wherein the polymer comprises at least one selected from a group consisting of a polymer with photocrosslinkable groups, a polymer monomer molecule with photocrosslinkable groups, and a composite of a polymer without photocrosslinkable groups and a polymer with photocrosslinkable groups.

[0088] According to a specific embodiment of the present disclosure, the form in step (2) can be the one in Fig. Figure 8 illustrates a model comprising an assembleable top cover plate and a lower concave form. The lower concave form serves as the pinhead position for filling with the solution that forms the microneedles; the remaining space within the form is filled with the solution that forms the substrate. This form can be designed using software such as Solidworks, creating three-dimensional models with varying pin counts, pin lengths, pin shapes, microneedle densities, and microneedle tapers as needed. A rigid convex form is fabricated using rapid prototyping methods such as 3D printing, which is then overmolded with PDMS to obtain the concave form as the final mold.Furthermore, the incorporation of polymer monomer molecules into the pre-prepared substrate solution during the fabrication of the substrate-microneedle assembly enables a covalent bond between the microneedle assembly and the substrate through cross-linking, thereby improving the interfacial adhesion between the two components.

[0089] According to a specific embodiment of the present disclosure, the polymer with photocrosslinkable groups comprises at least one selected from methacrylated gelatin, methacrylated chitosan, poly(ethylene glycol) F127 acrylate and poly(ethylene glycol) acrylate; wherein the polymer without photocrosslinkable groups comprises at least one selected from polyvinyl alcohol, sodium alginate, chitosan and cellulose; wherein the polymer monomer molecule with photocrosslinkable groups comprises at least one selected from acrylamide, acrylic acid, N,N-methyleneacrylamide and methyl acrylate.

[0090] According to a specific embodiment of the present disclosure, step (3) particularly comprises: producing a water-absorbing resin based on a natural polymer; introducing the water-absorbing resin based on a natural polymer into the interior of the substrate of the substrate microneedle assembly produced in step (2) to form a sealed sandwich structure, thereby obtaining the microneedle drug delivery device.

[0091] According to a specific embodiment of the present disclosure, the drug comprises at least one selected from biological macromolecule drugs and chemical small molecule drugs.

[0092] According to a specific embodiment of the present disclosure, the biological macromolecule drug comprises at least one selected from polypeptides, proteins, polysaccharides and nucleic acid drugs.

[0093] The drug type can be a single pure pharmaceutical active ingredient (API), a mixture of several drugs for cocktail therapy, or micro / nanoparticles containing the pharmaceutical active ingredient to enhance delayed release effects after drug delivery.

[0094] According to a specific embodiment of the present disclosure, the photocrosslinking process in step (1) comprises the following: Mixing the drug, polymer solution 1 and photoinitiator 1 to form a photocrosslinking solution, which is then dripped onto the needle tip position of the mold; ensuring that the photocrosslinking solution completely fills the needle tip position by ultrasonic movement, centrifugation or vacuum extraction, and performing crosslinking.

[0095] According to a specific embodiment of the present disclosure, the photoinitiator 1 comprises at least one selected from benzoin and its derivatives, benzoyl compounds, alkylphenones, acylphosphine oxides, and benzophenones. Benzoin and its derivatives may, for example, be benzoin dimethyl ketal (BDK); benzoyl compounds may be methyl 2-benzoyl benzoate (OMBB); alkylphenones may be 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (I 2959), 2-hydroxy-2-methyl-1-phenylpropan-1-one (1173), or 1-hydroxycyclohexyl phenyl ketone (184); and acylphosphine oxides may be (2,4,6-trimethylbenzoyl)diphenylphosphine oxide (TPO) or ethyl (2,4,6-trimethylbenzoyl)phenylphosphinate (TPO-L). and in the case of benzophenones, 4-chlorobenzophenone (CBP) or 4-phenylbenzophenone (PBZ).

[0096] According to a specific embodiment of the present disclosure, the photocrosslinking process in step (2) comprises: mixing the polymer solution 2 and the photoinitiator 2, introducing the mixture into the mold and performing UV crosslinking under an ice water bath.

