Microneedle drug delivery device and preparation method thereof

Abstract

The invention relates to the technical field of drug delivery, in particular to a microneedle drug delivery device and a preparation method thereof. The device comprises substrates, a microneedle array and a liquid absorption expansion material, the substrates bear the microneedle array, and the liquid absorption expansion material is arranged between the substrates to form a sandwich structure. According to the device, the microneedle is punctured into the intestinal wall by utilizing a mild water absorption expansion mechanism and a natural peristalsis behavior of the gastrointestinal tract to complete drug delivery, a physiological barrier for oral delivery and absorption of biological drugs is broken through in a physical mode, the oral availability of the biological drugs is improved, and the used materials are biodegradable soft materials, so that the safety is high.

Description

Microneedle drug delivery device and preparation method thereof Technical Field

[0001] The present disclosure relates to the field of drug delivery technology, and in particular, to a microneedle drug delivery device and a preparation method thereof. Background Art

[0002] Oral administration has always been a very popular way of drug delivery due to its advantages such as simple administration and high patient compliance. However, this method is not suitable for biological macromolecular drugs such as peptides, proteins, nucleic acids, and antibodies. At present, injection administration, including intramuscular injection and intravenous injection, is still the main delivery method for biological macromolecular drugs. However, because of the problems of easy pain, skin infection, allergic reaction, and poor patient compliance, the development of new administration methods to replace injection has always been an important way of new drug innovation. Take liraglutide, a hypoglycemic drug used in the intervention treatment of diabetes, as an example. It currently needs to be injected once a day, which adds a lot of inconvenience and pain to patients. Novo Nordisk (Novo Nordisk) ) has developed semaglutide, a drug with similar efficacy, reducing the injection frequency to once a week. However, the challenges of injection dosing remain, especially for patients with chronic diseases who require long-term monitoring and repeated dosing. Therefore, achieving oral delivery of biologic drugs has important medical significance.

[0003] However, the oral utilization rate of biological drugs is low. Analysis of the reasons behind this can be attributed to the three major physiological barriers in the drug delivery process. First, after oral administration, the drug needs to pass through the acid-base environment of the gastrointestinal tract and the physical and chemical barrier composed of various digestive enzymes. Biological drugs such as peptides, proteins and nucleic acids are prone to denaturation, inactivation or degradation, affecting the efficacy of the drug; secondly, after entering the gastrointestinal tract, the mucus layer constitutes the second drug absorption barrier. The mucus layer is a dynamic gel network composed of mucin and highly glycosylated glycoproteins. The electrostatic effect and molecular network block the invasion of pathogens, but also hinder the absorption and utilization of most large molecule drugs; finally, there is the absorption barrier of small intestinal epithelial cells. Due to the large size of biological macromolecules and the lack of corresponding receptors, it is often difficult for them to enter the blood through transcellular transport or paracellular transport.

[0004] In response to the oral administration dilemma of the above-mentioned biological drugs, pharmacists are trying a variety of solutions, including pH regulators, enzyme inhibitors, penetration enhancers and cell-penetrating peptides, etc., to protect large molecule drugs from degradation and promote their absorption and utilization. Take penetration enhancers as an example. They are essentially surfactants that promote drug absorption by temporarily destroying the epithelial cells of the small intestine. In 2019, Novo Nordisk (Novo Nordisk) ) developed semaglutide oral tablets, and the 8-(2-hydroxybenzamido) sodium salcaprozate used is a typical penetration enhancer. It is tightly bound to semaglutide through non-covalent interactions, which can effectively enhance the lipophilicity of the drug and promote epithelial cell absorption. By introducing various functional ingredients, the stability and absorption utilization rate of the drug can be improved, but because of the need to take into account biosafety, the above method can often only achieve a bioavailability of about 1%. In addition, due to differences in the chemical structure, hydrophilicity and degradation rate of different drugs, the types and ratios of adjuvants are often not universal, so the research and development time is long. New oral drug delivery technologies such as intestinal patches, gastrointestinal hydrogels, and external field controlled drug delivery devices are still difficult to pass through the above three physiological barriers, and there are problems such as complex operation and poor biocompatibility. Related technologies need further research and development. At present, there are few effective and universal oral delivery technologies for biological drugs.

[0005] The gastrointestinal wall microneedle drug delivery device is a highly promising oral drug delivery device proposed in recent years. As a physical drug delivery method, microneedles can effectively break through the mucus layer and epithelial cells, deliver drugs directly to the gastrointestinal wall tissue and absorb them through capillaries, regardless of the molecular weight of the loaded drug. Therefore, it has the versatility and effectiveness of drug delivery. In addition, since the intestinal wall lacks pain-sensing nerves, microneedles piercing the intestinal wall will not cause pain to the patient, and intestinal perforation can be avoided by controlling the size of the microneedles. Therefore, compared with other oral drug delivery methods, this type of microneedle drug delivery device is expected to achieve a higher drug utilization rate under the premise of safety.

[0006] One type of publicly reported gastrointestinal microneedle drug delivery technology requires the pre-installation of springs, elastomers, or reactive chemicals within the device. Rapid release of elastic potential energy or rapid reaction to generate gas propels the drug-loaded microneedles into the gastrointestinal wall. Alternatively, patents have been published for devices that incorporate external field-responsive materials, using external field control devices such as magnetic fields to complete the microneedle insertion process. This physical insertion method protects biomacromolecules from the body's triple barrier, allowing them to enter the bloodstream directly, thereby increasing the oral availability of biologic drugs. The problems faced by the above technologies are: first, poor biosafety. Hard materials such as springs, elastomers, and magnetically sensitive substances are used as driving units, which are difficult to degrade. Exposure or retention in the gastrointestinal tract for a long time will cause harm. At the same time, patient acceptance is low and compliance is poor; second, the success rate of drug administration is difficult to guarantee. The one-time rapid propulsion method represented by springs is difficult to guarantee the success rate when facing the physiological differences of different patients; third, the retention effect of microneedles is ignored. Existing microneedle drug delivery devices mainly focus on the process of breaking through the epithelial cells of the gastrointestinal wall, and do not pay attention to the retention effect of microneedles in the gastrointestinal wall. The microneedles may fall out of the gastrointestinal wall during gastrointestinal peristalsis, which will affect the drug delivery efficiency.

[0007] Therefore, there is an urgent need to develop a drug delivery device that can be taken orally and has high drug utilization.

[0008] Summary of the Invention

[0009] The present disclosure aims to solve at least one of the technical problems in the related art to a certain extent. To this end, one purpose of the present disclosure is to provide a microneedle drug delivery device and a preparation method thereof. The microneedle drug delivery device provided by the present disclosure utilizes a mild water absorption and expansion mechanism and the natural peristaltic behavior of the gastrointestinal tract to pierce the microneedle into the intestinal wall to complete drug delivery. It is easy to operate, has a mild driving mode, does not require external field control equipment and a hard, non-degradable driving unit, and has high safety. At the same time, the action mode based on the intestinal contraction force provides a safe and effective range, making the technical solution provided by the present disclosure more universal.

