Gastric residence drug delivery system based on intelligent deformation and anchoring of biomechanical response and preparation method thereof

Abstract

This invention relates to a gastric drug delivery system based on biomechanically responsive intelligent deformation and anchoring, and its preparation method. The system includes a main body, multiple microneedle structures, a drug-loading unit, and a controlled-release unit. The main body is made of a thermoresponsive shape memory polymer and includes a head and multiple tentacles. The head is spherical with an opening, and the tentacles are distributed around the opening. Multiple microneedle structures are disposed on the tentacles. The drug-loading unit contains a metal-organic framework carrier and a drug, with the drug loaded on the metal-organic framework carrier. The drug-loading unit is distributed in the main body and / or multiple microneedle structures. When a triggering factor occurs, the drug-loading unit releases the drug. The controlled-release unit is used to control the release rate of the drug in the drug-loading unit. The main body structure of this invention utilizes the shape-restoring force generated by thermo-induced mechanical deformation to achieve stable buoyancy and fluid obstruction in gastric juice. The microneedle structures anchor to the gastric wall, effectively counteracting mechanical displacement caused by gastric peristalsis, enabling precise on-demand drug delivery.

Description

Technical Field

[0001] This invention belongs to the field of implantable medical devices, and particularly relates to a gastric retention drug delivery system based on biomechanical response intelligent deformation and anchoring and its preparation method. Background Technology

[0002] Oral administration is considered an ideal route for drug delivery due to its convenience and high patient compliance. However, oral administration of many drugs, especially biomolecules such as peptides (e.g., insulin), faces significant challenges. This is primarily because drugs encounter various biological barriers in the gastrointestinal tract, including the highly acidic environment of gastric acid (pH 1.0–3.0), degradation by digestive enzymes, low permeability of the intestinal epithelium, and a strong first-pass effect, resulting in extremely low oral bioavailability.

[0003] Insulin, a crucial drug for diabetes treatment, is routinely administered via subcutaneous injection. This not only causes pain and inconvenience for patients, reducing treatment adherence, but also easily leads to blood glucose fluctuations and even severe hypoglycemic events due to improper dosage and timing control. Although researchers have tried various strategies to improve the oral bioavailability of insulin, such as using absorption enhancers, enzyme inhibitors, and nanocarriers, the results have been unsatisfactory, and to date, no truly effective oral insulin formulation has been successfully applied clinically.

[0004] To overcome the gastrointestinal barrier and improve the oral bioavailability of drugs, gastric retention drug delivery systems (GRDDS) have emerged. These systems increase the contact time between the drug and the absorption site by prolonging the retention time of the formulation in the stomach, thereby improving drug absorption efficiency. Traditional GRDDS systems are mainly based on mechanisms such as flotation, expansion, bioadhesion, or density control. However, these systems have significant limitations. For example, flotation systems may fail due to changes in stomach contents or body position, expansion systems may cause gastrointestinal discomfort or even obstruction, and bioadhesion systems are affected by the continuous renewal of the mucus layer, resulting in limited adhesion time.

[0005] Therefore, developing a novel intelligent gastric retention drug delivery system that can simultaneously achieve long-term gastric retention, intelligent drug release, and high bioavailability has significant clinical implications and market value. Summary of the Invention

[0006] The main objective of this invention is to provide a gastric retention drug delivery system based on biomechanical response intelligent deformation and anchoring, and its preparation method, in order to solve the problems of short gastric retention time, easy degradation of drugs, low absorption efficiency or inability to release on demand that are common in oral drug delivery systems in the prior art. In particular, it can solve the problems of extremely low bioavailability and large fluctuations in blood drug concentration of drugs with short half-lives such as insulin.

[0007] To achieve the above objectives, the present invention provides a gastric retention drug delivery system based on biomechanical response intelligent deformation and anchoring, comprising:

[0008] The main body is made of a thermally responsive shape memory polymer. The main body includes a head and multiple tentacles. The head is spherical and has an opening. The multiple tentacles are distributed around the opening.

[0009] Multiple microneedle structures are disposed on the multiple antennae;

[0010] A drug delivery unit comprises a metal-organic framework carrier and a drug, wherein the drug is loaded onto the metal-organic framework carrier; the drug delivery unit is distributed in the main body and / or the plurality of microneedle structures, and the drug delivery unit releases the drug when a triggering factor occurs;

[0011] A controlled-release unit is used to control the release rate of the drug in the drug delivery unit.

[0012] The gastric retention drug delivery system based on biomechanical response intelligent deformation and anchoring, as described in this invention, further includes a capsule shell in one embodiment. The main body, multiple microneedle structures, drug-carrying unit, and controlled-release unit are encapsulated within the capsule shell; and / or, the main body is in a contracted state before thermal response, exhibiting a near-cylindrical shape; and in an expanded state after thermal response, exhibiting a jellyfish-like shape. The spatial occupancy effect and hydrodynamic resistance generated after its expansion counteract gastric emptying.

[0013] In one embodiment of the gastric retention drug delivery system based on biomechanical response intelligent deformation and anchoring described in this invention, the phase transition temperature of the thermally responsive shape memory polymer is 35-38°C; and / or, the thermally responsive shape memory polymer includes, but is not limited to, polycaprolactone, polydodecanoic acid glycerol, polylactic acid, polylactic acid-glycolic acid copolymer, polyurethane, polyether ester polyol, copolymer of polycaprolactone-polydodecanoic acid glycerol, polycaprolactone-polylactic acid copolymer, copolymer or blend of polycaprolactone and polylactic acid-glycolic acid.

[0014] In one embodiment of the biomechanically responsive intelligent deformation and anchoring gastric retention drug delivery system of the present invention, the drug-carrying unit is uniformly distributed on the main body and the plurality of microneedle structures; and / or, a portion of the drug-carrying unit is uniformly distributed on the main body, and the remaining portion of the drug-carrying unit is uniformly distributed on the plurality of microneedle structures, wherein the ratio of the amount of drug in a portion of the drug-carrying unit to the amount of drug in the remaining portion of the drug-carrying unit is 0.01:5 to 5:0.01; and / or, a portion of the drug-carrying unit is distributed on the head, and the remaining portion of the drug-carrying unit is distributed on the plurality of tentacles and the plurality of microneedle structures, wherein the amount of drug in the remaining portion of the drug-carrying unit accounts for more than 70% of the total drug dosage.

[0015] In one embodiment of the biomechanical response-based intelligent deformation and anchoring gastric retention drug delivery system of the present invention, the microneedle structure includes a base and a tip, the axial length ratio of the base to the tip is 1:(1-5), the base is connected to the antenna, a portion of the drug-carrying unit is distributed in the body and the base of the microneedle structure, and the remaining portion of the drug-carrying unit is distributed in the tip of the microneedle structure, wherein the ratio of the amount of drug in a portion of the drug-carrying unit to the amount of drug in the remaining portion of the drug-carrying unit is 5:1 to 1:5, preferably, the amount of drug in the remaining portion of the drug-carrying unit accounts for more than 70% of the total drug dosage.

[0016] In one embodiment of the biomechanically responsive intelligent deformation and anchoring gastric drug delivery system of the present invention, the drug-loading unit further comprises a stimulus-responsive factor loaded on the metal-organic framework carrier or a stimulus-responsive metal-organic framework carrier; the metal-organic framework carrier includes, but is not limited to, at least one of zinc-based MOF, iron-based MOF, zirconium-based MOF, and copper-based MOF; the zinc-based MOF is ZIF-8, ZIF-90, MOF-5, MOF-74, etc.; the iron-based MOF is MIL-100(Fe), MIL-101(Fe), MIL-88B(Fe), etc.; the zirconium-based MOF is UiO-66, UiO-67, NU-1000, etc.; the copper-based MOF is HKUST-1, Cu-BTC, MOF-199, etc.; the stimulus-responsive factor includes, but is not limited to, pH-responsive factor, glucose-responsive factor, redox-responsive factor, magnetic-responsive factor, photoresponsive factor, or other physicochemical and biological triggering factors.

[0017] In one embodiment of the gastric retention drug delivery system based on biomechanical response intelligent deformation and anchoring described in this invention, the controlled-release unit is a sustained-release coating that covers the surface of the main body and the microneedle structure, and the sustained-release coating has microchannels at the locations corresponding to the microneedle structure.

[0018] In one embodiment of the gastric drug delivery system based on biomechanical response intelligent deformation and anchoring, the microneedle structure of the present invention is a needle-like structure with a length of 0.5-2 mm and an apex angle of 10-65°. The density of the microneedles on the apex is 5-20 needles / mm. 2 ; and / or, the apex of the microneedle structure is provided with a barb structure, the depth of the barb structure in the axial direction being 50-1000μm.

[0019] To achieve the above objectives, the present invention also provides a method for preparing the above-mentioned gastric drug delivery system based on biomechanical response intelligent deformation and anchoring, comprising the following steps:

[0020] Step 1: Load the drug onto the metal-organic framework carrier to obtain the drug-loaded unit;

[0021] Step 2: Mix the thermally responsive shape memory polymer and the drug delivery unit to prepare the main body and microneedle structure;

[0022] Step 3: Coat the main body and microneedle structure with a sustained-release coating, and set microchannels at the microneedle structure to obtain a controlled-release unit;

[0023] When a triggering factor occurs, the drug delivery unit releases the drug.

[0024] In one embodiment of the preparation method of the gastric retention drug delivery system based on biomechanical response intelligent deformation and anchoring, the method of loading the drug onto the metal-organic framework carrier includes, but is not limited to, at least one of the following: in-situ encapsulation, post-impregnation, surface modification, and core-shell structure; the triggering factors include, but are not limited to, pH triggering, biomarker triggering, redox triggering, or external stimulus triggering.

[0025] The system described in this invention achieves long-term retention in the gastric peristaltic environment through the combined action of the radial restoring force generated by the body temperature response of the main body, the fluid resistance generated by the biomimetic shape, and the mechanical locking force of the microneedle structure.

[0026] The beneficial effects of this invention are:

[0027] (1) The present invention constructs a biomimetic jellyfish structure based on thermally responsive shape memory polymer. It can be precisely transformed from a folded and contracted state to an unfolded state by utilizing its shape recovery force when triggered by body temperature. This greatly improves the retention capacity and anti-emptying performance in the stomach, ensuring the high stability of the system in a dynamic biomechanical environment and solving the technical problem that traditional gastric retention systems are easily discharged as food moves.

[0028] (2) The gastric retention drug delivery system of the present invention has a dual intelligent response mechanism. On the one hand, the drug is released by triggering factors. On the other hand, the bionic structure is used to make low-stress mechanical adaptive contact with the gastric mucosa through structural design, so as to change from floating to passive anchoring with the gastric emptying process. This ensures the gripping force and avoids mechanical damage to the gastric wall tissue, overcomes the operational complexity and safety problems of external energy-dependent systems, and realizes fully autonomous adaptive drug delivery.