[0097] According to a specific embodiment of the present disclosure, the photoinitiator 2 comprises at least one selected from benzoin and its derivatives, benzoyl compounds, alkylphenones, acylphosphine oxides, and benzophenones. Benzoin and its derivatives may, for example, be benzoin dimethyl ketal (BDK); benzoyl compounds may be methyl 2-benzoyl benzoate (OMBB); alkylphenones may be 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (I 2959), 2-hydroxy-2-methyl-1-phenylpropan-1-one (1173), or 1-hydroxycyclohexyl phenyl ketone (184); and acylphosphine oxides may be (2,4,6-trimethylbenzoyl)diphenylphosphine oxide (TPO) or ethyl (2,4,6-trimethylbenzoyl)phenylphosphinate (TPO-L). and in the case of benzophenones, 4-chlorobenzophenone (CBP) or 4-phenylbenzophenone (PBZ).

[0098] According to a specific embodiment of the present disclosure, step (2) further comprises performing a freeze-thaw cycle treatment after photocrosslinking.

[0099] According to a specific embodiment of the present disclosure, a polyvinyl alcohol substrate is produced by a freeze-thaw cycle. A polyvinyl alcohol solution with a mass concentration of 5-15% is prepared, frozen at -20°C for 6 hours, thawed at 25°C for 30 minutes, and subjected to 4-5 freeze-thaw cycles to obtain a polyvinyl alcohol substrate exhibiting a certain toughness, strength, and ductility. Simultaneously, the substrates obtained by this process form nanocrystals within the molecular structure, which facilitate energy absorption during material deformation.

[0100] According to a specific embodiment of the present disclosure, in step (3) the water-absorbing resin based on a natural polymer is filled into the cavity formed in the substrate and bound using a biological adhesive or by hot pressing.

[0101] According to a specific embodiment of the present disclosure, the raw materials for the production of the liquid-absorbing swelling material in step (3) comprise a water-absorbing polymer and a crosslinking agent.

[0102] According to a specific embodiment of the present disclosure, the water-absorbing polymer comprises at least one selected from sodium carboxymethylcellulose, carboxymethyl chitosan, sodium carboxymethyl alginate and hyaluronic acid; wherein the crosslinking agent comprises at least one selected from citric acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, glutaraldehyde and genipin.

[0103] According to a specific embodiment of the present disclosure, a process for producing a sodium carboxymethylcellulose hydrogel comprises: preparing a mixed solution containing 1 to 10 wt% sodium carboxymethylcellulose and 0.1 to 1 wt% citric acid; drying at 50°C for 6 hours; annealing at 120°C for 4 hours to complete crosslinking; when using crosslinking agents such as 1-ethyl(3-dimethylaminopropyl)carbodiimide, glutaraldehyde, or genipin, crosslinking can be carried out at ambient temperature. Furthermore, the expansion rate of the hydrogel itself correlates with its internal micro- and nanostructures. Techniques such as freeze-drying, antisolventing, and salting-out processes can create loose porous structures within the hydrogel, thereby increasing its water uptake and expansion rate.

[0104] In another aspect, the present disclosure provides an application of the aforementioned microneedle drug delivery device in the manufacture of a drug, wherein the drug is administered orally.

[0105] In another aspect, the present disclosure provides a medicinal product comprising the aforementioned microneedle drug delivery device and a pharmaceutical active ingredient.

[0106] In a further aspect, the present disclosure provides a method for the manufacture of a medicinal product, wherein a pharmaceutical active ingredient is introduced into the aforementioned microneedle drug delivery device or the microneedles of a microneedle drug delivery device manufactured according to the aforementioned method.