[0010] To this end, the present disclosure provides, in one aspect, a microneedle drug delivery device. According to an embodiment of the present disclosure, the device comprises a substrate, a microneedle array, and a liquid-swelling material. The substrate supports the microneedle array, the liquid-swelling material is wrapped by the substrate to form a closed sandwich structure, and the tips of the microneedles are loaded with drugs.

[0011] According to an embodiment of the present disclosure, the drug includes at least one selected from biological macromolecule drugs and chemical small molecule drugs.

[0012] According to an embodiment of the present disclosure, the biomacromolecule drug includes at least one selected from the group consisting of polypeptides, proteins, polysaccharides and nucleic acid drugs.

[0013] According to an embodiment of the present disclosure, the microneedles contained in the microneedle array are in a single-layer cone shape or have a barbed structure, and the number of the microneedles is 1-1000.

[0014] According to an embodiment of the present disclosure, the barb structure includes at least one selected from a pine tree shape, a tower shape, or a thorn shape.

[0015] According to an embodiment of the present disclosure, the microneedles contained in the microneedle array have a length of 30-5000 μm, a bottom dimension of 10-5000 μm, and a tip dimension of 1-300 μm, wherein the bottom dimension is greater than or equal to the tip dimension.

[0016] According to an embodiment of the present disclosure, the substrate is a flexible and stretchable substrate, and the material used to prepare the substrate includes at least one selected from sodium alginate, chitosan, cellulose, and polyvinyl alcohol.

[0017] According to an embodiment of the present disclosure, the substrate surface has a microporous structure.

[0018] According to an embodiment of the present disclosure, the micropores have a diameter of 10-1000 μm.

[0019] According to an embodiment of the present disclosure, the micropores have a diameter of 80-500 μm.

[0020] According to the embodiment of the present disclosure, the micropore density is 0.01-1000 / mm 2 .

[0021] According to an embodiment of the present disclosure, the liquid-absorbing and swelling material includes at least one selected from the group consisting of water-absorbing gel, water-absorbing rubber, and water-absorbing resin.

[0022] According to an embodiment of the present disclosure, the liquid-absorbing and swelling material is selected from polymeric water-absorbing resins.

[0023] According to an embodiment of the present disclosure, the particle size of the polymer water-absorbing resin is 0.01-20 mm.

[0024] According to an embodiment of the present disclosure, the particle size of the polymer water-absorbing resin is 0.5-5 mm.

[0025] According to an embodiment of the present disclosure, the microneedle drug delivery device further comprises a controllable exposure device, wherein the controllable exposure device encloses the substrate, the microneedle array and the liquid-swelling material.

[0026] According to an embodiment of the present disclosure, the controlled exposure device has an enteric coating.

[0027] According to an embodiment of the present disclosure, the size of the microneedle drug delivery device at swelling equilibrium does not exceed the inner diameter of the intestinal cavity of a subject.

[0028] Another aspect of the present disclosure provides a method for preparing the aforementioned microneedle drug delivery device, the method comprising the following steps:

[0029] (1) preparing a microneedle array;

[0030] (2) preparing a substrate, and loading the microneedle array obtained in step (1) on the surface of the substrate to obtain a substrate-microneedle array;

[0031] (3) preparing a liquid-swelling material, and placing the liquid-swelling material inside the substrate of the substrate-microneedle array obtained in step (2) to form a closed sandwich structure.

[0032] According to an embodiment of the present disclosure, the method for preparing the microneedle array in step (1) includes at least one selected from 3D printing, photolithography, soft lithography, thermoplastic extrusion stretching, laser cutting, and casting.

[0033] According to the embodiment of the present disclosure, the method for preparing the microneedle array in step (1) is: mixing the drug and the polymer solution 1, filling the mixture into the needle tip position of the mold, and performing photocrosslinking to obtain the microneedle array;

[0034] The polymer comprises at least one selected from methacrylated gelatin, methacrylated dextran, methacrylated sodium alginate, methacrylated hyaluronic acid, polyethylene glycol diacrylate, and polyethylene glycol.

[0035] According to an embodiment of the present disclosure, the method for preparing the substrate in step (2) includes at least one selected from spin coating, blade coating, photocrosslinking, chemical crosslinking, physical crosslinking, and freeze-thaw cycle method.

[0036] According to an embodiment of the present disclosure, the method of loading the microneedle array on the surface of the substrate in step (2) includes at least one method selected from photocrosslinking, chemical crosslinking, and physical connection.

[0037] According to the embodiment of the present disclosure, the method for preparing the substrate in step (2) is: placing the polymer solution 2 in a mold and photocrosslinking it with the microneedle array obtained in step (1), and demolding to obtain the substrate-microneedle array;

[0038] The polymer comprises at least one selected from a polymer having a photocrosslinking group, a polymer monomer molecule having a photocrosslinking group, and a polymer without a photocrosslinking group / a polymer monomer molecule complex having a photocrosslinking group.

[0039] According to an embodiment of the present disclosure, the polymer having a photocrosslinking group includes at least one selected from methacrylated gelatin, methacrylated chitosan, polyether F127 acrylate, and polyethylene glycol acrylate;

[0040] The polymer having no photocrosslinking group comprises at least one selected from polyvinyl alcohol, sodium alginate, chitosan and cellulose;

[0041] The polymer monomer molecules having photocrosslinking groups include at least one selected from acrylamide, acrylic acid, N,N-methylene acrylamide, and methyl acrylate.

[0042] According to the embodiment of the present disclosure, the step (3) specifically comprises: preparing a natural polymer water-absorbing resin, placing the natural polymer water-absorbing resin inside the substrate of the substrate-microneedle array prepared in step (2) to form a closed sandwich structure, and obtaining the microneedle drug delivery device.

[0043] According to an embodiment of the present disclosure, the drug includes at least one selected from a biological macromolecule drug and a chemical small molecule drug.

[0044] According to an embodiment of the present disclosure, the biomacromolecule drug includes at least one selected from the group consisting of polypeptides, proteins, antibodies, polysaccharides and nucleic acid drugs.

[0045] According to an embodiment of the present disclosure, the photocrosslinking process in step (1) includes:

[0046] The drug, polymer solution 1 and photoinitiator 1 are mixed to obtain a photocrosslinking solution, which is then added dropwise to the needle tip of the mold. The photocrosslinking solution is fully filled into the needle tip by ultrasound, centrifugation or vacuuming to perform crosslinking.

[0047] According to an embodiment of the present disclosure, the photoinitiator 1 includes at least one selected from benzoin and its derivatives, benzoyls, alkylphenones, acylphosphine oxides, and benzophenones.