[0029] (3) The gastric retention drug delivery system of the present invention can be safely degraded and discharged after drug delivery without removal. It not only achieves intelligent sustained release for several days, but also provides an efficient and safe platform solution for oral delivery of macromolecular drugs such as proteins and peptides, and has significant clinical translation prospects. Attached Figure Description

[0030] Figure 1 This is a schematic diagram of the intelligent gastric retention drug delivery system of the present invention in the extended state;

[0031] Figure 2 This is a schematic diagram of the intelligent gastric retention drug delivery system of the present invention in the contracted state;

[0032] Figure 3 This is another schematic diagram of the intelligent gastric retention drug delivery system of the present invention in the extended state;

[0033] Figure 4 This is a schematic diagram of the microneedle structure of the intelligent gastric retention drug delivery system of the present invention;

[0034] Figure 5 This is a schematic diagram of the delivery process of the intelligent gastric retention drug delivery system of the present invention;

[0035] Figure 6 This is a diagram showing the state changes of the intelligent gastric retention drug delivery system before and after gastric emptying in one embodiment of the present invention;

[0036] Figure 7 This is a diagram showing the state changes of the intelligent gastric retention drug delivery system before and after stimulus response in another embodiment of the present invention;

[0037] Figure 8 This is a schematic diagram of the drug release process of the intelligent gastric retention drug delivery system in Example 1;

[0038] Figure 9 This is a schematic diagram of the drug release process of the intelligent gastric retention drug delivery system in Example 2;

[0039] Figure 10 This is a schematic diagram of the drug release process of the intelligent gastric retention drug delivery system in Example 3;

[0040] Figure 11 This is a schematic diagram of the drug release process of the intelligent gastric retention drug delivery system in Example 4;

[0041] Figure 12 This is a schematic diagram of the drug release process of the intelligent gastric retention drug delivery system in Example 5;

[0042] Figure 13 This is a Fourier transform infrared spectrum of a polymer printing ink according to one embodiment of the present invention.

[0043] Figure 14 This is an X-ray diffraction pattern of a polymer printing ink according to one embodiment of the present invention;

[0044] Figure 15 This is a contact angle test diagram of polymer printing ink according to one embodiment of the present invention;

[0045] Figure 16 This is a thermodynamic test diagram of a polymer in one embodiment of the present invention;

[0046] Figure 17 This is a test graph showing the shape fixation rate and shape recovery rate of the polymer in one embodiment of the present invention;

[0047] Figure 18A This is a morphological diagram of the microneedle structure in one embodiment of the present invention;

[0048] Figure 18B This is a morphological diagram of the microneedle structure in another embodiment of the present invention;

[0049] Figure 18C This is a quasi-static mechanical test insertion depth diagram of the microneedle structure in one embodiment of the present invention;

[0050] Figure 18D This is a dynamic mechanical test insertion depth diagram of the microneedle structure in one embodiment of the present invention;

[0051] Figure 19 This is a force-displacement curve obtained by quasi-static puncture of a microneedle structure in one embodiment of the present invention.

[0052] Figure 20 The results of the test on release behavior at different blood glucose concentrations are shown in the figure.

[0053] Figure 21 To gradually release the behavioral test results graph;

[0054] Figure 22 The graph shows the test results of the pulse release behavior.

[0055] Figure 23 This is a graph showing the degradation amount versus time of the thermally responsive shape memory polymer cured sample of the present invention under simulated gastric acid conditions.

[0056] Figure 24 This is a graph showing the density versus time of a thermally responsive shape memory polymer cured sample under simulated gastric acid conditions.

[0057] In the attached figures, the following labels are used:

[0058] 1. Head

[0059] 2. Antennae

[0060] 3. Microneedle structure

[0061] 31. Barbed structure

[0062] 4 Controlled-release units Detailed Implementation

[0063] The technical solution of the present invention will be described in detail below. Experimental methods or structures not specified in the following embodiments are generally conventional methods or structures in the art.

[0064] This invention provides a gastric drug delivery system based on biomechanically responsive intelligent deformation and anchoring, and its preparation method. The system utilizes a thermo-responsive shape memory polymer to construct a biomimetic jellyfish-like body. At room temperature, it has a compact structure for easy encapsulation and swallowing. Upon triggering with body temperature within the stomach, it precisely recovers to a floating shape, significantly prolonging the gastric retention time. The system integrates microneedles with a higher antennal density than the head, allowing them to passively puncture the gastric wall during gastric emptying or actively puncture in response to external factors, releasing drug-loading units. These units can release drugs in a cascade based on triggering factors, thereby significantly improving drug bioavailability, reducing side effects, and providing a novel, efficient, and safe oral drug delivery strategy for various chronic diseases such as diabetes.

[0065] In one implementation, please refer to Figure 1 , Figure 1 This is a schematic diagram of the intelligent gastric retention drug delivery system of the present invention in its extended state. The intelligent gastric retention drug delivery system of the present invention includes a main body, multiple microneedle structures 3, a drug-loading unit (not shown), and a controlled-release unit 4. The main body is made of a thermally responsive shape memory polymer and includes a head 1 and multiple tentacles 2. The head 1 is spherical and has an opening, and the multiple tentacles 2 are distributed around the opening. Multiple microneedle structures 3 are disposed on the multiple tentacles 2. The drug-loading unit contains a metal-organic framework carrier and a drug, with the drug loaded on the metal-organic framework carrier. The drug-loading unit is distributed in the main body and / or multiple microneedle structures 3. When a triggering factor occurs, the drug-loading unit releases the drug. The controlled-release unit 4 is used to control the release rate of the drug in the drug-loading unit.

[0066] Please also see Figure 2 , Figure 2This is a schematic diagram of the intelligent gastric retention drug delivery system of the present invention in its contracted state. The main body of the intelligent gastric retention drug delivery system of the present invention is made of a thermally responsive shape memory polymer, and is in a contracted state before thermal response, exhibiting a near-cylindrical shape, such as... Figure 2 As shown. At this point, it can be called a compact "temporary structure," which is conducive to being packaged into oral capsules and to oral administration. After the thermal response, it is in a stretched state, resembling a jellyfish, as... Figure 1 As shown, the thermal response here is, for example, a body temperature response. When the intelligent gastric retention drug delivery system of the present invention enters the stomach, under the influence of the stomach's body temperature, the main body gradually unfolds and returns to a jellyfish-like shape. At this point, it can be called a "permanent structure," with the head and tentacles unfolding to achieve stable floating in the gastric juice.

[0067] In one embodiment, the radial dimension of the intelligent gastric retention drug delivery system of the present invention in the extended state (e.g.) Figure 1 Lateral dimension) is 1-40mm, for example 1mm, 5mm, 10mm, 15mm, 20mm, 25mm, 30mm, 35mm or 40mm, etc., and axial height in the extended state (e.g. Figure 1 The longitudinal dimension is 10-30mm, such as 10mm, 12mm, 15mm, 20mm, 25mm, 27mm or 30mm, but the present invention is not limited thereto.

[0068] In one embodiment, the intelligent gastric retention drug delivery system of the present invention further includes a capsule shell, and the main body, multiple microneedle structures 3, drug loading unit and controlled release unit 4 are encapsulated within the capsule shell. Therefore, the size of the intelligent gastric retention drug delivery system of the present invention is adjustable to adapt to the encapsulation requirements of different sizes of oral capsule shells, including but not limited to size 000, 00, 0, 1, 2, 3, 4 and 5 capsule shells.

[0069] In one embodiment, when the intelligent gastric retention drug delivery system of the present invention is in its extended state, the diameter of the head 1 is 1-20 mm, for example 5 mm, and the length of the tentacle 2 is, for example, 7.5 mm. The tentacle 2 is a near-cylindrical shape with a diameter of, for example, 500-800 μm, more specifically, 650 μm. The projected length of the tentacle 2 in the radial direction is 0.5-1 times the tentacle length, for example, 0.5 times, 0.75 times, or 1.0 times. In another embodiment, the intelligent gastric retention drug delivery system of the present invention includes 6-10 tentacles 2, for example, 6, 7, 8, 9, or 10, evenly distributed around the opening of the head 1. The tentacle 2 of the present invention is a flexible tentacle, and the multiple tentacles work together to form a stable biomimetic floating configuration, effectively increasing the fluid resistance and stability of the system in gastric juice and preventing it from being prematurely emptied during gastric peristalsis. In another embodiment, when the intelligent gastric retention drug delivery system of the present invention is in its extended state, the angle formed between the antennae 2 and the central axis of the head 1 is 30°-180°, for example, 30°, 45°, 60°, 80°, 120°, 180°, etc. In yet another embodiment, please also refer to... Figure 3 , Figure 3 This is another schematic diagram of the intelligent gastric retention drug delivery system of the present invention in its extended state. In the extended state, the antenna 2 of the intelligent gastric retention drug delivery system of the present invention is bent to have an angle α, which is, for example, 120-180°, more specifically, 140°.

[0070] The main body of the intelligent gastric retention drug delivery system of this invention is made of a thermally responsive shape memory polymer, the phase transition temperature of which is 35-38°C, i.e., the shape transition temperature (Ti) of the thermally responsive shape memory polymer. trans The temperature is 35-38°C, which ensures precise triggering of shape recovery within the gastric temperature environment. In one embodiment, the thermoresponsive shape memory polymer is selected from polyesters, polyurethanes, polyether esters, or blends and copolymers thereof. Preferably, the thermoresponsive shape memory polymer includes, but is not limited to, polycaprolactone (PCL), polydodecanoic acid glycerol (PGD), polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), polyurethane (PU), polyether ester polyols, PCL-PGD (polycaprolactone-polydodecanoic acid glycerol copolymer), PCL-PLA, and copolymers or blends of PCL-PLGA. More preferably, the thermoresponsive shape memory polymer of the present invention is PCL-PGD.

[0071] In one embodiment, the head 1 of the intelligent gastric retention drug delivery system of the present invention is made of a thermally responsive shape memory polymer, and the antennae 2 and microneedle structure 3 are made of thermally responsive shape memory polymers or biodegradable polymers to ensure appropriate flexibility and mechanical strength. The biodegradable polymers include, but are not limited to, one or more of gelatin, polylactic-co-glycolic acid copolymer (PLGA), chitosan, starch and its derivatives, collagen, etc.

[0072] In one embodiment, the wall thickness of the head 1 of the intelligent gastric retention drug delivery system of the present invention is 0.1-2 mm, such as 0.1 mm, 0.2 mm, 0.5 mm, 0.8 mm, 1.0 mm, 1.2 mm, 1.5 mm, 1.8 mm or 2.0 mm, so that its degradation cycle matches the gastric emptying time, can maintain structural integrity during the gastric retention period, and gradually degrade as the retention time prolongs.

[0073] The microneedle structure 3 of this invention refers to a needle-like structure with a size substantially in the micrometer range, typically arranged in an array. In one embodiment, the length of the microneedle structure 3 is 100-2000 μm, preferably 500-1500 μm, such as 100 μm, 300 μm, 500 μm, 800 μm, 1000 μm, 1200 μm, or 1500 μm. The tip cone angle (i.e., apex angle) is 10-65°, preferably 10°-60°, such as 10°, 20°, 30°, 40°, 50°, or 60°, and the array distribution density is 4-25 needles / mm², preferably 5-20 needles / mm². 2 .

[0074] In one embodiment, please also refer to Figure 4 , Figure 4 This is a schematic diagram of the microneedle structure of the intelligent gastric retention drug delivery system of the present invention. The microneedle structure 3 has a barb structure 31 at its apex. The barb structure has an axial depth of 50-1000 μm and an apex angle of 0-70°, more specifically 0-60°. This design further enhances the anchoring ability of the intelligent gastric retention drug delivery system of the present invention on the gastric wall, ensuring that the system maintains effective retention even after gastric emptying. The microneedle structure of the present invention can penetrate the mucus layer and epithelial barrier, directly delivering drugs into the tissue, significantly improving the local drug concentration and absorption efficiency.

[0075] It should be noted that the number of tentacles 2, the angle formed by the tentacles 2 with the central axis of the head 1 when in the extended state, and the ratio of the projected length of the tentacles 2 in the radial direction to the total length of the tentacles have been optimized through fluid dynamics simulation. This ensures that the gastric retention drug delivery system achieves maximum floating stability in the stomach while maintaining a small size for easy swallowing. Simultaneously, this gastric retention drug delivery system adaptively softens at body temperature and can deform adaptively with the peristalsis of the stomach wall, avoiding mechanical damage to tissues.