[0107] The present disclosure is explained below in combination with exemplary embodiments. Those skilled in the art in this field will understand that the following exemplary embodiments serve only to illustrate the present disclosure; however, the scope of the present disclosure is not limited thereto. Unless specific techniques or conditions are indicated in the exemplary embodiments, they correspond to the techniques or conditions described in the relevant literature or to the information in the product specification. The reagents or instruments used without manufacturer identification are all commercially available products. Examples of implementation Example 1 Production of a substrate microneedle array 1. If the microneedles have a conical shape, the manufacturing process for the substrate microneedle array is in Fig. 9(a) and reads in particular as follows: (I) An aqueous mixture is prepared containing 20 mg / mL of human recombinant insulin, 33% (v / v) polyethylene glycol diacrylate-600, 33% (v / v) polyethylene glycol-300, and 1% (v / v) of the photoinitiator 2-hydroxy-2-methylpropiophenone. 100 µL of this solution is placed in a mold. Air bubbles are removed by ultrasound, centrifugation, or evacuation to ensure complete filling of the microneedle mold holes with the mixture. Irradiation with 365 nm light for 15 seconds is applied to cure the microneedle array. (II) Preparation of an aqueous mixture containing 8% (w / v) acrylamide, 0.1% (w / v) N,N'-methylenebisacrylamide, 10% polyvinyl alcohol (molecular weight 89,000–98,000) and 0.1% (w / v) of the photoinitiator I 2959. 500 µl of this solution are placed in a mold, which is sealed with a special transparent PVC plate and then UV-cured in an ice water bath for 10–30 minutes. (III) The mold is subjected to 4-5 freeze-thaw cycles and then demolded to obtain a flexible, stretchable substrate with drug-loaded microneedles. (IV) Micropores with a diameter of 100 µm are created in the spaces between the microneedles of the flexible, stretchable substrate by means of laser perforation. 2. If the microneedles have a pine-like or tower-like shape, the manufacturing process for the substrate microneedle array is in Fig. 9(b) is shown and reads in particular as follows: Based on the fabrication of a substrate-microneedle array with conical microneedles, the flexible, stretchable substrate obtained in step (III), containing drug-loaded microneedles, is placed into a mold whose needle tips are pine-shaped or tower-like. The needle tips of this mold are pre-filled with a mixture of photoinitiator, drug, and crosslinkable polymer. A subsequent photocrosslinking process yields microneedles with a pine-shaped or tower-like structure. After demolding, a flexible substrate loaded with the pine-shaped or tower-like microneedle array is obtained. Finally, micropores with a diameter of 100 µm are created in the spaces between the microneedles of the flexible substrate using laser perforation. The tips of the pre-fabricated conical microneedles can remain drug-free. Exemplary embodiment 2: Production of the microneedle drug delivery device loaded into a controllable release device (I) A 6% (w / v) sodium carboxymethylcellulose solution is prepared. To this, 0.5% (w / v) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is added. Cross-linking occurs at room temperature while stirring; (II) The crosslinking product obtained in step (I) is dried at 50°C in a drying oven and then comminuted into hydrogel particles using a high-speed comminution machine. The particle size is adjusted to approximately 0.5 mm; (III) A suitable quantity of the hydrogel particles is added to the substrate produced in embodiment 1, which is loaded with the microneedle assembly, and bonded with biocompatible adhesive to obtain a microneedle drug delivery device. This is dried, filled into a commercially available size 00 capsule, and provided with an enteric coating to protect the microneedle drug delivery device. Fig. 10 microneedle drug delivery devices are to be obtained. Example 3: Dimensional determination of the microneedle drug delivery device

[0108] The present embodiment uses Bama miniature pigs as model organisms. Capsule-shaped pressure sensors with diameters of 10 mm, 12 mm, and 14 mm are inserted into the small intestine using gastroscopy to measure the force exerted on the intestinal wall at different diameters. The results are presented in Fig. Figure 11 illustrates this. Based on the pressures (P) measured by the capsule-shaped sensor and the microneedle density (ρ) on the drug delivery device, the force (F1) acting on each individual microneedle in the body can be calculated for various diameters: F1 = P / ρ. Additionally, the force (F2) required to insert the microneedles into the small intestinal tissue is measured outside the body (in vitro) using a force measuring device. By comparing F1 and F2, the minimum diameter of the microneedle drug delivery device that ensures reliable insertion of the microneedles into the intestinal wall can be determined. The maximum diameter is determined by the inner diameter of the filled small intestine. In this way, the dimensional range for the microneedle drug delivery device is defined. The pressures and forces acting on the microneedles are shown in Figure 11. Fig. 12 can be found here.

[0109] Furthermore, the size of the microneedle drug delivery device is primarily determined by the expandable substrate and the hydrogel particles incorporated within it. During the expansion process of the microneedle drug delivery device, the tension (σ) in the expandable substrate gradually increases, while the osmotic pressure (Ps) of the hydrogel gradually decreases due to water absorption. When both values ​​are equal, the dimensions of the microneedle drug delivery device reach equilibrium. Specifically, this means that the lower the strength (i.e., the modulus of elasticity) of the expandable substrate, the larger the maximum expansion dimension of the microneedle drug delivery device can be. Conversely, the higher the osmotic pressure of the hydrogel and the greater the amount of hydrogel incorporated, the larger the maximum expansion dimension of the microneedle drug delivery device can be.Theoretical calculations and experimental validations show that the use of sodium carboxymethylcellulose as a superabsorbent, a hydrogel filling rate of 12.5–37.5%, and a stretchable substrate with an elastic modulus of 60–200 kPa results in the microneedle drug delivery device expanding to a dimension of 10–14 mm after complete water absorption. Example 4: Functional validation of the microneedle drug delivery device