[0048] According to the embodiment of the present disclosure, the photocrosslinking process in step (2) includes: mixing the polymer solution 2 and the photoinitiator 2, placing the mixture in a mold, and performing UV crosslinking in an ice-water bath.

[0049] According to an embodiment of the present disclosure, the photoinitiator 2 includes at least one selected from benzoin and its derivatives, benzoyls, alkyl phenones, acylphosphine oxides, and benzophenones.

[0050] According to an embodiment of the present disclosure, the step (2) further comprises: performing a freeze-thaw cycle treatment after the photocrosslinking.

[0051] According to the embodiment of the present disclosure, in step (3), the natural polymer water-absorbing resin is loaded into the cavity formed by the substrate and connected using biological glue or hot pressing.

[0052] According to an embodiment of the present disclosure, the raw materials for preparing the liquid-absorbing and swelling material in step (3) include a water-absorbing polymer and a cross-linking agent.

[0053] According to an embodiment of the present disclosure, the water-absorbing polymer includes at least one selected from sodium carboxymethylcellulose, carboxymethyl chitosan, sodium carboxymethyl alginate, and hyaluronic acid;

[0054] The cross-linking agent includes at least one selected from citric acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, glutaraldehyde, and genipin.

[0055] Another aspect of the present disclosure provides use of the aforementioned microneedle drug delivery device in the preparation of a drug, wherein the drug is administered orally.

[0056] In another aspect, the present disclosure provides a drug comprising the aforementioned microneedle drug delivery device and a pharmaceutical active ingredient.

[0057] Another aspect of the present disclosure provides a method for preparing a drug, wherein the active ingredient of the drug is placed in the microneedle of the aforementioned microneedle drug delivery device or the microneedle drug delivery device prepared according to the aforementioned method.

[0058] The present disclosure has the following beneficial effects compared to the prior art:

[0059] (1) Compared with existing pharmaceutical technologies, the present disclosure can physically break through the physiological barriers to oral delivery and absorption of biological drugs, thereby improving the oral availability of biological drugs;

[0060] (2) Compared with existing gastrointestinal delivery devices, the present invention does not use springs, elastomers, magnetically sensitive particles, or other non-degradable hard objects such as metal and rubber as the driving module of the drug delivery device. The materials used are all biodegradable soft materials that will not remain in the human body for a long time or block the digestive tract. It is highly safe and has good patient compliance.

[0061] (3) The present invention avoids the use of a one-time triggered delivery mode and an external field controlled delivery mode. Instead, it utilizes the volume effect of the device after expansion and the peristaltic contraction force of the intestine itself to penetrate the microneedle into the intestinal wall to complete the delivery. The operation is simple and natural, and the driving mode is gentle.

[0062] (4) The present disclosure improves the retention effect of microneedles in intestinal wall tissue by using a barbed microneedle structure, thereby preventing the microneedles that have penetrated the intestinal wall from falling off during intestinal peristalsis;

[0063] (5) The present disclosure can adjust the drug release rate by adjusting the degree of cross-linking, and the swelling equilibrium volume by adjusting the filler amount of the liquid-absorbing swelling material and the mechanical strength of the flexible stretchable substrate, which is convenient and controllable. At the same time, the present disclosure focuses on using normal intestinal contraction movement to drive the drug-loaded microneedles to penetrate the intestinal wall, and sets a safe and effective swelling equilibrium volume range based on the action mode of intestinal contraction force, making the device provided by the present disclosure more universal.

[0064] Additional aspects and advantages of the present disclosure will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] The advantages of the above and / or additional aspects of the present disclosure will become apparent and readily understood from the description of the embodiments in conjunction with the following drawings, in which:

[0066] Figures 1-7 show the appearance of the microneedle drug delivery devices prepared in the present disclosure. Figures 1-3 show the appearance of the spherical, cylindrical, and capsule-shaped microneedle drug delivery devices prepared in the present disclosure, respectively. Figures 4-6 show the appearance of the spherical, cylindrical, and capsule-shaped microneedle drug delivery devices prepared in the present disclosure after water absorption and expansion, respectively. Figure 7 shows a longitudinal cross-sectional view of the capsule-shaped microneedle drug delivery device of the present disclosure before and after water absorption and expansion.

[0067] FIG8 shows a mold for making a microneedle array according to the present disclosure;

[0068] FIG9 shows a flow chart for preparing a substrate-microneedle array in Example 1 of the present disclosure. FIG. a shows a flow chart for preparing a substrate-conical microneedle array; FIG. b shows a flow chart for preparing a substrate-pine tree-shaped or tower-shaped microneedle array;

[0069] FIG10 shows the appearance of the microneedle drug delivery device loaded in a commercial capsule shell in Example 2 of the present disclosure;

[0070] FIG11 shows a diagram of the pressure of the intestine acting on sensors of different sizes in Example 3 of the present disclosure;

[0071] FIG12 shows the pressure of the intestine acting on the microneedles and the pressure results in Example 3 of the present disclosure;

[0072] Figures 13-14 show the hypoglycemic effect of the insulin-loaded microneedle drug delivery device in Example 4 of the present disclosure on experimental miniature pigs;

[0073] FIG15 shows the drug delivery effect of the insulin-loaded microneedle drug delivery device in Example 4 of the present disclosure;

[0074] FIG16 shows a comparison of the areas under the pharmacokinetic curves of enteric delivery, subcutaneous injection, enteric delivery by a tapered microneedle delivery device, and enteric delivery by a tower-shaped microneedle delivery device for insulin in Example 4 of the present disclosure;

[0075] FIG17 shows a gastrointestinal endoscopic photograph of the microneedle drug delivery device in the small intestine in Example 5 of the present disclosure;

[0076] FIG18 shows the small intestine sections of the in vivo intestine, in vitro intestine and blank control group of the experimental miniature pig after the microneedle drug delivery device in Example 5 of the present disclosure has been used.

[0077] Detailed Description of the Invention

[0078] The embodiments of the present disclosure are described in detail below. The embodiments described below are exemplary and are only used to explain the present disclosure, and should not be understood as limiting the present disclosure.

[0079] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features being referred to. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. Throughout the present disclosure, "plurality" means at least two, such as two, three, etc., unless otherwise specifically defined.

[0080] In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by those skilled in the art to which the present disclosure belongs.

[0081] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present disclosure, but not excluding other contents.

[0082] The term "peptide" refers to compounds formed by α-amino acids linked together by peptide bonds. It is an intermediate product of protein hydrolysis. A compound formed by the dehydration condensation of two amino acid molecules is called a dipeptide. Similarly, there are tripeptides, tetrapeptides, and pentapeptides.

[0083] The term "polypeptide" refers to a peptide composed of three or more amino acid molecules. In the present disclosure, when the drug encapsulated in the microneedle is a polypeptide drug, it includes but is not limited to antibody drugs.