[0076] In one specific embodiment, the present invention utilizes computer-aided design tools to parametrically model the main body structure, spatial distribution of tentacles, and microneedle arrangement pattern of a biomimetic jellyfish. Applicable 3D modeling platforms include, but are not limited to, one or more combinations of SolidWorks, 3DS Max, CINEMA 4D, Maya, Rhino, SketchUp, CATIA, NX, AutoCAD, Pro / E, Cimatron, LightWave, Poser, Creo, FormZ, Blender, FreeCAD, Fusion 360, ZBrush, TinkerCAD, and Onshape. The standard triangular mesh file (STL format) output from the 3D model needs to be layered using a slicing engine. Applicable slicing systems include, but are not limited to, any one or more combinations of Ultimaker Cura, PrusaSlicer, Simplify3D, Slic3r, MatterControl, Tinkerine Suite, AstroPrint, OctoPrint, CraftWare, IceSL, and IdeaMaker.

[0077] The drug delivery unit of this invention comprises a metal-organic framework carrier and a drug. In one embodiment, the particle size D of the drug delivery unit is... 50 The particle size is 50nm-10μm, such as 50nm, 100nm, 500nm, 1μm, 2μm, 5μm, 8μm, or 10μm. Based on the total mass of the drug-loading unit, the drug loading capacity of the drug-loading unit is 5%-50% (w / w), such as 5%, 10%, 20%, 30%, 40%, or 50%. However, this invention is not limited to these values; the particle size and drug loading capacity of the drug-loading unit can be flexibly adjusted according to clinical needs.

[0078] In another embodiment, the mass ratio of the metal-organic framework carrier to the drug in the drug delivery unit is (1:1)-(100:1), for example, 1:1, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1 or 100:1.

[0079] Generally, the density of the drug-carrying unit is greater than the density of the thermally responsive shape memory polymer of the main body. Therefore, the density of the intelligent gastric retention drug delivery system of the present invention can be adjusted by the amount and distribution of the drug-carrying units. In one embodiment, the initial density of the intelligent gastric retention drug delivery system of the present invention is less than the density of gastric fluid to enable the system to remain floating in the gastric fluid. In another embodiment, the initial density is, for example, less than 1.0 g / cm³, more specifically less than or equal to 0.9 g / cm³, and the retention time of the intelligent gastric retention drug delivery system in gastric fluid is, for example, 2-72 hours, more specifically ≥4 hours. As the thermally responsive shape memory polymer of the main material degrades, the density of the intelligent gastric retention drug delivery system gradually increases. When it exceeds the density of gastric fluid, such as greater than 1.05 g / cm³, a smooth transition from a floating state to a gastric wall anchored state can be achieved. Combined with gastric peristalsis or external signals, this facilitates the insertion of the microneedle array and the continuous release of the drug-carrying units.

[0080] In one embodiment, the metal-organic framework carrier is a stimulus-responsive MOF, such as a structure with different pH stability responding to changes in the microenvironment pH, a structure containing disulfide bonds responding to high concentrations of glutathione (GSH), or achieving targeted drug delivery by loading or surface-functionalizing magnetic particles and photothermal conversion particles.

[0081] In one embodiment, the metal-organic framework carrier includes, but is not limited to, at least one of zinc-based MOFs, iron-based MOFs, zirconium-based MOFs, and copper-based MOFs; the zinc-based MOFs are ZIF-8, ZIF-90, MOF-5, MOF-74, etc.; the iron-based MOFs are MIL-100(Fe), MIL-101(Fe), MIL-88B(Fe), etc.; the zirconium-based MOFs are UiO-66, UiO-67, NU-1000, etc.; and the copper-based MOFs are HKUST-1, Cu-BTC, MOF-199, etc. In another embodiment, the drug delivery unit further includes a stimulus-response factor loaded on the metal-organic framework carrier. The stimulus-response factor includes, but is not limited to, pH-response factors, biomarker-response factors such as glucose-response factors, enzyme-response factors, redox-response factors, etc., or external stimulus response factors. In another embodiment, the metal-organic framework carrier is a metal-organic framework structure that has stimulus-responsive properties, such as pH-responsive MIL-53(Al), glucose-responsive GOx@ZIF-8, or redox-responsive SOD@HKUST-1.

[0082] Specifically, examples include: pH-triggered type: when the local pH drops to 4.0-6.0, the framework structures such as MIL-53(Al) and ZIF-8 undergo protonation decomposition; enzyme-triggered type: pepsin / trypsin catalyzes the breakage of sensitive bonds on the MOF surface; redox-triggered type: an increase in glutathione (GSH) concentration leads to Cu in the structure 2+ / Cu + Reduction and decomposition of HKUST-1, etc.; Biomarker-triggered type: ZIF-8 loaded with glucose oxidase catalyzes glucose oxidation to produce acid and decompose the ZIF-8 structure, etc., or MIL-100 loaded with uricase catalyzes uric acid oxidation to degrade the MIL-100 structure, etc.; External stimulus response type: ZIF-8 with or loaded with magnetic / photothermal conversion nanoparticles, such as ZIF-8 loaded with Fe3O4 or gold nanoparticles, responds to external magnetic fields or light to generate heat, triggering polymer phase transition, or directly regulating the magnitude of the interaction force with drug molecules to control drug release behavior.

[0083] This invention does not specifically limit the distribution of drug-carrying units in the head 1, tentacles 2, and microneedle structures 3, and can be configured according to the needs of drug release amount and release rate. In one embodiment, the drug-carrying units are uniformly distributed in the main body (head 1 and tentacles 2) and multiple microneedle structures 3. In another embodiment, a portion of the drug-carrying units is uniformly distributed in the main body, and the remaining portion is uniformly distributed in multiple microneedle structures 3, wherein the ratio of the amount of drug in a portion of the drug-carrying unit to the amount of drug in the remaining portion is 0.01:5 to 5:0.01. Alternatively, a portion of the drug-carrying units is distributed in the head, and the remaining portion is distributed in multiple tentacles and multiple microneedle structures, wherein the amount of drug in the remaining portion accounts for more than 70% of the total drug dose. In another embodiment, the microneedle structure 3 includes a base and a tip, with the axial length ratio of the base to the tip being 1:(1-5). The base is connected to the antenna 2. A portion of the drug-carrying unit is distributed in the body and the base of the microneedle structure; this distribution can be uniform or non-uniform. The remaining portion of the drug-carrying unit is distributed in the tip of the microneedle structure; this distribution can also be uniform or non-uniform. The ratio of the amount of drug in a portion of the drug-carrying unit to the amount of drug in the remaining portion of the drug-carrying unit is 5:1 to 1:5. Preferably, the amount of drug in the remaining portion of the drug-carrying unit accounts for more than 70% of the total drug dosage. In the axial length ratio of the base to the tip, the axial direction refers to the axial direction of the microneedle structure 3. In yet another embodiment, the drug-carrying unit is distributed in the body and the base of the microneedle structure, while the tip of the microneedle structure 3 is directly distributed with drug.

[0084] In one embodiment, the drug loading per needle in the microneedle structure of the present invention is 0.01-0.5 mg, for example, 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg or 0.5 mg.

[0085] The intelligent gastric retention drug delivery system of the present invention further includes a controlled-release unit 4. In one embodiment, the controlled-release unit is a sustained-release coating that covers the surface of the main body and the microneedle structure 3. The sustained-release coating has microchannels corresponding to the microneedle structure, through which the drug-carrying unit can flow out of the intelligent gastric retention drug delivery system. In another embodiment, the microchannels are strip-shaped, with a length of 10-200 μm in the short side direction, such as 10 μm, 50 μm, 80 μm, 100 μm, 120 μm, 150 μm, or 200 μm. The number of microchannels is 1-10 per microneedle structure. The microchannels are distributed parallel to the axial direction of the microneedle structure, radially distributed along the radial direction of the microneedle structure, or a combination of both.

[0086] It should be noted that by adjusting parameters such as material composition, wall thickness, microneedle size and distribution density, the present invention can achieve flexible adjustment of system size to adapt to the encapsulation requirements of different capsule models; by controlling the degradation rate and density change curve of the material, it can achieve matching with the gastric emptying time to ensure that the system is smoothly expelled from the body after drug delivery is completed.

[0087] This invention relates to an intelligent gastric retention drug delivery system, which is custom-designed using orally biodegradable materials to maintain drug retention in the stomach for an extended period during oral drug delivery. By incorporating a gastric anchoring system with a microneedle structure designed to accommodate gastric emptying time, and a transdermal release of an intelligent responsive drug delivery unit, it significantly reduces drug side effects and improves oral bioavailability. Furthermore, the drug dosage of this intelligent gastric retention drug delivery system can be flexibly adjusted according to clinical needs through changes in the main body size and MOF drug loading capacity. The drugs are packaged into 00-5 size oral capsules for easy swallowing by patients, meeting personalized needs, reducing dosing frequency, and improving patient adaptability.

[0088] In one embodiment, the present invention also provides a method for preparing the above-mentioned intelligent gastric retention drug delivery system, comprising the following steps:

[0089] Step 1: Load the drug onto the metal-organic framework carrier to obtain the drug-loaded unit;

[0090] Step 2: Mix the thermally responsive shape memory polymer and the drug delivery unit to prepare the main body and microneedle structure;

[0091] Step 3: Coat the main body and microneedle structure with a sustained-release coating, and set microchannels at the microneedle structure to obtain a controlled-release unit;

[0092] When a triggering factor occurs, the drug delivery unit releases the drug.

[0093] In one embodiment, the metal-organic framework carrier further loads a stimulus-response factor, meaning both the stimulus-response factor and the drug are loaded onto the metal-organic framework carrier, resulting in a drug-loaded unit. The metal-organic framework carrier and the dosage relationship between the metal-organic framework carrier and the drug have been described in detail above and will not be repeated here. This invention does not particularly limit the drug; any drug for treating chronic diseases that requires response to in vivo biological signals and on-demand drug release is suitable, such as drugs for treating diabetes, obesity, chronic gastrointestinal diseases, local chemotherapy, or diseases requiring long-acting gastric retention therapy. It is particularly suitable for drugs that are easily degraded by digestive enzymes, are slowly absorbed, or require maintaining a steady-state blood drug concentration. Specifically, metabolic disease drugs can be insulin, GLP-1 analogs, metformin, etc.; antitumor drugs can be doxorubicin, paclitaxel, PD-1 inhibitors, etc.; anti-inflammatory drugs can be antibodies (TNF-α inhibitors), small molecule inhibitors (JAK inhibitors), etc.; and nucleic acid drugs can be siRNA, mRNA, CRISPR-Cas9 ribonucleoprotein, etc.

[0094] This invention relates to a method for loading drugs onto metal-organic frameworks (MOFs). The method for loading stimulus-response factors onto MOFs is not particularly limited; conventional methods in the art are acceptable, such as in-situ encapsulation, post-impregnation, surface modification, and core-shell structure methods. The in-situ encapsulation method involves blending the drug with an MOF precursor to simultaneously form a drug-loaded MOF. Specifically, the drug, metal salt, and organic ligand are dissolved in a solvent and reacted at 25-160°C for 2-72 hours, followed by centrifugation and washing to obtain the drug-loaded MOF. The solvent can be an aqueous system, such as water, ethanol, or a water / ethanol mixture (volume ratio 1:1-1:4); a non-polar system, such as N,N-dimethylformamide (DMF) or dichloromethane (DCM); or an ionic liquid system, such as 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM]BF4). The post-immersion method involves immersing the prepared MOF in a solution containing the drug, forming drug-loaded units through diffusion adsorption. Specifically, a blank MOF is immersed in an ethanol / water solution containing the drug (water to ethanol volume ratio of 1:1-1:4), and adsorbed by shaking at 25-80℃ for 12-72 hours. The surface modification method involves grafting stimuli-responsive factors onto the surface of the drug-loaded MOF. These stimuli-responsive factors can be, for example, polyacrylic acid (PAA) or poly(N-isopropylacrylamide) (PNIPAM). The core-shell structure method involves constructing composite drug-loaded units of MOF@mesoporous silica or MOF@liposomes. This invention does not impose a particular limitation on the amount of stimuli-responsive factors used and can adjust it as needed.