[0110] Due to the similarities in the digestive system and physiological functions between pigs and humans, miniature pigs are used as an animal model for functional validation in this embodiment. To prevent damage to the device from the pigs' chewing behavior, and due to individually varying gastric emptying times, the pigs are anesthetized. The microneedle drug delivery device manufactured according to embodiment 2 is then endoscopically inserted into the pig's duodenum. This point in time is defined as the baseline for monitoring serum drug concentration and pharmacodynamic effects. Blood samples are taken from the central vein every 20 minutes over a period of 4 hours. (1) Blood sugar lowering effect

[0111] Blood glucose concentration is measured in real time using a portable glucose meter ( Fig. 13 and Fig. 14) Comparison shows that intestinal administration of insulin alone achieves only a short-term blood glucose-lowering effect, followed by a renewed rise in blood glucose levels, indicating overall low efficacy. Administration using the microneedle drug delivery device of the present disclosure consistently achieves better blood glucose-lowering effects than simple intestinal administration. The barbed microneedle drug delivery device achieves an effect comparable to that following subcutaneous injection, with a blood glucose reduction of 23.7% in 3 hours. (2) Bioavailability

[0112] The additional blood samples are placed in coagulation tubes, incubated for approximately 40 minutes, and then centrifuged to obtain serum. The insulin concentration in the serum is measured using a human insulin ELISA kit to determine the insulin level in the serum. Fig. The pharmacokinetic curve shown in Figure 15 was obtained. Due to differences in insulin sensitivity and intestinal peristalsis between animals, which lead to varying pressure on the device, the time of maximum plasma concentration varies considerably, resulting in large error bars. The area under these curves (AUC) is used to compare the bioavailability of the different administration methods.

[0113] Bioavailability refers to the relative amount of a drug absorbed into the systemic circulation after non-vascular administration. It is calculated as the ratio of the area under the pharmacokinetic curve (AUC) divided by the administered dose to the corresponding data from the subcutaneous injection group and serves to evaluate the efficacy of a drug delivery method. Statistical analysis of the AUC values ​​for each curve in Fig. 15 equals Fig. 16. The bioavailability for each drug delivery method is calculated using the following formula: (AUC with rods / D) / (AUC Sub / 0.2) × 100%. The bioavailability values ​​for intestinal administration, the tower-shaped microneedle drug delivery device, and the conical microneedle drug delivery device are 0.6%, 23.6%, and 4.2%, respectively. This demonstrates that the microneedle drug delivery devices manufactured in this disclosure, whether tower-shaped or conical, can achieve high bioavailability when administering drugs. Example 5: Biological validation of the microneedle drug delivery device

[0114] Using experimental Bama miniature pigs as model animals, the microneedle drug delivery device is inserted into the small intestine via a gastroscope. Continuous gastroscopic observation shows (as in Fig. 17), that the expanded microneedle drug delivery device is subject to significant compression in the intestinal tract.

[0115] After a waiting period of 4 hours, once the microneedle drug delivery device has completed its function, the abdomen of the Bama miniature pig is incised. The intestine is removed, the position of the microneedle drug delivery device is identified, and the adjacent small intestinal wall is excised. Additionally, the microneedle drug delivery device is used to directly puncture a section of the small intestinal wall in vitro. Both small intestinal wall samples are fixed in formalin, dehydrated, embedded in paraffin, sectioned, and examined by hematoxylin and eosin (H&E) staining. The results are presented in Fig.Figure 18 shows clear microneedle penetration marks on both the in vivo and in vitro small intestinal walls, while no such marks were observed in the small intestinal segments of the blinded control group. This confirms that the microneedle drug delivery device can effectively penetrate the intestinal wall.

[0116] In this description, the explanations associated with the terms "an embodiment," "some embodiments," "an example," "a specific example," or "some examples" mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of this publication. In this description, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the described specific features, structures, materials, or characteristics may be combined appropriately in one or more embodiments or examples.In the absence of conflicts, experts in this field may additionally combine and connect the various embodiments or examples explained in this description, or the features in the various embodiments or examples.