[0084] The term "chemical small molecule drugs" refers to small molecule drugs that are chemically synthesized and usually have a relative molecular mass below 1000.

[0085] The term "size of the microneedle drug delivery device at swelling equilibrium" refers to the size of the microneedle drug delivery device achieved when the gradually decreasing expansion force and the gradually increasing substrate tension are balanced during the expansion process of the microneedle drug delivery device.

[0086] The term "area under the pharmacokinetic curve (AUC)" refers to the mean area under the plasma drug concentration-time curve calculated by the trapezoidal rule over the entire sample collection interval.

[0087] According to a specific embodiment of the present disclosure, on the one hand, the present disclosure provides a microneedle drug delivery device, which includes a substrate, a microneedle array and a liquid-swelling material. The substrate supports the microneedle array, and the liquid-swelling material is wrapped by the substrate to form a closed sandwich structure. The tips of the microneedles are loaded with drugs.

[0088] Among them, because the liquid-absorbing and swelling material has the property of swelling upon absorption of liquid, when the device is in a dry state, the microneedles in the device are in a prone state and can resist the squeezing of the gastric tract; when external digestive fluid or water enters the interior of the device, the liquid-absorbing and swelling material absorbs water and swells, the substrate extends, and the microneedles standing on it stand upright outward and penetrate the intestinal wall with the help of intestinal peristalsis. This design can reduce the impact of gastric peristalsis on the microneedles and prevent the microneedle array from breaking or falling off before entering the intestine. See Figures 1-7, wherein Figure 1-3 is an appearance diagram of the microneedle drug delivery device provided by the present disclosure. The shape of the device can be spherical, rectangular, or capsule-shaped, and is not limited to the above shapes. Figures 4-6 are appearance diagrams of the microneedle drug delivery device provided by the present disclosure after expansion, and Figure 7 is a longitudinal cross-sectional view of the capsule-shaped microneedle drug delivery device before and after absorption of water and expansion. Assuming that the frequency and amplitude of the peristaltic contraction of the small intestine are constant, the larger the volume of the microneedle drug delivery device, the greater the force it is subjected to. However, since the small intestinal tissue is soft and can conform to the shape of the device when contracting, the shape of the microneedle drug delivery device provided by the present disclosure is not limited to cylindrical, spherical, and capsule shapes. Assuming that the radial extrusion force of the small intestinal wall is uniform, when the apparent compression modulus and apparent compression strength of the device are greater, the deformation of the small intestine during peristaltic extrusion is smaller, the force it is subjected to is greater, and the more conducive it is for the microneedle to penetrate the small intestinal wall. At the same time, because the material of the microneedles that encapsulate the drug does not have a substantial impact on the drug, the microneedle drug delivery device provided by the present disclosure can encapsulate any desired drug.

[0089] 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.

[0090] According to a specific embodiment of the present disclosure, the biomacromolecule drug includes at least one selected from the group consisting of 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.

[0091] According to a specific embodiment of the present disclosure, the microneedles contained in the microneedle array are in a single-layer cone shape or have a barbed structure, and the number of the microneedles is 1-1000.

[0092] According to a specific embodiment of the present disclosure, the barb structure includes at least one selected from pine tree shape, tower shape or thorn shape.

[0093] Designing microneedles into cone-shaped, pine-shaped, tower-shaped or thorn-shaped structures can increase the detachment force of the microneedles after they penetrate the intestinal wall, enhance the retention effect of the microneedles in the intestinal wall, and thereby improve the bioavailability of the drug.

[0094] According to a specific embodiment of the present disclosure, the microneedles contained in the microneedle array have a length of 30-5000 μm, a bottom size of 10-5000 μm, and a tip size of 1-300 μm, wherein the bottom size is greater than or equal to the tip size.

[0095] According to a specific embodiment of the present disclosure, the substrate is a flexible stretchable substrate, and the material for preparing the substrate includes at least one selected from sodium alginate, chitosan, cellulose, and polyvinyl alcohol. The flexible stretchable substrate can be stretched and extended, and the property of the liquid-swelling material to absorb and expand can be used to achieve the shape change of the microneedle drug delivery device in the intestine. When the microneedle drug delivery device is squeezed by the intestine, assuming that the volume of the liquid-swelling material remains unchanged, the intestinal squeezing force is mainly balanced by the tension generated by the continued extension of the flexible stretchable membrane. Therefore, a flexible stretchable membrane with high toughness and fatigue resistance is needed to resist the frequent contraction movements of the intestinal wall and maintain the integrity of the device in the early stage.

[0096] According to a specific embodiment of the present disclosure, the substrate surface has a microporous structure. The microporous structure can be constructed by acupuncture, laser or other drilling methods, and serves as a water absorption channel to facilitate external digestive fluid or water to enter the interior of the device.

[0097] According to a specific embodiment of the present disclosure, the diameter of the micropores is 10-1000 μm.

[0098] According to a preferred embodiment of the present disclosure, the diameter of the micropores is 80-500 μm.

[0099] According to a specific embodiment of the present disclosure, the micropore density is 0.01-1000 / mm 2 .

[0100] According to a specific embodiment of the present disclosure, the liquid-absorbing and swelling material includes at least one selected from water-absorbing gel, water-absorbing rubber, and water-absorbing resin.

[0101] According to a specific embodiment of the present disclosure, the liquid-absorbing and swelling material is selected from polymer water-absorbing resins.

[0102] According to a specific embodiment of the present disclosure, the particle size of the polymer water-absorbing resin is 0.1-20 mm.

[0103] According to a preferred embodiment of the present disclosure, the particle size of the polymer water-absorbing resin is 0.5-5 mm.

[0104] According to a specific embodiment of the present disclosure, the microneedle drug delivery device further comprises a controllable exposure device, wherein the controllable exposure device encapsulates the substrate, the microneedle array and the liquid-swelling material.

[0105] According to a specific embodiment of the present disclosure, the controlled exposure device has an enteric coating.

[0106] The enteric coating can be prepared by spraying or dipping. Specifically, the spraying method involves preparing a 95% ethanol solution containing 6% Eudragit L-100, 0.6% triethyl citrate, and 1.25% talc, spraying micron-sized droplets onto the controlled exposure device using a spray gun at an appropriate air pressure and liquid output, and repeating the above steps multiple times after the solvent has fully evaporated to form the enteric coating. The dipping method involves preparing a 7% ethanol solution of Eudragit L-100, immersing the controlled exposure device therein, and repeating the above steps multiple times after the solvent has fully evaporated to form the enteric coating.