[0095] Step 2 involves mixing the thermally responsive shape memory polymer and the drug delivery unit to prepare the host and microneedle structure.

[0096] The selection of thermally responsive shape memory polymers, the structure of the host and the microneedle structure have been described in detail above, and will not be repeated here.

[0097] The dosage relationship between the drug-carrying unit and the thermally responsive shape memory polymer of the present invention can be adjusted as needed. In one embodiment, the initial density of the formed intelligent gastric retention drug delivery system should be less than the density of gastric fluid, such as less than 1.0 g / cm³, so that the system can remain floating in the gastric fluid.

[0098] The distribution of the drug-loading units in the main body and microneedle structure of this invention can be configured as needed, and this invention does not impose any particular limitation. Furthermore, the distribution methods of the drug-loading units in the main body and microneedle structure have been listed and described above, and will not be repeated here.

[0099] In one embodiment, the present invention employs any one or a combination of at least two of 3D printing, casting, and thermoforming to prepare the body and microneedle structure. Alternatively, the body and microneedle structure can be prepared as a single unit or by preparing the parts separately and then connecting and fixing the parts together with a biocompatible adhesive (e.g., PVP).

[0100] The 3D printing includes, but is not limited to, any one or a combination of at least two of the following: fused deposition modeling (FDM) rapid prototyping, cryogenic extrusion, laser sintering, digital light processing, electron beam melting, layered solid fabrication, powder bonding, photopolymerization, stereolithography, inkjet printing, lamination, or multi-material printing. In one embodiment, the parameters for fused deposition modeling (FDM) 3D printing are: nozzle temperature 80-120°C, plateau temperature 40-60°C, extrusion pressure 200 kPa, layer thickness 0.1-0.45 mm, fill rate 90-100%, and the final product is dried in a vacuum oven at 120°C for 48 hours.

[0101] Casting molds include, but are not limited to, any one or a combination of at least two of sand casting, investment casting, pressure casting, continuous casting, foam mold casting, soft mold casting, or centrifugal casting.

[0102] Hot pressing includes, but is not limited to, any one or a combination of at least two of the following: flatbed hot pressing, vacuum hot pressing, compression hot pressing, blow molding hot pressing, injection molding hot pressing, hot roll hot pressing, or transfer hot pressing.

[0103] In one specific embodiment, the method for integrally molding the main body and microneedle structure includes: constructing a model of the main body (head and multiple tentacles) and microneedle structure using 3D design software and generating an STL file; slicing the model file, converting it into G-code instructions, selecting a thermally responsive shape memory polymer material, and using fused deposition modeling 3D printing technology to prepare the main body (head and multiple tentacles) and microneedle structure. In another specific embodiment, the main body (head and multiple tentacles) and microneedle structure are prepared by micromolding: a microneedle negative mold is made using polydimethylsiloxane (PDMS), a thermally responsive shape memory polymer solution containing drug-loaded units is injected into the mold, and the mold is demolded after centrifugation and drying. In yet another specific embodiment, the main body (head and multiple tentacles) and microneedle structure are prepared by thermoforming: based on the three-dimensional structure of the main body and the distribution characteristics of the microneedle structure, a thermoforming mold with upper and lower parts joined is made using precision machining or electrical discharge machining technology, the pretreated thermally responsive shape memory polymer and drug-loaded units are placed in the mold cavity, and molding is performed on a thermoforming press. In another specific embodiment, the main body (head and multiple tentacles) and microneedle structure are prepared using a post-assembly process: each different component is made by using one or more methods such as 3D printing, casting, or thermoforming, and finally the components are integrated and assembled, and encapsulated using a biocompatible adhesive.

[0104] Step 3 involves coating the main body and microneedle structure with a sustained-release coating and setting microchannels at the microneedle structure to obtain a controlled-release unit.

[0105] This invention does not impose any particular limitation on the coating method; conventional methods in the art are acceptable, such as dip coating or spin coating. In one embodiment, the microchannels are fabricated, for example, using femtosecond laser processing technology. The structure and distribution of the microchannels have been described in detail above and will not be repeated here.

[0106] In one embodiment, the sustained-release coating is, for example, an enteric material, more specifically, a carbomer.

[0107] This invention relates to an intelligent gastric retention drug delivery system, in which the drug delivery unit releases the drug when a triggering factor is present. These triggering factors include, for example, pH triggering, enzyme triggering, redox triggering, biomarker triggering, and external stimuli triggering.

[0108] The intelligent gastric retention drug delivery system of this invention, through the stimulus responsiveness and biomimetic structural design of the drug delivery unit, can achieve intelligent retention, anchoring and controlled release of the system in the complex environment of the stomach, significantly improving the bioavailability and therapeutic safety of oral drugs.

[0109] This invention provides a brief description of the delivery process of an intelligent gastric retention drug delivery system; please also refer to [link to other documentation]. Figure 5-7 , Figure 5This is a schematic diagram of the delivery process of the intelligent gastric retention drug delivery system of the present invention. Figure 6 This is a diagram showing the state changes of the intelligent gastric retention drug delivery system before and after gastric emptying, according to one embodiment of the present invention. Figure 7 This diagram illustrates the state changes of the intelligent gastric retention drug delivery system before and after stimulation response, according to another embodiment of the present invention. The intelligent gastric retention drug delivery system is in a contracted state at room temperature, allowing for easy encapsulation in a capsule shell. When orally administered, the capsule shell dissolves under the influence of gastric juices, triggering a thermally responsive shape memory polymer to expand. At this point, the intelligent gastric retention drug delivery system takes on a jellyfish-like shape and floats in the gastric juices. The thermally responsive shape memory polymer gradually degrades, maintaining structural integrity (degradation rate <5 wt%) during the gastric emptying cycle (2-4 hours). While floating in the gastric juices, the controlled-release coating gradually dissolves, and some drug-carrying units enter the gastric juices through microchannels and the dissolved areas of the controlled-release coating, continuously releasing the baseline dose of drug using sustained-release kinetics. After 2-4 hours of gastric emptying, due to the increased density of the intelligent gastric retention drug delivery system and gastric peristalsis, the microneedle structure of the intelligent gastric retention drug delivery system is passively anchored to the gastric wall. Furthermore, the intelligent gastric retention drug delivery system can also actively anchor microneedle structures to the stomach wall under the influence of external stimuli such as magnetic fields, by loading magnetically responsive particles (MOFs). Infrared light can also be used as an external stimuli. The anchoring of the microneedle structure can penetrate the mucus barrier and reach the submucosa of the stomach, where the drug delivery unit releases a burst dose of medication. When the drug delivery unit senses triggering factors such as biological or external signals, it accelerates drug release. The release rate of the drug delivery unit can be adjusted by regulating the thickness of the controlled-release unit and the number or depth of the microchannels. This system can significantly improve patient compliance, especially for drugs with severe side effects.

[0110] To better illustrate the present invention and facilitate understanding of its technical solutions, the present invention provides the following typical but non-limiting embodiments.

[0111] Example 1

[0112] This embodiment provides a gastric retention drug delivery system based on biomechanical response intelligent deformation and anchoring. Figure 8 This is a schematic diagram of the drug release process of the intelligent gastric retention drug delivery system in Example 1. The intelligent gastric retention drug delivery system includes a main body, a microneedle structure 3, a drug-carrying unit, and a controlled-release unit 4. The main body includes a head 1 and multiple tentacles 2.

[0113] In a preferred embodiment, the head 1 of the main body is 3D printed using polycaprolactone-polyglycerol dodecanoate (PCL-PGD) copolymer. At room temperature, it has a compact cylindrical structure (5 mm in diameter and 11 mm in height) that can be filled into a No. 3 oral capsule. When triggered by the gastric temperature (37±0.5℃), it reverts to a preset biomimetic jellyfish shape. The diameter of the main body composed of the head 1 and tentacles 2 expands to 16 mm, the height decreases to 6 mm, and the overall density decreases to 0.95 g / cm³, achieving stable buoyancy in gastric juice.

[0114] Ten tentacles 2 are provided in total, evenly distributed circumferentially at the bottom of the head 1, and are integrally printed using the same PCL-PGD material as the head 1. When unfolded, the tentacles 2 form a 70° angle with the central axis of the head, with a projected length of 7.0 mm; each tentacle has an array of 2×30 microneedle structures 3 integrated at its end, with a single microneedle length of 650 μm and a tip cone angle of 25°.

[0115] The drug-loading unit is a ZIF-8 metal-organic framework particle loaded with insulin, with a particle size distribution of 150-250 nm and a drug loading of 15% (w / w). The molar ratio of zinc ions to 2-methylimidazole is 1:30, and glucose oxidase and insulin are co-loaded (mass ratio 1:20).

[0116] The controlled-release unit 4 includes a polylactic acid sustained-release coating (thickness 50±5μm) covering the surface of the main body and three microchannels (diameter 20±2μm) processed in each microneedle structure using a femtosecond laser. The drug release rate is controlled by adjusting the coating thickness and the number of channels.

[0117] (1) 3D model design and slicing

[0118] A biomimetic jellyfish digital model was constructed using Cinema 4D software. The head is a flattened spherical structure with a diameter of 5 mm and a height of 4 mm. Ten tentacles are evenly distributed around the bottom (140° spread angle, 8 mm length). The tentacles are designed with a 2×30 microneedle array at the end (single needle height 650 μm, base diameter 200 μm, needle tip cone angle 25°, each microneedle has 5×2 barbs with a barb apex angle of 30°). The model was exported as an STL file and sliced ​​using Ultimaker Cura 5.1 software: layer height 0.1 mm, printing temperature 80℃, platform temperature 40℃, printing speed 20 mm / s, infill density 100%, generating a G-code instruction file.

[0119] (2) Preparation of stimulus-responsive drug delivery units (impregnation method)

[0120] 0.986 mmol Zn(CH3COO)2·2H2O and 29.577 mmol 2-methylimidazole were mixed in 160 mL of deionized water to preserve Zn.2+ The molar ratio of / 2-Hmim / H2O was 1:30:1800. The resulting solution was stirred at room temperature (~25℃) for about 5 min, and then transferred to a Teflon-lined stainless steel autoclave for hydrothermal synthesis. The synthesis temperature was fixed at 120℃, and the synthesis time was set to 24 hours. After synthesis, the reaction was stopped by cooling to room temperature. The resulting milky white product was washed three times with methanol, collected by centrifugation at 10000 rpm for 5 min, and then dried overnight in an air oven at 60℃.

[0121] First, a drug solution was prepared by weighing 40 mg of insulin and 16 mg of GOx into 20 mL of 0.01 M HCl and adjusting the pH to approximately 7 using 1 M NaOH. ZIF-8 was then loaded using the impregnation method: 20 mg of ZIF-8 was weighed into 5 mL of the loading solution and stirred at room temperature for 12 h.

[0122] (3) Fused Deposition Modeling Printing

[0123] 50 mg of the obtained ZIF-8 drug-loaded nanoparticles were dispersed in 1 mL of 10% (w / v) PCL-PGD 5% hyaluronic acid solution and ultrasonically treated for 30 min to form a paste-like printing ink. A CELLLINK BIO X6 was used. ™ The 3D printer's main nozzle is immediately loaded with PCL-PGD copolymer paste printing ink (1.75mm diameter, glass transition temperature 35℃). Printing parameters are set as follows: The paste is extruded continuously through the print head onto an acrylic plate fixed to the printing area (120*120mm). The selected dimensions for this device are X=12.5mm (diameter) and Y=12.5mm. The fill percentage is set to 50% to produce a low-density solid form. Other printer settings are as follows: extrusion speed (0.0075mm / s), travel speed 6mm / s, extrusion temperature (80℃), extrusion pressure 200kPa, layer height (0.45mm), compensation value (0.25), number of layers (13); number of bottom layers (2), number of top layers (2); bottom contour value (3 times), top contour value (2 times), other contour values ​​(1 time). The final product was cured in an oven at 120°C for 48 hours, soaked in ethanol for 30 minutes, rinsed in pure water overnight, and then dried.