[0117] Although the embodiments of the present disclosure are presented and explained above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present disclosure. The person skilled in the art in this field can make the changes, modifications, substitutions, and variations to the embodiments within the scope of the present disclosure.

Claims

[1] Microneedle drug delivery device, the device comprising a substrate, a microneedle assembly and a liquid-absorbing swelling material, the substrate supporting the microneedle assembly, the liquid-absorbing swelling material being enclosed in the substrate to form a sealed sandwich structure, the tips of the microneedles being loaded with the drug. [2] Microneedle drug delivery device according to claim 1, wherein the drug comprises at least one selected from biological macromolecule drugs and chemical small molecule drugs; wherein the biological macromolecule drug optionally comprises at least one selected from polypeptides, proteins, polysaccharides and nucleic acid drugs. [3] Microneedle drug delivery device according to claim 1, wherein the microneedles contained in the microneedle arrangement have a monolayer conical shape or a barbed structure, wherein the number of microneedles is 1 to 1000. [4] Microneedle drug delivery device according to claim 3, wherein the barbed structure comprises at least one structure selected from a jaw-like, turret-like or spike-like configuration. [5] Microneedle drug delivery device according to claim 1, wherein the microneedles contained in the microneedle arrangement have a length of 30 to 5000 µm, a base dimension of 10 to 5000 µm and a tip dimension of 1 to 300 µm, wherein the base dimension is greater than or equal to the tip dimension. [6] Microneedle drug delivery device according to claim 1, wherein the substrate is a flexible, stretchable substrate, wherein the material for producing the substrate comprises at least one selected from sodium alginate, chitosan, cellulose and polyvinyl alcohol. [7] Microneedle drug delivery device according to claim 1, wherein the substrate surface has a microporous structure. [8] Microneedle drug delivery device according to claim 7, wherein the micropore diameter is 10 to 1000 µm. [9] Microneedle drug delivery device according to claim 7, wherein the micropore diameter is 80 to 500 µm. [10] Microneedle drug delivery device according to claim 7, wherein the micropore density is 0.01 to 1000 per mm 2 amounts. [11] Microneedle drug delivery device according to claim 1, wherein the liquid-absorbing swelling material comprises at least one selected from hydrogels, water-absorbing rubbers and water-absorbing resins. [12] Microneedle drug delivery device according to claim 1, wherein the liquid-absorbing swelling material is selected from water-absorbing polymeric resins. [13] Microneedle drug delivery device according to claim 12, wherein the particle size of the water-absorbing polymeric resin is 0.01 to 20 mm. [14] Microneedle drug delivery device according to claim 12, wherein the particle size of the water-absorbing polymeric resin is 0.5 to 5 mm. [15] Microneedle drug delivery device according to claim 1, wherein the microneedle drug delivery device further comprises a controllable release device, wherein the controllable release device encapsulates the substrate, the microneedle arrangement and the liquid-absorbing swelling material. [16] Microneedle drug delivery device according to claim 15, wherein the controllable release device has an enteric coating. [17] Microneedle drug delivery device according to any one of claims 1 to 16, wherein the dimensions of the microneedle drug delivery device in source equilibrium do not exceed the inner diameter of the patient's intestinal lumen. [18] Method for manufacturing a microneedle drug delivery device according to any one of claims 1 to 17, comprising the following steps: (1) Production of a microneedle array; (2) Preparation of a substrate, application of the microneedle array obtained in step (1) to the substrate surface to obtain a substrate microneedle array; (3) Producing a liquid-absorbing swelling material, wherein the liquid-absorbing swelling material is arranged within the substrate of the substrate-microneedle arrangement obtained in step (2) to form a sealed sandwich structure. [19] Method according to claim 18, wherein the method for producing the microneedle assembly in step (1) comprises at least one method selected from 3D printing, photolithography, soft photolithography, thermoplastic extrusion stretching, laser cutting and casting. [20] Method according to claim 18, wherein the method for producing the microneedle assembly in step (1) comprises: mixing the drug product and the polymer solution 1, filling the tip position of the mold, performing photocrosslinking to obtain the microneedle assembly; wherein the polymer comprises at least one selected from methacrylated gelatin, methacrylated dextran, methacrylated sodium alginate, methacrylated hyaluronic acid, polyethylene