[0107] According to a specific embodiment of the present disclosure, the size of the microneedle drug delivery device at swelling equilibrium does not exceed the inner diameter of the subject's intestinal cavity, allowing the device to deform and move under axial pressure to avoid intestinal blockage. The size of the device at swelling equilibrium is crucial for utilizing the radial extrusion force generated by small intestinal peristalsis. If the radial extrusion force of the small intestinal wall is uniform, when the apparent compression modulus and apparent compression strength of the device are greater, the deformation during small intestinal peristalsis is smaller, the force is greater, and the more conducive it is for the microneedles to penetrate the small intestinal wall. At the same time, the filling amount of the liquid-swelling material and the tensile properties of the substrate will affect the size of the device at swelling equilibrium.

[0108] Another aspect of the present disclosure provides a method for preparing the aforementioned microneedle drug delivery device, the method comprising the following steps:

[0109] (1) Preparation of microneedle arrays;

[0110] (2) preparing a substrate, and loading the microneedle array obtained in step (1) on the surface of the substrate to obtain a substrate-microneedle array;

[0111] (3) preparing a liquid-swelling material, and placing the liquid-swelling material inside the substrate of the substrate-microneedle array obtained in step (2) to form a closed sandwich structure.

[0112] According to a specific embodiment of the present disclosure, the method for preparing the microneedle array in step (1) includes at least one selected from 3D printing, photolithography, soft lithography, thermoplastic extrusion and stretching, laser cutting, and casting.

[0113] According to a specific embodiment of the present disclosure, the method for preparing the microneedle array in step (1) is: mixing the drug and the polymer solution 1, filling the mixture into the needle tip position of the mold, and performing photocrosslinking to obtain the microneedle array;

[0114] The polymer comprises at least one selected from methacrylated gelatin, methacrylated dextran, methacrylated sodium alginate, methacrylated hyaluronic acid, polyethylene glycol diacrylate, and polyethylene glycol.

[0115] According to a specific embodiment of the present disclosure, the method for preparing the substrate in step (2) includes at least one selected from spin coating, blade coating, photocrosslinking, chemical crosslinking, physical crosslinking, and freeze-thaw cycle method.

[0116] According to a specific embodiment of the present disclosure, the method of loading the microneedle array on the surface of the substrate in step (2) includes at least one method selected from photocrosslinking, chemical crosslinking, and physical connection.

[0117] According to a specific embodiment of the present disclosure, the method for preparing the substrate in step (2) is: placing the polymer solution 2 in a mold and photocrosslinking it with the microneedle array obtained in step (1), and demolding to obtain the substrate-microneedle array;

[0118] The polymer comprises at least one selected from a polymer having a photocrosslinking group, a polymer monomer molecule having a photocrosslinking group, and a polymer without a photocrosslinking group / a polymer monomer molecule complex having a photocrosslinking group.

[0119] According to a specific embodiment of the present disclosure, the mold in step (2) can be the model shown in Figure 8, including an assembleable upper cover plate and a lower concave mold. The lower concave mold is the needle tip position of the mold, which is used to fill the solution for forming the microneedles; the remaining space in the mold is used to fill the solution for forming the substrate. This mold can be assisted by software such as Solidworks to design a three-dimensional model with different needle numbers, needle lengths, needle types, microneedle densities, and microneedle tapers according to requirements. A hard convex mold is obtained through rapid prototyping technology such as 3D printing, and a concave mold is obtained as the required mold through PDMS molding. In addition, in the preparation process of the substrate-microneedle array, the addition of polymer monomer molecules to the substrate pre-prepared solution can achieve a covalent connection between the microneedle array and the substrate in a co-crosslinking manner, thereby enhancing the connectivity between the two components.

[0120] According to a specific embodiment of the present disclosure, the polymer having a photocrosslinking group includes at least one selected from methacrylated gelatin, methacrylated chitosan, polyether F127 acrylate, and polyethylene glycol acrylate;

[0121] The polymer having no photocrosslinking group comprises at least one selected from polyvinyl alcohol, sodium alginate, chitosan and cellulose;

[0122] The polymer monomer molecules having photocrosslinking groups include at least one selected from acrylamide, acrylic acid, N,N-methylene acrylamide, and methyl acrylate.

[0123] According to a specific embodiment of the present disclosure, step (3) specifically comprises: preparing a natural polymer water-absorbing resin, placing the natural polymer water-absorbing resin inside the substrate of the substrate-microneedle array prepared in step (2) to form a closed sandwich structure, thereby obtaining the microneedle drug delivery device.

[0124] 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.

[0125] According to a specific embodiment of the present disclosure, the biomacromolecule drug includes at least one selected from the group consisting of polypeptides, proteins, polysaccharides and nucleic acid drugs.

[0126] Among them, the drug type can be a single pure API, a mixture of multiple drugs for cocktail therapy, or micro-nanoparticles containing APIs to increase the sustained-release effect after drug delivery.

[0127] According to a specific embodiment of the present disclosure, the photocrosslinking process in step (1) includes:

[0128] The drug, polymer solution 1 and photoinitiator 1 are mixed to obtain a photocrosslinking solution, which is then added dropwise to the needle tip of the mold. The photocrosslinking solution is fully filled into the needle tip by ultrasound, centrifugation or vacuuming to perform crosslinking.

[0129] According to a specific embodiment of the present disclosure, the photoinitiator 1 includes at least one selected from benzoin and its derivatives, benzoyls, alkyl phenones, acylphosphine oxides, and benzophenones. Among them, benzoin and its derivatives can be benzoin dimethyl ether (BDK) and the like; benzoyls can be methyl o-benzoylbenzoate (OMBB); alkyl phenones can be 2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone (I2959), 2-hydroxy-2-methyl-1-phenyl-1-propanone (1173), 1-hydroxy-cyclohexyl-phenyl ketone (184), and the like; acylphosphine oxides can be 2,4,6-(trimethylbenzoyl)-diphenylphosphine oxide (TPO), 2,4,6-trimethylbenzoylphosphonic acid ethyl ester (TPO-L), and the like; benzophenones can be 4-chlorobenzophenone (CBP), 4-phenylbenzophenone (PBZ), and the like.

[0130] According to a specific embodiment of the present disclosure, the photocrosslinking process in step (2) includes: mixing the polymer solution 2 and the photoinitiator 2, placing the mixture in a mold, and performing UV crosslinking in an ice-water bath.

[0131] According to a specific embodiment of the present disclosure, the photoinitiator 2 includes at least one selected from benzoin and its derivatives, benzoyls, alkyl phenones, acylphosphine oxides, and benzophenones. Among them, benzoin and its derivatives can be benzoin dimethyl ether (BDK) and the like; benzoyls can be methyl o-benzoylbenzoate (OMBB); alkyl phenones can be 2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone (I2959), 2-hydroxy-2-methyl-1-phenyl-1-propanone (1173), 1-hydroxy-cyclohexyl-phenyl ketone (184), and the like; acylphosphine oxides can be 2,4,6-(trimethylbenzoyl)-diphenylphosphine oxide (TPO), 2,4,6-trimethylbenzoylphosphonic acid ethyl ester (TPO-L), and the like; benzophenones can be 4-chlorobenzophenone (CBP), 4-phenylbenzophenone (PBZ), and the like.