[0124] (4) Surface functionalization treatment

[0125] Polylactic acid (PLA, Mw=50kDa) was dissolved in acetone to prepare a 5% (w / v) solution, which was then used to form a coating with a thickness of 50±5μm on the surface of the substrate and microneedle structure using a spin coater (parameters: 1000rpm, 30s). Three interconnected microchannels with a diameter of 20±2μm were fabricated on the surface of each microneedle using a femtosecond laser processing system (Spectra-Physics Spirit One), with parameters: wavelength 1030nm, pulse width 350fs, repetition rate 100kHz, and power 0.5W.

[0126] The working process of the intelligent gastric retention drug delivery system in the stomach

[0127] (1) After oral administration, the capsule shell dissolves in the stomach, and body temperature triggers the main body to revert to the jellyfish form. The system density is less than that of the gastric juice, thus achieving initial buoyancy.

[0128] (2) During gastric emptying, the system density gradually increases to 1.05 g / cm³ as it degrades. 3 It naturally sinks and is passively anchored to the stomach wall by the barbed structure of the microneedles. The drug-carrying unit is gradually released into the bloodstream through transdermal transmission as the controlled-release unit dissolves.

[0129] (3) When blood glucose concentration increases, glucose oxidase catalyzes glucose to produce gluconic acid, which lowers the local pH, decomposes the ZIF-8 framework, and insulin is continuously released through microchannels.

[0130] (4) The system gradually degrades after 7 days of drug release and is eventually safely excreted from the body.

[0131] Example 2

[0132] This embodiment provides an intelligent gastric retention drug delivery system based on biomechanical deformation-responsive biphasic drug release. Figure 9 This is a schematic diagram of the drug release process of the intelligent gastric retention drug delivery system in Example 2. The system is specifically designed for diabetic patients who require the simulation of physiological insulin secretion. It achieves a biphasic drug release mode of "rapid release + sustained release" through a unique double-layer microneedle structure, better simulating the postprandial insulin secretion peak and maintaining daily basal levels. The system includes a main body, a microneedle structure 3, a drug-carrying unit, and a controlled-release unit 4. The main body includes a head 1 and multiple tentacles 2.

[0133] In a preferred embodiment, the head 1 is 3D printed from a polycaprolactone-polyglycerol dodecanoate (PCL-PGD) copolymer. At room temperature, it has a compact cylindrical shape (5mm in diameter, 11mm in height) suitable for containing a No. 3 oral capsule. Upon triggering at gastric temperature (37±0.5℃), it reverts to a pre-defined biomimetic jellyfish shape, with the head diameter expanding to 16mm, the height decreasing to 6mm, and the overall density decreasing to 0.95g / cm³.3 This allows it to float stably in gastric juice.

[0134] Ten tentacles are arranged in total, evenly distributed around the bottom of the main body, and are integrally printed using the same PCL-PGD material as the main body. When unfolded, the tentacles form a 70° angle with the central axis of the main body, with a projected length of 7.0 mm. Each tentacle has a 2×30 microneedle structure array integrated at its end, with a single microneedle length of 650 μm and a tip cone angle of 25°, adopting a unique double-layer structure design.

[0135] The drug delivery unit includes the following core components:

[0136] (1) Immediate-release unit: The tip of the microneedle is composed of a rapidly degradable gelatin matrix, in which insulin raw material is directly dispersed, accounting for 30% of the total insulin dose;

[0137] (2) Sustained-release unit: The drug-loading unit at the base and main body of the microneedle is loaded with insulin & glucose oxidase@ZIF-8 complex, accounting for 70% of the total insulin dose;

[0138] (3) Controlled release unit: The base and body of the microneedle are coated with a polylactic acid sustained-release coating (thickness 40±5μm), and 0-2 microchannels with a diameter of 15±2μm are processed on each microneedle.

[0139] The preparation method of the system described in this embodiment includes the following detailed steps:

[0140] (1) 3D model design and slicing:

[0141] A biomimetic jellyfish digital model was constructed using Cinema 4D software. The head is a flattened spherical structure with a diameter of 5 mm and a height of 4 mm. Ten tentacles are evenly distributed around the bottom (140° spread angle, 8 mm length). The tentacles are designed with a 2×30 microneedle array (single needle height 650 μm, base diameter 200 μm, needle tip cone angle 25°). The model was exported as an STL file and sliced ​​using Ultimaker Cura 5.1 software: layer height 0.1 mm, printing temperature 80℃, platform temperature 40℃, printing speed 20 mm / s, infill density 100%, generating a G-code instruction file.

[0142] (2) Preparation of biphasic drug delivery units:

[0143] Preparation of the immediate-release phase: 30% of the total dose of insulin (6 mg) was mixed with a 25% (w / v) gelatin solution, and drug-loaded gelatin microspheres with a particle size of 50-100 μm were prepared by spray freeze-drying.

[0144] Preparation of sustained-release phase: The remaining 70% insulin (14 mg) and glucose oxidase (0.7 mg) were co-loaded into the ZIF-8 framework using the impregnation method, with the same parameters as in Example 1.

[0145] (3) Fabrication of a double-layer microneedle array:

[0146] Bilayer microneedles were prepared using a two-step micromolding method:

[0147] Step 1 - Base Forming: Inject the PCL-PGD solution containing drug-loaded ZIF-8 particles into the PDMS mold, centrifuge (2000 rpm, 5 min) to fill the microneedle base (bottom diameter 200 μm).

[0148] Step 2 - Tip Forming: Before the tip is fully cured, the drug-loaded gelatin solution is precisely dropped onto the microneedle tip area (height 650μm) and cross-linked and cured at 4℃ for 2h;

[0149] After demolding, a double-layered microneedle with a distinct interface is obtained.

[0150] (4) Fused deposition modeling printing:

[0151] The head and antennae were prepared using the same 3D printing equipment and parameters as in Example 1 to ensure the consistency of the overall system structure.

[0152] (5) System integration and functionalization:

[0153] A dual-layer microneedle array was integrated onto the antennal tip using a bio-adhesive.

[0154] Spin-coating a polylactic acid slow-release coating onto the microneedle base and the main body;

[0155] The microchannels were fabricated using femtosecond lasers, with the same parameters as in Example 1.

[0156] The system operates within the stomach as follows:

[0157] (1) The system completes morphological transformation and achieves initial buoyancy within the stomach;

[0158] (2) As the stomach empties, the needle gradually anchors to the stomach wall and penetrates the gastric mucosa;

[0159] (3) Immediate release phase initiation: The gelatin matrix at the tip of the microneedle dissolves rapidly within 10-30 minutes under the action of tissue fluid, releasing the first dose of insulin (accounting for 30% of the total dose), simulating the postprandial insulin secretion peak;

[0160] (4) Sustained-release phase initiation: As blood glucose concentration increases, glucose oxidase catalyzes acid production, and the ZIF-8 framework responds by decomposing, continuously releasing the basal dose of insulin (accounting for 70% of the total dose) through microchannels to maintain stable blood glucose levels;

[0161] (5) The system safely degrades and is discharged after 5-7 days of drug release.

[0162] The innovation of this embodiment compared with the prior art lies in:

[0163] (1) A true biphasic drug release mode is achieved through a double-layer microneedle structure, which better simulates the physiological insulin secretion curve;

[0164] (2) The immediate-release phase uses a gelatin matrix to ensure rapid onset of action, while the sustained-release phase utilizes a glucose response mechanism to achieve intelligent regulation;

[0165] (3) The two drug release mechanisms work synergistically in the same system, significantly improving the treatment effect and medication safety of diabetes.

[0166] This design is particularly suitable for diabetic patients who require precise blood glucose control, effectively avoiding blood glucose fluctuations caused by traditional drug administration methods and improving patients' quality of life.

[0167] Example 3

[0168] This embodiment provides an intelligent gastric retention drug delivery system based on biomechanical deformation and enzyme-responsive inflammation or tumor targeting. Figure 10 This is a schematic diagram of the drug release process of the intelligent gastric retention drug delivery system in Example 3. The system is specifically designed for inflammatory diseases of the stomach (such as local chemotherapy for gastric ulcers, gastritis, and gastric cancer). It triggers drug release through the high expression of matrix metalloproteinase-9 (MMP-9) at the site of inflammation, achieving targeted therapy to the lesion. The system includes a main body, microneedle structures 3, a drug-carrying unit, and a controlled-release unit 4. The main body includes a head 1 and multiple tentacles 2.

[0169] In a preferred embodiment, the head 1 is 3D printed from a polycaprolactone-polyglycerol dodecanoate (PCL-PGD) copolymer. At room temperature, it has a compact cylindrical shape (5 mm in diameter and 11 mm in height) that can be filled into a No. 3 oral capsule. When triggered by the gastric temperature (37±0.5℃), it reverts to a preset biomimetic jellyfish shape. The diameter of the main body composed of the head 1 and tentacles 2 expands to 16 mm, the height decreases to 6 mm, and the overall density decreases to 0.95 g / cm³, achieving stable buoyancy in gastric juice.

[0170] Ten tentacles are arranged in total, evenly distributed around the bottom of the main body, and are integrally printed using the same PCL-PGD material as the main body. When unfolded, the tentacles form a 70° angle with the central axis of the main body, with a projected length of 7.0 mm. Each tentacle has a 2×30 microneedle structure array integrated at its end, with a single microneedle length of 650 μm and a tip cone angle of 25°.

[0171] The drug delivery unit includes:

[0172] (1) ZIF-8 particles loaded with curcumin (anti-inflammatory and anticancer drug), dexamethasone (anti-inflammatory), or paclitaxel (antitumor) have a particle size distribution of 50 nm-10 µm and a drug loading of 20-30% (w / w). The molar ratio of zinc ions to dimethylimidazole is 1:30, and the framework specific surface area reaches 1500 m². 2 / g, suitable for loading macromolecular drugs. The MMP-9 specific enzymatic hydrolysis blocker is prepared by cross-linking gelatin hydrogel, in which an MMP-9 specific enzymatic hydrolysis peptide sequence (GPLGIAGQ) is embedded, and the peptide concentration is 5mg / mL;

[0173] (2) Adhesion-controlled release coating: A chitosan-polyacrylic acid composite coating (thickness 30±5μm) is coated on the surface of the system to enhance adhesion to the gastric mucosa;

[0174] (3) Controlled release microchannels: Two microchannels with a diameter of 15±2μm are fabricated on the surface of each microneedle.

[0175] The preparation method of the system described in this embodiment includes the following detailed steps:

[0176] (1) 3D model design and slicing:

[0177] A biomimetic jellyfish digital model was constructed using Cinema 4D software. The head is a flattened spherical structure with a diameter of 10 mm and a height of 8 mm. Ten tentacles (140° spread angle, 8 mm length) are evenly distributed around the bottom. The tentacles are designed with a 2×30 microneedle array (single needle height 650 μm, base diameter 200 μm, needle tip cone angle 25°). The model was exported as an STL file and sliced ​​using Ultimaker Cura 5.1 software: layer height 0.1 mm, printing temperature 80℃, platform temperature 40℃, printing speed 20 mm / s, infill density 100%, generating a G-code instruction file.