glycol diacrylate and polyethylene glycol. [21] Method according to claim 18, wherein the method for producing the substrate in step (2) comprises at least one method selected from spin coating, doctor blade coating, photopolymerization, chemical crosslinking, physical crosslinking and freeze-thaw cycles. [22] Method according to claim 18, wherein the method for applying the microneedle arrangement to the substrate surface in step (2) comprises at least one method selected from photochemical crosslinking, chemical crosslinking and physical bonding. [23] Method according to claim 18, wherein the method for producing the substrate in step (2) comprises: introducing the polymer solution 2 into a mold and performing photocrosslinking with the microneedle array obtained in step (1), demolding to obtain a substrate-microneedle array; wherein the polymer comprises at least one selected from a polymer with photocrosslinkable groups, a polymer monomer molecule with photocrosslinkable groups, and a composite of a polymer without photocrosslinkable groups and a polymer with photocrosslinkable groups. [24] Method according to claim 23, wherein the polymer with photocrosslinkable groups comprises at least one selected from methacrylated gelatin, methacrylated chitosan, poly(ethylene glycol) F 127 acrylate and poly(ethylene glycol) acrylate; wherein the polymer without photocrosslinkable groups comprises at least one selected from polyvinyl alcohol, sodium alginate, chitosan and cellulose; wherein the polymer monomer molecule with photocrosslinkable groups comprises at least one selected from acrylamide, acrylic acid, N,N-methyleneacrylamide and methyl acrylate. [25] The method of claim 18, wherein step (3) further comprises: producing a water-absorbing resin based on a natural polymer; and introducing the water-absorbing resin based on a natural polymer into the interior of the substrate of the substrate microneedle assembly produced in step (2) to form a sealed sandwich structure, thereby obtaining the microneedle drug delivery device. [26] Method according to claim 20, wherein the drug comprises at least one selected from biological macromolecule drugs and chemical small molecule drugs; wherein the biological macromolecule drug optionally includes at least one selected from polypeptides, proteins, polysaccharides and nucleic acid drugs. [27] Method according to claim 19, wherein the photocrosslinking process in step (1) comprises: Mixing the drug, polymer solution 1 and photoinitiator 1 to form a photocrosslinking solution, which is then dropped onto the needle tip position of the mold; Ensure that the photocrosslinking solution completely fills the needle tip position by ultrasonic movement, centrifugation or vacuum extraction, and perform crosslinking. [28] Method according to claim 27, wherein the photoinitiator 1 comprises at least one selected from benzoin and its derivatives, benzoyl compounds, alkylphenones, acylphosphine oxides and benzophenones. [29] Method according to claim 23, wherein the photocrosslinking process in step (2) comprises: Mixing the polymer solution 2 and the photoinitiator 2, introducing the mixture into the mold and Performing UV crosslinking under an ice water bath. [30] Method according to claim 29, wherein the photoinitiator 2 comprises at least one selected from benzoin and its derivatives, benzoyl compounds, alkylphenones, acylphosphine oxides and benzophenones. [31] Method according to claim 23, wherein step (2) further comprises performing a freeze-thaw cycle treatment after photocrosslinking. [32] Method according to claim 25, wherein in step (3) the water-absorbing resin based on a natural polymer is filled into the cavity formed in the substrate and bonded using a biological adhesive or by hot pressing. [33] Method according to claim 18, wherein the raw materials for the production of the liquid-absorbing swelling material in step (3) comprise a water-absorbing polymer and a crosslinking agent. [34] Method according to claim 33, wherein the water-absorbing polymer comprises at least one selected from sodium carboxymethylcellulose, carboxymethyl chitosan, sodium carboxymethyl alginate and hyaluronic acid; wherein the crosslinking agent comprises at least one selected from citric acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, glutaraldehyde and genipin. [35] Use of a microneedle drug delivery device according to any one of claims 1 to 17 in the manufacture of a drug, wherein the drug is administered orally. [36] Drug comprising a microneedle drug delivery device according to any one of claims 1 to 17 and a pharmaceutical active ingredient. [37] Method for the manufacture of a pharmaceutical drug, wherein a pharmaceutical active ingredient is introduced into the microneedle drug delivery device according to any one of claims 1 to 17 or the microneedles of a microneedle drug delivery device manufactured according to the method according to any one of claims 18 to 34.

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