[0132] According to a specific embodiment of the present disclosure, the step (2) further comprises: performing a freeze-thaw cycle treatment after the photocrosslinking.

[0133] According to a specific embodiment of the present disclosure, a polyvinyl alcohol substrate is prepared using a freeze-thaw cycle method. A polyvinyl alcohol solution with a mass concentration of 5-15% is prepared, frozen at -20°C for 6 hours, and thawed at 25°C for 30 minutes. After 4-5 freeze-thaw cycles, a polyvinyl alcohol substrate with a certain toughness, strength, and stretchability is obtained. Furthermore, this method forms nanocrystals within the molecules of the substrate, which facilitates energy absorption during deformation.

[0134] According to a specific embodiment of the present disclosure, in step (3), the natural polymer water-absorbing resin is loaded into the cavity formed by the substrate and connected using biological glue or hot pressing.

[0135] According to a specific embodiment of the present disclosure, the raw materials for preparing the liquid-absorbing swelling material in step (3) include a water-absorbing polymer and a cross-linking agent.

[0136] According to a specific embodiment of the present disclosure, the water-absorbing polymer includes at least one selected from sodium carboxymethyl cellulose, carboxymethyl chitosan, sodium carboxymethyl alginate, and hyaluronic acid;

[0137] The cross-linking agent includes at least one selected from citric acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, glutaraldehyde, and genipin.

[0138] According to a specific embodiment of the present disclosure, a method for preparing sodium carboxymethyl cellulose hydrogel is as follows: a mixed solution of 1-10% sodium carboxymethyl cellulose by mass and 0.1-1% citric acid by mass is prepared, dried at 50°C for 6 hours, and annealed at 120°C for 4 hours to complete cross-linking; when using 1-ethyl-(3-dimethylaminopropyl)carbodiimide, glutaraldehyde, genipin and other cross-linking agents, cross-linking can be carried out at room temperature. In addition, the expansion rate of the hydrogel itself is related to its internal micro-nano structure. Using freeze-drying, anti-solvent method, salting-out method, etc., a loose porous structure can be constructed inside the hydrogel, thereby accelerating the water absorption and expansion rate of the hydrogel.

[0139] Another aspect of the present disclosure provides use of the aforementioned microneedle drug delivery device in the preparation of a drug, wherein the drug is administered orally.

[0140] In another aspect, the present disclosure provides a drug comprising the aforementioned microneedle drug delivery device and a pharmaceutical active ingredient.

[0141] Another aspect of the present disclosure provides a method for preparing a drug, wherein the active ingredient of the drug is placed in the microneedle of the aforementioned microneedle drug delivery device or the microneedle drug delivery device prepared according to the aforementioned method.

[0142] The scheme of the present disclosure will be explained below in conjunction with the examples. Those skilled in the art will understand that the following examples are only used to illustrate the present disclosure and should not be considered to limit the scope of the present disclosure. Where specific techniques or conditions are not specified in the examples, they are carried out according to the techniques or conditions described in the literature in this area or according to the product instructions. Where the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be obtained commercially. Example

[0143] Example 1 Preparation of substrate-microneedle array

[0144] 1. When the microneedle shape is conical, the preparation process of the substrate-microneedle array is shown in Figure 9(a), specifically:

[0145] (I) Prepare a mixed aqueous solution containing 20 mg / ml human recombinant insulin, 33% (v / v) polyethylene glycol diacrylate-600, 33% (v / v) polyethylene glycol-300, and 1% (v / v) photoinitiator 2-hydroxy-2-methylpropiophenone. Take 100 μl and add it to the mold. Remove bubbles by ultrasound, centrifugation, or vacuuming to ensure that the mixed solution fully fills the microneedle template pinholes. Remove and light cure at 365 nm for 15 seconds to obtain a microneedle array.

[0146] (II) preparing a mixed aqueous solution containing 8% (w / v) acrylamide, 0.1% (w / v) N,N-methylene acrylamide, 10% polyvinyl alcohol (molecular weight 89,000-98,000), and 0.1% (w / v) photoinitiator I2959, adding 500 μl to a mold, sealing with a specially prepared transparent PVC plate, and UV crosslinking in an ice-water bath for 10-30 minutes;

[0147] (III) subjecting the mold to a freeze-thaw cycle 4-5 times, and demolding to obtain a flexible, stretchable substrate loaded with drug-loaded microneedles;

[0148] (IV) Laser drilling was used to construct micropores with a diameter of 100 μm in the gaps between microneedles on a flexible stretchable substrate.

[0149] 2. When the microneedle shape is a pine tree or tower structure, the preparation process of the substrate-microneedle array is shown in Figure 9(b), specifically:

[0150] On the basis of preparing a microneedle-shaped substrate-microneedle array, the flexible stretchable substrate loaded with drug-loaded microneedles obtained in step (III) is placed in a template with a pine tree-shaped or tower-shaped needle tip position. The needle tip position of the template is pre-filled with a mixed solution containing a photoinitiator, drug, and a cross-linkable polymer. Photocrosslinking is performed again to obtain microneedles with a pine tree-shaped or tower-shaped structure. The mold is demolded to obtain a flexible substrate loaded with a pine tree-shaped or tower-shaped microneedle array. Finally, laser drilling is also used to construct micropores with a diameter of 100 μm in the gaps between the microneedles of the flexible substrate. The needle tips of the pre-prepared conical microneedles do not need to be filled with drugs.

[0151] Example 2 Preparation of a microneedle drug delivery device loaded in a controlled exposure device

[0152] (I) preparing a 6% (w / v) sodium carboxymethylcellulose solution, adding 0.5% (w / v) 1-ethyl-(3-dimethylaminopropyl)carbodiimide, stirring and cross-linking at room temperature;

[0153] (II) drying the cross-linked product obtained in step (I) in an oven at 50° C., and then crushing the cross-linked product using a high-speed crusher to obtain hydrogel particles with a particle size of about 0.5 mm;

[0154] (III) An appropriate amount of hydrogel particles was added to the substrate loaded with the microneedle array prepared in Example 1, and the microneedle drug delivery device was obtained by bonding with a biocompatible glue. After drying, the microneedle drug delivery device was encapsulated in a No. 00 commercial capsule and coated with an enteric coating to obtain the microneedle drug delivery device shown in FIG. 10 .