[0178] (2) Preparation of stimulus-responsive drug delivery units (in-situ synthesis):

[0179] 0.123 mmol Zn(CH3COO)2·2H2O and 50 mg MMP-9 specific polypeptide (GPLGIAGQ sequence) were weighed and dissolved in 10 mL deionized water to obtain solution A; 3.697 mmol 2-methylimidazole and 0.1 mmol curcumin or dexamethasone or paclitaxel were weighed and dissolved in 10 mL ethanol to obtain solution B. Solution B was added to solution A and stirred at room temperature (~25℃) for about 5 min, then transferred to a Teflon-lined stainless steel autoclave for hydrothermal synthesis. The synthesis temperature was fixed at 120℃ and the synthesis time was set to 24 hours. After synthesis, the reaction was stopped by cooling to room temperature, the resulting milky white product was washed three times with methanol, collected by centrifugation at 10000 rpm for 5 min, and then dried overnight in an air oven at 60℃.

[0180] (3) Fused deposition modeling printing:

[0181] The main body and microneedle structure were prepared using the same 3D printing equipment and parameters as in Example 1 to ensure the consistency of the overall system structure.

[0182] (4) Surface functionalization treatment:

[0183] Chitosan (85% deacetylation) and polyacrylic acid were dissolved in a 1% (v / v) acetic acid solution at a mass ratio of 2:1, and an adhesive coating was formed on the system surface by dip coating. Three interconnected microchannels with a diameter of 20±2 μm were fabricated on the surface of each microneedle using a femtosecond laser processing system with the following parameters: wavelength 1030 nm, pulse width 350 fs, repetition frequency 100 kHz, and power 0.5 W.

[0184] The system operates within the stomach as follows:

[0185] (1) After oral administration, the capsule dissolves in the stomach, and the body temperature triggers the deformation of the main body to restore the jellyfish shape. The system density is less than that of the gastric juice, thus achieving initial floating.

[0186] (2) The system flows with the gastric juice to the inflamed area, and the chitosan-carbomer coating enhances the adhesion to the inflamed gastric mucosa;

[0187] (3) High concentrations of MMP-9 at the site of inflammation and tumor site enzymatically hydrolyze specific peptides in ZIF-8, triggering drug release. Curcumin, dexamethasone, or paclitaxel are continuously released from the ZIF-8 framework and act directly on the site of inflammation.

[0188] (4) The system gradually degrades and is discharged after 5-7 days of drug release.

[0189] The innovation of this embodiment compared with the prior art lies in:

[0190] (1) Using MMP-2 / MMP-9, which are specifically highly expressed in gastric inflammation or tumor areas, as a smart trigger signal, targeted drug delivery to gastric lesions can be achieved;

[0191] (2) By controlling the density of PCL-PGD material and designing a chitosan-carbomer adhesive coating, the system is ensured to remain effectively in the stomach and be positioned.

[0192] (3) The macroporous properties of the ZIF-8 framework significantly improve the loading capacity and release efficiency of drugs such as curcumin, dexamethasone, or paclitaxel.

[0193] This design is particularly suitable for the treatment of inflammatory gastric diseases that require local targeted drug delivery, effectively increasing the drug concentration at the lesion site and reducing the side effects of systemic administration.

[0194] Example 4

[0195] This embodiment provides an intelligent gastric drug delivery system based on biomechanical deformation-responsive redox targeting for deep tissues. Figure 11 This is a schematic diagram of the drug release process of the intelligent gastric retention drug delivery system in Example 4. The system is specifically designed for deep tissue inflammation and oxidative stress-related diseases (such as deep gastric ulcers and radiation gastritis), achieving targeted drug delivery to deep tissues by detecting high concentrations of reduced glutathione (GSH) unique to the deep layers of the lesion. The system includes a main body, microneedle structures 3, a drug-carrying unit, and a controlled-release unit 4. The main body includes a head 1 and multiple tentacles 2.

[0196] In a preferred embodiment, the head 1 is 3D printed from a polycaprolactone-polyglycerol dodecanoate (PCL-PGD) copolymer. At room temperature, it has a compact cylindrical shape (5 mm in diameter and 11 mm in height) that can be filled into a No. 3 oral capsule. When triggered by the gastric temperature (37±0.5℃), it reverts to a preset biomimetic jellyfish shape, with the diameter of the head 1 and tentacles 2 expanding to 16 mm, the height decreasing to 6 mm, and the overall density decreasing to 0.95 g / cm³, thus achieving stable buoyancy in gastric juice.

[0197] Ten tentacles are arranged in total, evenly distributed around the bottom of the main body, and are integrally printed using the same PCL-PGD material as the main body. When unfolded, the tentacles form a 70° angle with the central axis of the main body, with a projected length of 7.0 mm. Each tentacle has a 2×30 microneedle array integrated at its end, with a single microneedle length of 650 μm and a tip cone angle of 25°.

[0198] The drug delivery unit and controlled release unit include the following core components:

[0199] (1) The HKUST-1 copper-based metal-organic framework is used, wherein the molar ratio of copper ions to pyromellitic acid is 3:2, and superoxide dismutase (SOD) and anti-inflammatory drugs such as curcumin or dexamethasone or compound drugs for treating deep gastric ulcers (mass ratio 1:3) are loaded.

[0200] (2) Deep penetration enhancement component: microneedle surface modified with cell penetration peptide (TAT peptide, sequence YGRKKRRQRRR), concentration 0.5mg / mL;

[0201] (3) Controlled release unit: Agarose-chitosan composite hydrogel coating (thickness 60±5μm) is coated on the microneedle base and the biomimetic body.

[0202] The preparation method of the system described in this embodiment includes the following detailed steps:

[0203] (1) 3D model design and slicing:

[0204] A biomimetic jellyfish digital model was constructed using Cinema 4D software. The head is a flattened spherical structure with a diameter of 5 mm and a height of 4 mm. Ten tentacles are evenly distributed around the bottom (140° spread angle, 8 mm length). The tentacles are designed with a 2×30 microneedle array (single needle height 650 μm, base diameter 200 μm, needle tip cone angle 25°). The model was exported as an STL file and sliced ​​using Ultimaker Cura 5.1 software: layer height 0.1 mm, printing temperature 80℃, platform temperature 40℃, printing speed 20 mm / s, infill density 100%, generating a G-code instruction file.

[0205] (2) Preparation of redox-responsive drug delivery units:

[0206] 2.5 mmol of trimesic acid was dissolved in 200 mL of sodium acetate buffer (0.2 M, pH 7.0) as solution A, and then mixed with 200 mL of acetonitrile. Subsequently, 10 mg of SOD (10000 U / mg) and curcumin or dexamethasone (30 mg) were added to 200 mL of 0.0125 mol / L Cu(CH3COO)2 solution (solution B), and the mixture was sonicated for 15 min. Solution A and solution B were then mixed under nitrogen protection and stirred at room temperature for 5 min. After filtration, the product was collected, washed several times with 200 mL of ethanol, dried overnight at 90 °C, and stored in a desiccator. The product was washed with DMF and then vacuum dried at 60 °C for 24 h.

[0207] (3) Fused deposition modeling printing:

[0208] The head, antennae, and microneedle structures were prepared using the same 3D printing equipment and parameters as in Example 1 to ensure the consistency of the overall system structure.

[0209] (4) Surface functionalization treatment:

[0210] Cell-penetrating peptide modification: TAT peptide was dissolved in PBS buffer (pH 7.4) and a monolayer was formed on the surface of microneedles by dip-coating.

[0211] Composite coating preparation: Agarose (2%, w / v) and chitosan (1%, w / v) were mixed at a volume ratio of 3:1, and a gradient coating was formed on the microneedle base and the main body by microfluidic coating technology.

[0212] The specific working process of the system within the body is as follows:

[0213] (1) The system completes morphological transformation and anchors to the stomach wall within the stomach;

[0214] (2) Microneedles penetrate the mucosal layer and enter deep tissues;

[0215] (3) Redox response phase: In deep inflammatory regions (GSH concentration 2-10 mM), Cu in the HKUST-1 framework 2+ Reduced to Cu + The frame structure collapsed;

[0216] (4) Synergistic treatment phase: SOD rapidly eliminates superoxide free radicals, and anti-inflammatory drugs are released simultaneously to inhibit the inflammatory response;

[0217] (5) Continuous protection phase: The composite hydrogel coating provides continuous drug release and maintains the local effective concentration for 5-7 days.

[0218] The innovation of this embodiment compared with the prior art lies in:

[0219] (1) For the first time, the redox response mechanism was used for deep tissue targeting, solving the problem of signal attenuation in deep tissues in traditional enzyme response systems;

[0220] (2) By using SOD and curcumin or dexamethasone in synergistic action, two key pathological processes, oxidative stress and inflammation, can be addressed simultaneously.

[0221] (3) Cell-penetrating peptide modification significantly enhances the penetration and distribution of drugs in deep tissues.

[0222] This design provides an innovative treatment strategy for deep tissue inflammatory diseases, and is particularly suitable for treating deep lesions that are difficult to reach with conventional drugs, which has important clinical translational value.

[0223] Example 5

[0224] This embodiment provides an intelligent gastric retention drug delivery system based on biomechanical deformation and magnetic / photothermal triggering remote control. Figure 12This is a schematic diagram of the drug release process of the intelligent gastric retention drug delivery system in Example 5. The system is specifically designed for the treatment of diseases requiring local chemotherapy, such as gastric cancer. It utilizes an external alternating magnetic field or near-infrared light to induce a phase change in the polymer substrate, melting the microneedle tips. Remote control enables precise, on-demand drug delivery, significantly improving treatment efficacy and reducing systemic toxicity. The system includes a main body, microneedle structures 3, a drug-carrying unit, and a controlled-release unit 4. The main body includes a head 1 and multiple tentacles 2.

[0225] In a preferred embodiment, the head 1 is 3D printed from a polycaprolactone-polyglycerol dodecanoate (PCL-PGD) copolymer. At room temperature, it has a compact cylindrical shape (5 mm in diameter and 11 mm in height) that can be filled into a No. 3 oral capsule. When triggered by the gastric temperature (37±0.5℃), it reverts to a preset biomimetic jellyfish shape. The diameter of the main body composed of the head 1 and tentacles 2 expands to 16 mm, the height decreases to 6 mm, and the overall density decreases to 0.95 g / cm³, achieving stable buoyancy in gastric juice.

[0226] Ten tentacles are arranged in total, evenly distributed around the bottom of the main body, and are integrally printed using the same PCL-PGD material as the main body. When unfolded, the tentacles form a 70° angle with the central axis of the main body, with a projected length of 7.0 mm. Each tentacle has a 2×30 microneedle array integrated at its end, with a single microneedle length of 650 μm and a tip cone angle of 25°.

[0227] The drug delivery unit and controlled release unit include the following core components:

[0228] (1) Magnetic / photothermal responsive particles: Metal-organic framework materials that are loaded with or functionalized with magnetic nanoparticles such as Fe3O4 or photothermal conversion agents such as CuS nanoparticles, gold nanoparticles, polydopamine, and graphene oxide.

[0229] (2) Drug-loading unit: Metal-organic framework material loaded with anticancer drugs such as paclitaxel;

[0230] (3) Controlled release unit: microneedles coated with Eudragit ® L100-55 and other acid-stable enteric coatings (thickness 30±5μm).

[0231] The preparation method of the system described in this embodiment includes the following detailed steps:

[0232] (1) 3D model design and slicing:

[0233] A biomimetic jellyfish digital model was constructed using Cinema 4D software. The head is a flattened spherical structure with a diameter of 5 mm and a height of 4 mm. Ten tentacles are evenly distributed around the bottom (140° spread angle, 8 mm length). The tentacles are designed with a 2×30 microneedle array (single needle height 650 μm, base diameter 200 μm, needle tip cone angle 25°). The model was exported as an STL file and sliced ​​using Ultimaker Cura 5.1 software: layer height 0.1 mm, printing temperature 80℃, platform temperature 40℃, printing speed 20 mm / s, infill density 100%, generating a G-code instruction file.