[0155] Example 3: Dimensional confirmation of microneedle drug delivery device

[0156] This embodiment uses Bama miniature pigs as model animals, and uses a gastroenteroscopy to deliver capsule-type pressure sensors with diameters of 10mm, 12mm, and 14mm to the small intestine to measure the force exerted on contents of different diameters when squeezed by the small intestine. The results are shown in Figure 11. The force (F1) exerted on each microneedle at different diameters in the body can be calculated by measuring the pressure reading (P) of the capsule-type sensor and the density of microneedles (ρ) distributed on this drug delivery device, that is, F1 = P / ρ. In addition, in vitro, the force (F2) required for the microneedle to penetrate the small intestinal tissue can be measured by a force gauge. By comparing F1 with F2, the minimum diameter of the microneedle drug delivery device that can ensure that the microneedle penetrates the intestinal wall can be obtained, and the inner diameter when the small intestine is filled is used as the maximum diameter, that is, the size range of the microneedle drug delivery device is determined. The pressure and pressure of the intestine acting on the microneedle are shown in Figure 12.

[0157] In addition, the size of the microneedle drug delivery device is mainly regulated by the stretchable substrate and the hydrogel filled therein. That is, during the expansion process of the microneedle drug delivery device, the tension (σ) of the stretchable substrate gradually increases, and the water absorption osmotic pressure (Ps) of the hydrogel gradually decreases. When the two are equal, the size of the microneedle drug delivery device reaches equilibrium. Specifically, the smaller the strength of the stretchable substrate, that is, the smaller the Young's modulus, the larger the expandable size of the microneedle drug delivery device; the greater the water absorption osmotic pressure of the hydrogel and the greater the filling amount, the larger the expandable size of the microneedle drug delivery device. After theoretical calculation and experimental verification, the microneedle drug delivery device prepared by selecting sodium carboxymethyl cellulose hydrogel particles, a hydrogel filling ratio of 12.5-37.5% and a stretchable substrate with a Young's modulus of 60-200kPa can expand to 10-14mm after sufficient water absorption.

[0158] Example 4 Functional Verification of Microneedle Drug Delivery Device

[0159] Considering the similarities between the digestive system structure and physiological functions of pigs and humans, this example used experimental miniature pigs as an animal model for device functional verification. To prevent the pigs' chewing behavior from damaging the microneedle drug delivery device, and to account for individual variations in gastric emptying time, the microneedle drug delivery device prepared in Example 2 was delivered into the pig's duodenum using a gastroscope after anesthesia. Serum drug levels and drug efficacy were monitored, with central venous blood drawn every 20 minutes for four hours, starting at time zero.

[0160] (1) Hypoglycemic effect

[0161] Real-time blood glucose measurements were performed using a portable blood glucose meter, with the results shown in Figures 13-14. Comparison revealed that when insulin is delivered via the intestinal tract, the blood glucose lowering effect is only achieved for a short period of time, with subsequent increases in blood glucose levels, resulting in a poor blood glucose lowering effect. However, when delivered via the microneedle drug delivery device prepared in the present disclosure, the blood glucose lowering effect was superior to that achieved by intestinal delivery. The microneedle drug delivery device with a barbed structure achieved an effect comparable to that achieved by subcutaneous injection, with a 23.7% reduction in blood glucose over a three-hour period.

[0162] (2) Bioavailability

[0163] Excess blood was drawn and placed in a coagulation tube, allowed to stand for approximately 40 minutes, and then centrifuged to separate the serum. The drug content in the blood was assayed using a human insulin ELISA kit, yielding the pharmacokinetic curve shown in Figure 15. Due to varying insulin sensitivity and intestinal peristalsis rhythms among individual animals, the extrusion microneedle delivery device exhibits varying patterns, resulting in varying peak blood drug concentration times and large error bars at each point. The area under the curve can be used to compare the bioavailability of various drug delivery methods.

[0164] Bioavailability indicates the relative amount of a drug absorbed into the systemic blood circulation after administration via the extravascular route. It is calculated as the ratio of the area under the pharmacokinetic curve (AUC) / dose to the corresponding data of the subcutaneous injection group, and is used to evaluate the efficiency of a drug delivery method. The AUC of each curve in Figure 15 is statistically obtained to obtain Figure 16, and the bioavailability of each drug delivery method is calculated by the formula (AUC with barbs / D) / (AUC Sub / 0.2)×100%. The bioavailability of intestinal delivery, tower-shaped microneedle drug delivery device, and cone-shaped microneedle drug delivery device are 0.6%, 23.6%, and 4.2%, respectively, indicating that the microneedle drug delivery device prepared by the present disclosure, whether it is a tower-shaped microneedle drug delivery device or a cone-shaped microneedle drug delivery device, can achieve higher bioavailability when delivering drugs.

[0165] Example 5 Biological Validation of Microneedle Drug Delivery Device

[0166] Using Bama miniature pigs as a model animal, the microneedle drug delivery device was delivered to the small intestine using a gastroenteroscope. Continuous observation using the gastroenteroscope, as shown in Figure 17, shows that the microneedle drug delivery device, after expansion, is fully squeezed in the intestine.

[0167] After waiting for 4 hours for the microneedle drug delivery device to work, the abdomen of the Bama miniature pig was cut open, the intestine was taken out, the location of the microneedle drug delivery device was found, and the nearby small intestinal wall was removed. In addition, the microneedle drug delivery device was used to directly pierce a piece of small intestinal wall in vitro. The two small intestinal walls were immersed and fixed in formalin, and then dehydrated, paraffin-embedded, and sectioned for HE staining and observation. The results are shown in Figure 18. It can be clearly seen that there are traces of microneedle penetration on the small intestinal wall both in vivo and in vitro, while there are no such traces on the small intestinal sections of the blank control group, indicating that the microneedle drug delivery device can indeed pierce the microneedle into the intestinal wall.

[0168] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present disclosure. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine different embodiments or examples described in this specification and features of different embodiments or examples, unless they are mutually inconsistent.

[0169] Although the embodiments of the present disclosure have been shown and described above, it is understood that the above embodiments are illustrative and are not to be construed as limitations on the present disclosure. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present disclosure.

Claims

1. A microneedle drug delivery device, in, The device comprises a substrate, a microneedle array and a liquid-swelling material, wherein the substrate carries the microneedle array, the liquid-swelling material is wrapped by the substrate to form a closed sandwich structure, and the tips of the microneedles are loaded with drugs.

2. The microneedle drug delivery device according to claim 1, in, The drug comprises at least one selected from biological macromolecular drugs and chemical small molecule drugs; Optionally, the biomacromolecule drug comprises at least one selected from the group consisting of polypeptides, proteins, polysaccharides and nucleic acid drugs.

3. The microneedle drug delivery device according to claim 1, in, The microneedles contained in the microneedle array are in a single-layer cone shape or have a barbed structure, and the number of the microneedles is 1-1000.

4. The microneedle drug delivery device according to claim 3, in, The barb structure includes at least one selected from a pine tree shape, a tower shape or a thorn shape.

5. The microneedle drug delivery device according to claim 1, in, The microneedles contained in the microneedle array have a length of 30-5000 μm, a bottom size of 10-5000 μm, and a tip size of 1-300 μm, wherein the bottom size is greater than or equal to the tip size.

6. The microneedle drug delivery device according to claim 1, in, The substrate is a flexible and stretchable substrate, and the material used to prepare the substrate includes at least one selected from sodium alginate, chitosan, cellulose, and polyvinyl alcohol.

7. The microneedle drug delivery device according to claim 1, in, The substrate surface has a microporous structure.

8. The microneedle drug delivery device according to claim 7, in, The micropores have a diameter of 10-1000 μm.

9. The microneedle drug delivery device according to claim 7, in, The micropores have a diameter of 80-500 μm.

10. The microneedle drug delivery device according to claim 7, in, The micropore density is 0.01-1000 / mm 2 .

11. The microneedle drug delivery device according to claim 1, in, The liquid-absorbing and swelling material comprises at least one selected from water-absorbing gel, water-absorbing rubber, and water-absorbing resin.

12. The microneedle drug delivery device according to claim 1, in, The liquid-absorbing and swelling material is selected from polymer water-absorbing resins.

13. The microneedle drug delivery device according to claim 12, in, The particle size of the polymer water-absorbing resin is 0.01-20 mm.

14. The microneedle drug delivery device according to claim 12, in, The particle size of the polymer water-absorbing resin is 0.5-5 mm.

15. The microneedle drug delivery device according to claim 1, in, The microneedle drug delivery device further comprises a controllable exposure device, wherein the controllable exposure device covers the substrate, the microneedle array and the liquid swelling material.

16. The microneedle drug delivery device according to claim 15, in, The controlled exposure device has an enteric coating.

17. The microneedle drug delivery device according to any one of claims 1 to 16, in, The size of the microneedle drug delivery device under swelling equilibrium does not exceed the inner diameter of the intestinal cavity of the subject.

18. A method for preparing the microneedle drug delivery device according to any one of claims 1 to 17, in, The following steps are involved: (1) preparing a microneedle array; (2) preparing a substrate, and loading the microneedle array obtained in step (1) on the surface of the substrate to obtain a substrate-microneedle array; (3) preparing a liquid-swelling material, placing the liquid-swelling material in the substrate-microneedle array obtained in step (2) Into a closed sandwich structure.

19. The method according to claim 18, in, The method for preparing the microneedle array in step (1) comprises at least one selected from 3D printing, photolithography, soft photolithography, thermoplastic extrusion stretching, laser cutting, and casting.

20. The method according to claim 18, in, The method for preparing the microneedle array in step (1) is: mixing the drug and the polymer solution 1, filling the mixture into the needle tip position of the mold, and performing photocrosslinking to obtain the microneedle array; Wherein, the polymer includes at least one selected from methacryloyl gelatin, methacryloyl dextran, methacryloyl sodium alginate, methacryloyl hyaluronic acid, polyethylene glycol diacrylate, and polyethylene glycol.

21. The method according to claim 18, in, The method for preparing the substrate in step (2) includes at least one selected from spin coating, scraping, photocrosslinking, chemical crosslinking, physical crosslinking, and freeze-thaw cycle.

22. The method according to claim 18, in, The method for loading the microneedle array onto the surface of the substrate in step (2) includes at least one method selected from photocrosslinking, chemical crosslinking, and physical connection.

23. The method according to claim 18, in, The method for preparing the substrate in step (2) is: placing the polymer solution 2 in a mold to photo-crosslink with the microneedle array obtained in step (1), and demolding to obtain the substrate-microneedle array; The polymer comprises at least one selected from a polymer having a photo-crosslinking group, a polymer monomer molecule having a photo-crosslinking group, and a polymer without a photo-crosslinking group / a polymer monomer molecule complex having a photo-crosslinking group.

24. The method according to claim 23, in, The polymer having a photo-crosslinking group includes at least one selected from methacrylated gelatin, methacrylated chitosan, polyether F127 acrylate, and polyethylene glycol acrylate; The polymer of the light-free cross-linking group includes at least one selected from polyvinyl alcohol, sodium alginate, chitosan, and cellulose; The polymer monomer molecules having photo-crosslinking groups include at least one selected from acrylamide, acrylic acid, N,N-methylene acrylamide, and methyl acrylate.

25. The method according to claim 18, in, The step (3) further comprises: preparing a natural polymer water-absorbing resin, placing the natural polymer water-absorbing resin inside the substrate of the substrate-microneedle array prepared in step (2) to form a closed sandwich structure, thereby obtaining the microneedle drug delivery device.

26. The method according to claim 20, in, The drug includes at least one selected from biological macromolecular drugs and chemical small molecule drugs; Optionally, the biomacromolecule drug comprises at least one selected from the group consisting of polypeptides, proteins, polysaccharides and nucleic acid drugs.

27. The method according to claim 19, in, The photocrosslinking process in step (1) comprises: The drug, polymer solution 1 and photoinitiator 1 are mixed to obtain a photocrosslinking solution, which is then added dropwise to the needle tip of the mold. The photocrosslinking solution is fully filled to the needle tip by ultrasound, centrifugation or vacuuming to perform crosslinking.

28. The method according to claim 27, in, The photoinitiator 1 includes at least one selected from benzoin and its derivatives, benzoyls, alkyl phenones, acylphosphine oxides, and benzophenones.

29. The method according to claim 23, in, The photocrosslinking process in step (2) includes: mixing the polymer solution 2 and the photoinitiator 2, placing the mixture in a mold, and performing ultraviolet crosslinking in an ice water bath.

30. The method according to claim 29, in, The photoinitiator 2 includes at least one selected from benzoin and its derivatives, benzoyls, alkyl phenones, acylphosphine oxides, and benzophenones.

31. The method according to claim 23, in, The step (2) further comprises: performing a freeze-thaw cycle treatment after the photo-crosslinking.

32. The method according to claim 25, in, In step (3), the natural polymer water-absorbing resin is loaded into the cavity formed by the substrate and connected using biological glue or hot pressing.

33. The method according to claim 18, in, The raw materials for preparing the liquid-absorbing swelling material in step (3) include a water-absorbing polymer and a cross-linking agent.

34. The method according to claim 33, in, The water-absorbing polymer includes at least one selected from sodium carboxymethyl cellulose, carboxymethyl chitosan, sodium carboxymethyl alginate, and hyaluronic acid; The cross-linking agent includes at least one selected from citric acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, glutaraldehyde, and genipin.

35. Use of the microneedle drug delivery device according to any one of claims 1 to 17 in the preparation of a drug, in, The drug is administered orally.

36. A drug, in, The drug comprises the microneedle drug delivery device according to any one of claims 1 to 17 and a drug active ingredient.

37. A method for preparing a drug, in, The active pharmaceutical ingredient is placed in the microneedle of the microneedle drug delivery device according to any one of claims 1 to 17 or the microneedle drug delivery device prepared by the method according to any one of claims 18 to 34.

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