[0234] (2) Preparation of magnetic / photothermal responsive particles:

[0235] Magnetothermic Response Particles: Synthesis of Fe3O4 Nanoparticles: 6 mmol FeCl3·6H2O and 5 mmol FeSO4·7H2O were dissolved in 40 mL of water. Then, 5 mL of 28% ammonia solution was added, and the mixture was heated at 90 °C. Then, 14.9 mmol of sodium citrate was added to the flask, and the mixture was stirred vigorously for 30 min. Fe3O4 nanoparticles were recovered by magnetic separation, washed several times with ethanol, and redispersed in water (100 mL). Synthesis of Fe3O4@ZIF-8 Nanoparticles: Under vigorous stirring, 15 mL of freshly prepared citrate-terminated Fe3O4 particle aqueous solution was mixed with 5.546 mmol 2-methylimidazole and stirred for 5 min. Then, 15 mL of 0.012 mol / L zinc nitrate aqueous solution was added, and the mixture was stirred for 10 min. Fe3O4@ZIF-8 particles were recovered by magnetic separation and purified by washing three times with water.

[0236] Photothermal Response Particles: The composite of photothermal conversion particles with ZIF-8 requires the mediation of surfactants, such as CuS nanoparticles. CuS Nanoparticle Modification: 10 mL of CuCl2 aqueous solution (3.5 mg / mL) and 10 mL of PVP aqueous solution (20 mg / mL) were added to 180 mL of water. The mixture was stirred at room temperature for 30 min. 800 μL of Na2S aqueous solution (60.54 mg / mL) was added to the mixture. The resulting mixture was stirred for another 5 min, then transferred to a 90 °C water bath and allowed to stand for 15 min. The PVP-modified CuS solution was cooled to room temperature and centrifuged to remove excess free PVP. Finally, the PVP-modified CuS nanoparticles were dispersed in methanol at a concentration of 96 mg / L. CuS@ZIF-8 Nanoparticle Preparation: 2 mL of 2-methylimidazolium methanol solution (8 mg / mL) and 1.5 mL of PVP-modified CuS methanol solution were added to 10 mL of methanol. After gently mixing by inversion, 2 mL of Zn(NO3)2 methanol solution (27.5 mg / mL) was immediately added to the mixture with gentle stirring. The reaction solution was then allowed to stand at 50 °C for 2.5 h. After the reaction, the color of the solution changed from transparent green to yellow-green, indicating the formation of CuS@ZIF-8NP. The obtained NP was centrifuged at 13000 rpm for 8 min, washed twice with methanol, and dried to obtain the final product.

[0237] (3) Preparation of drug-loaded particles (impregnation method): Prepare a methanol solution with a paclitaxel concentration of 10 mg / mL, measure 10 mL and add 50 mg of ZIF-8 magnetic / photothermal responsive particles, stir at room temperature for 24 h, centrifuge and filter at 10000 rpm, wash three times with ethanol, and dry to obtain the product.

[0238] (4) Fused deposition modeling printing:

[0239] The head, antennae, and microneedle structures were fabricated using the same 3D printing equipment and parameters as in Example 1 to ensure the consistency of the overall system structure. Eudragit was formed on the system surface using spray coating technology. ® L100-55 enteric coating.

[0240] (5) External control system configuration:

[0241] A portable alternating magnetic field generator was developed to complement it, with parameters set as follows: frequency 100kHz, magnetic field strength 10kA / m, which can be used to precisely irradiate the stomach area with a handheld probe.

[0242] A near-infrared exciter was used in conjunction with the device, with the following parameters set: wavelength 880nm, power 0-3W / cm². 2 The exciter power and spot size can be flexibly changed by adjusting the focal length.

[0243] The system operates within the stomach as follows:

[0244] (1) After oral administration, the system completes morphological transformation and achieves initial buoyancy in the stomach;

[0245] (2) The system gradually anchors to the stomach wall during the gastric emptying process and is in a "waiting to be triggered" state;

[0246] (3) Remote triggering stage: Under the guidance of a doctor, the patient uses an alternating magnetic field generator or a near-infrared light exciter to irradiate the stomach (10-15 minutes each time).

[0247] (4) Magnetoresistance / photothermal conversion process: Nanoparticles generate heat under the action of an alternating magnetic field, and the local temperature rises to above 45℃;

[0248] (5) Triggered release: Due to the thermal response of the shape memory polymer bulk phase change caused by temperature, the drug-loaded ZIF-8 particles are continuously released from the microneedle array and act directly on the tumor site;

[0249] (6) The system is safely degraded and excreted after 3-5 as-needed doses.

[0250] The innovation of this embodiment compared with the prior art lies in:

[0251] (1) Combining the magnetic / photothermal triggering mechanism with the gastric retention system to achieve remote and precise controlled release of drugs;

[0252] (2) By optimizing the concentration of magneto / photothermal conversion nanoparticles and the T of PCL-PGD g The value ensures that the trigger temperature is within a safe range;

[0253] (3) The ZIF-8 framework provides protection for chemotherapy drugs and reduces the toxic side effects caused by gastric acid degradation and systemic absorption.

[0254] This design provides an innovative solution for local chemotherapy of gastrointestinal tumors such as gastric cancer, enabling doctors to precisely control the timing and dosage of drug administration according to treatment needs, significantly improving treatment outcomes and enhancing patients' quality of life.

[0255] The present invention also tested and characterized the structure and properties of the intelligent gastric retention drug delivery system, the morphology and mechanical strength of the microneedle structure, and the in vitro performance of the gastric retention drug delivery system.

[0256] 1. Fourier transform infrared spectroscopy test of polymer printing ink

[0257] Fourier transform infrared (FTIR) spectroscopy was performed on polymer printing ink samples using the potassium bromide pelleting method, with humidity and temperature controlled throughout the process. First, approximately 3 μg of the polymer printing ink sample was weighed into an agate mortar; then, approximately 200 μg of potassium bromide powder was weighed into the mortar; the sample and potassium bromide powder were thoroughly ground; the ground mixture was placed in a pelleting mold, and pressure was applied using a hydraulic press to form a transparent pellet. The prepared samples were measured using a Fourier transform infrared spectrometer at 500-4000 cm⁻¹. -1 The absorption peaks in the infrared band are recorded, and their spectral characteristics are analyzed to determine the functional group composition of the sample molecules.

[0258] Figure 13 This is a Fourier transform infrared (FTIR) spectrum of a polymer printing ink according to one embodiment of the present invention, such as... Figure 13 As shown, PGD at 1104cm -1 The CO stretching vibration peak at 956 cm⁻¹ disappears after mixing with PCL, indicating that the two are tightly bonded at the molecular level through hydrogen bonds, forming a well-compatible complex. The newly generated 956 cm⁻¹ peak... -1 The peak is the out-of-plane rocking vibration peak of the -CH2 group in PCL. When copolymerized with PCL, the -OH group of PGD forms hydrogen bonds with the C=O group of PCL, causing a red shift (moving to the right) and further broadening of the -OH stretching vibration peak, a typical characteristic of hydrogen bond formation. In mixtures with different ratios (e.g., mass ratios of 2:1, 1:1, 1:2), the red shift increases with increasing PCL content because more C=O groups are available to interact with the OH groups. However, the strength of the hydrogen bond is also affected by the ratio; the interaction may be most pronounced when the OH and C=O ratios are close (e.g., 1:1). PGD at 1335 cm⁻¹... -1 The -OH bending vibration peak at PGD showed a blue shift (moving to the left) after the addition of PCL, revealing that intermolecular hydrogen bonds may have formed between PGD and PCL (PGD's OH...O=C-PCL). A new 1532 cm⁻¹ peak appeared in the PGD-PCL blend. -1 The characteristic peaks may indicate that the PGD-PCL system is not a simple physical blend, but rather a more complex composite system containing chemical bonds formed through transesterification. This system may form branched or cross-linked structures, and the decrease in PCL molecular weight usually leads to brittleness and reduced strength in the material.

[0259] 2. X-ray diffraction test of polymer printing ink

[0260] On an XRD diffractometer, a CuKα X-ray source was used to operate at a voltage of 40 kV and a current of 30 mA. X-ray images were obtained by scanning within a dual-angle θ range of 5-90° at a scanning speed of 5° / min.

[0261] Figure 14The X-ray diffraction pattern of the polymer printing ink in an embodiment of the present invention is shown by Figure 14 As shown, when the mass ratio of PGD:PCL = 1:1, the pattern shows a single broadened peak or a peak position shift. Combining Figure 13 It can be seen that the two polymers form a compatible blend, and the hydrogen bond interaction inhibits the independent crystallization of each.

[0262] Furthermore, as shown by Figure 14 When the proportion of PGD is relatively high (such as 2:1), the peak position is closer to the characteristic peak of PGD; when the proportion of PCL is relatively high (such as 1:2), the peak position is closer to the characteristic peak of PCL; but at a ratio of 1:1, a new peak or a change in the peak shape appears, which further supports the intermolecular interaction. The hydrogen bond interaction makes PGD and PCL form a partially compatible blend, thereby affecting the crystallization kinetics and crystal form.

[0263] 3. Contact angle test of the polymer printing ink

[0264] The surface of polymer printing ink samples with different synthesis parameters (n = 5, that is, 5 samples) was cleaned with deionized water and tested after being fully dried. The polymer printing ink samples were preheated before the test to ensure that they were in the high elastic state; the samples were placed on the stage, and the focal length of the imaging device was adjusted to the sample surface to make the image clear; a micro syringe was used to suck deionized water, and then 1 μL was dropped on the sample surface through the robotic arm, and the water droplet was kept in contact with the sample surface for about 20 s; then the imaging device was used to take a photo, and the software was used to mark the contact angle between the liquid droplet and the sample and record it.

[0265] Figure 15 The contact angle test diagram of the polymer printing ink in an embodiment of the present invention is shown by Figure 15 As shown, the larger the water contact angle, the worse the hydrophilicity. Therefore, the hydrophilicity of polymer printing inks with different ratios is: PGD < PCL:PGD (mass ratio 1:2) < PCL:PGD (mass ratio 1:1) < PCL:PGD (mass ratio 2:1) < PCL. As the content of PGD increases, the hydrophilicity of the polymer gradually becomes worse, which may improve the stability of the system in the gastric acid environment.

[0266] 4. Thermodynamic property test of the polymer

[0267] The thermodynamic properties of the polymer were tested using a differential scanning calorimeter (DSC). A certain mass of polymer was weighed and placed in an aluminum lidded crucible. The sample inside the crucible was sealed using a molding machine and then placed at the sample end of the calorimeter. Simultaneously, a blank crucible without a sample was placed at the reference end of the calorimeter. The calorimeter program was set as follows: the temperature was raised to 80°C and held for 3 minutes, then cooled to -30°C at a rate of 10°C / min, and then heated to 80°C at a rate of 10°C / min. The change in thermal power of the sample during this period was recorded, resulting in a heat flow curve of the sample versus temperature. The obtained heat flow curve was analyzed using Prim software.

[0268] Figure 16 This is a thermodynamic test diagram of the polymer in one embodiment of the present invention, by... Figure 16 As shown, the transition temperature of pure PGD is around 36.5℃, which is close to human body temperature. This means that above 36.5℃, the polymer is in a highly elastic state, and its shape can be programmed to obtain a temporary shape (contraction state). Below 36.5℃, the polymer is in a glassy state, and the set shape at this time is a permanent shape (expansion state). The transition temperature of pure PCL is 56.2℃, and the transition temperature of PCL:PGD (mass ratio 1:1) is 36.1℃, which is close to human body temperature. The transition temperature of PCL:PGD (mass ratio 2:1) is around 52.6℃ due to the higher PCL content. The transition temperature of PCL:PGD (mass ratio 1:2) shows two peaks, which may be due to the poor compatibility of the two polymers at this ratio.

[0269] 5. Testing of polymer shape fixation rate and shape recovery rate

[0270] The bending-unfolding method was used to measure the shape retention ability of polymer materials under room temperature conditions and their shape recovery ability under body temperature conditions. A rectangular polymer sample (16×5×1mm) was immersed in a 40℃ water bath for 5 minutes. The sample was then removed and placed in a U-shaped mold, and left at room temperature for approximately 10 minutes to allow it to cool and reshape. The included angle between the two ends of the U-shaped sample at this point was measured using a digital image analysis device and recorded as θ. max Remove the sample from the mold and measure the included angle between the two ends of the U-shaped sample, recording it as θ. fix The sample was immersed in a 37°C water bath, and the unfolding process was recorded in real time using an image analysis device. The included angle between the two ends of the U-shaped sample at the final moment was measured and recorded as θ. i The shape fixation rate (R) of the sample is calculated using the following formula. f ) and shape recovery rate (R r ):

[0271] Figure 17This is a test graph showing the shape fixation rate and shape recovery rate of the polymer in one embodiment of the present invention. Figure 17 As shown, the shape retention rate and shape recovery rate of the PGD-PCL blend are both above 90%. The shape retention rate of PGD:PCL (mass ratio 1:1) is 99.5±0.88%, and the shape recovery rate is 96.3±0.67%, exhibiting the best shape memory performance. This may be related to the good compatibility of the two polymers. Therefore, the polymer matrix of the gastric retention drug delivery system of the present invention preferably uses PCL:PGD=1:1, but the present invention is not limited thereto.

[0272] 6. Morphology and mechanical strength testing of microneedle structures

[0273] The microstructure of the microneedle structure was observed using an optical microscope, and the dimensions of the microneedle patch were measured and evaluated, including the tip height, inter-needle spacing, and tip base width.

[0274] Quasi-static puncture strength testing was performed using an ElectroForce 3200 universal testing machine (TA Instruments). A custom-made flat-headed cylinder (Ø 2mm, 316L stainless steel) was used as the upper clamp to hold a glass slide with the microneedle structure base fixed with medical epoxy resin. Ex vivo porcine gastric mucosa-muscular layer composite tissue (thickness 3±0.5mm, kept moist at 37℃) was held in the lower clamp within a temperature-controlled bath (containing simulated gastric fluid, pH 1.2). The tissue sample's movement speed relative to the microneedles was set to 0.5mm / s. Force-displacement curves were recorded in real time.

[0275] The microchannels formed by the microneedle structure were studied using the inner wall of a porcine stomach. A 0.2 Hz sinusoidal load (amplitude 0.15 N, simulating gastric peristalsis) was applied to an ElectroForce for 10 min, allowing the microneedle structure to act on the isolated porcine gastric mucosa (pretreatment: soaking in SGF at 37℃ for 1 h). One hour later, the microneedle structure was dissected and observed under an optical microscope.

[0276] Figure 18A This is a morphological diagram of the microneedle structure in one embodiment of the present invention. Figure 18B This is a morphological diagram of the microneedle structure in another embodiment of the present invention. Figure 18C This is a quasi-static mechanical test insertion depth diagram of the microneedle structure in one embodiment of the present invention. Figure 18D This is a dynamic mechanical testing insertion depth diagram of the microneedle structure in one embodiment of the present invention, provided by... Figures 18A-18DAs shown, under an optical microscope, the microneedle structure on the surface of the jellyfish-like tentacles exhibits a regular distribution, a tight overall arrangement without obvious misalignment, and strong adhesion to the tentacles' base. Each microneedle is a regular cone shape with consistent tip direction, a length concentrated in the range of 570–650 μm, a base diameter of 300–330 μm, and a tip diameter of 10–20 μm. The taper is uniform, and no obvious bending or breakage is observed. Under low magnification, the spacing between adjacent microneedles is 120–150 μm. This spacing design reduces pressure damage to the gastric mucosa while ensuring anchoring density. The needle surface is smooth, without obvious pores or cracks, indicating a stable 3D printing process. After the microneedles were removed, clear and regular imprints were left on the porcine gastric mucosa, indicating that the microneedle array can firmly penetrate the stomach wall during gastric peristalsis.

[0277] Figure 19 This is a force-displacement curve obtained by quasi-static puncture of a microneedle structure according to an embodiment of the present invention. Figure 19 As shown, the destructive force of each microneedle structure is 1.47±0.12N, which is much greater than the minimum required force of 0.058N per needle, ensuring that the MN patch has sufficient strength to penetrate the skin without breaking.

[0278] 7. Test of the extracorporeal buoyancy and shape memory recovery ability of the intelligent gastric retention drug delivery system

[0279] A gastric retention drug delivery system (with a polymer mass of approximately 0.1 g) containing varying amounts of MOF particles was introduced into 900 ml of 0.1 N HCl (pH 1.2) maintained at 37°C for in vitro buoyancy and shape memory recovery tests. Results were investigated using float lag time (FLT) and total float time (TFT). The recovery time (SRT) was defined as the time it took for the tentacles to fully extend and return to the fully extended state of the biomimetic jellyfish. The dimensional recovery rate (ΔS) was calculated as the ratio of the projected diameter of the tentacles after full recovery to the designed size. The time required for the system to rise on the surface was considered the float lag time (FLT). The time the system maintained buoyancy was determined as the total float time (TFT). The test results are shown in Table 1 below.

[0280] Table 1. Test results of in vitro buoyancy and shape memory recovery ability of the intelligent gastric retention drug delivery system.

[0281] Using a polymer of PGD:PCL (mass ratio 1:1), the in vitro shape memory recovery ability of ZIF-8 systems loaded with different amounts of glucose oxidase and insulin was good and showed no significant difference. In vitro floating behavior results showed that for doses <200mg, there was almost no significant difference in floating lag time; for doses >200mg, the floating initiation time gradually increased with increasing MOF content; for doses <500mg, the total floating time gradually increased with increasing MOF content, but as the dosage exceeded 500mg, the total floating time significantly decreased. Therefore, the optimal MOF dosage is considered to be within 500mg.

[0282] 8. In vitro retention test of microneedle structure

[0283] The anchoring performance of microneedles is characterized by the forces and displacements experienced by the microneedles after undergoing a three-stage motion (tissue penetration, linear movement, and withdrawal). During testing, an ElectroForce 3200 universal testing machine (TAInstruments) with tensile and compression modes and a ±50N load cell was used. Thawed porcine gastric mucosa tissue was cut into 5×1cm patches, with the non-mucosal side adhered to the fixation device. The tissue samples were then fixed to the lower clamp of the tensile testing machine base, and the microneedles on the PDMS substrate were connected to the upper clamp with the sensor. During testing, the upper column moved downwards, inserting the microneedles into the tissue mucosa at a speed of 0.01 mm / s until they reached a distance of 0.4 mm from the initial needle / tissue contact point, and held for 30 seconds. After a 1 mm lateral movement perpendicular to the penetration direction, the microneedles moved upwards at a speed of 0.01 mm / s until they were completely withdrawn from the tissue, thus simulating gastric peristalsis.

[0284] Table 2. Results of in vitro retention tests of microneedle structures

[0285] Table 2 shows the in vitro retention test results of the microneedle structure. The pull-out / penetration ratio (PPR) obtained by linear fitting of the data in Table 2 is 7.65, which is close to the PPR value of the biomimetic microneedles in the current research.

[0286] 9. In vitro drug release test of the drug delivery unit

[0287] The glucose-responsive insulin release of synthesized drug-loaded and stimulus-responsive metal-organic frameworks (MOFs) was assessed in simulated gastric fluid (SGF, pH 1.2) at 37°C. Glucose dissolved in this buffer served as the release medium throughout the study. Insulin concentrations in the extracted samples were determined by HPLC. Insulin release was studied under three different conditions, as described below.

[0288] Release behavior at different blood glucose concentrations: 50 mg of GOx&Ins@ZIF-8 was added to a glass bottle, and 30 mL of dissolution medium (glucose concentrations of 0 mg / mL, 1 mg / mL, and 4 mg / mL) was added respectively. The glass bottle was fixed in a constant temperature shaker at 37℃ and shaken at 100 r / min. 1 mL of supernatant was collected at 15 min, 30 min, 60 min, 90 min, 120 min, 150 min, 180 min, and 240 min respectively, and 1 mL of dissolution medium was added. The sample was filtered and injected by HPLC.

[0289] Stepwise release behavior: 50 mg of GOx&Ins@ZIF-8 was added to 30 mL of a glucose solution with a concentration of 1 mg / mL and incubated at 37°C for one hour. The solution was then centrifuged, and the supernatant was collected. To the remaining supernatant, 30 mL of a glucose solution with a concentration of 2 mg / mL was added, and the mixture was incubated at 37°C for one hour. The solution was then centrifuged again, and the supernatant was collected. To the remaining supernatant, 30 mL of a glucose solution with a concentration of 4 mg / mL was added, and the mixture was incubated at 37°C for one hour. The supernatant was then centrifuged again to obtain the final supernatant. The amount of insulin released from all supernatants at all time points was assessed.

[0290] Pulsating Release Behavior: Pulsating insulin release in glucose solution simulating daily blood glucose fluctuations was investigated using a method similar to stepwise release behavior. Initially, 50 mg GOx&Ins@ZIF-8 was dispersed in 30 mL of glucose solution (4 mg / mL) at 37 °C. After 15 min, the solution was centrifuged, and the supernatant was replaced with 30 mL of glucose solution (1 mg / mL). Glucose solution (1 or 4 mg / mL) was alternately introduced at specified time points. Insulin concentration was analyzed in the supernatant extracted at each time point.

[0291] Table 3 shows the validated chromatographic test conditions for the drug. Under these chromatographic conditions, chromatograms with good stability and specificity can be obtained.

[0292] Table 3 Chromatographic test conditions

[0293] Figure 20 The graph shows the test results for release behavior at different blood glucose concentrations. Figure 20As shown, compared to the ZIF-8 delivery system without GOx loading, in a hyperglycemic environment, GOx&Ins@ZIF-8 can rapidly respond to an increase in glucose concentration and release insulin quickly, with a release rate of 0.145 mg / mL, which is 123% higher than Ins@ZIF-8. Furthermore, in a hypoglycemic environment, GOx&Ins@ZIF-8 can maintain a total release rate below 0.025 mg / mL, thus avoiding the serious side effects caused by the continued release of oral insulin under hypoglycemic conditions.

[0294] Figure 21 To gradually release the behavioral test results. (Image from...) Figure 21 As shown, in a stepwise release experiment, the insulin release rate was investigated by increasing the glucose concentration from 1 to 4 mg / mL and maintaining each glucose concentration for 1 hour. The results showed that the insulin release rate increased with the corresponding increase in glucose concentration in the release medium.

[0295] Figure 22 The image shows the results of the pulse release behavior test. Figure 22 As shown, the insulin release behavior of ZIF-8 was studied by alternating between normoglycemic and hyperglycemic conditions every 30 minutes to simulate the alternating blood glucose levels experienced by diabetic patients. When GOx&Ins@ZIF-8 was incubated with a 4 mg / mL glucose solution, the insulin release was 0.01 mg / mL in the first 30 minutes, while changing the glucose concentration to 1 mg / mL reduced the insulin release to 0.006 mg / mL. This alternating release trend was consistent over 240 minutes, with final release concentrations of 0.09 mg / mL and 0.02 mg / mL in the presence of 4 and 1 mg / mL glucose solutions, respectively.

[0296] 10. In vitro degradation test of polymers

[0297] Each group of polymer-cured samples was cut into rectangular blocks measuring 5×4×2mm using a carbon dioxide laser, and their initial mass was weighed before degradation in a simulated gastric acid environment. After sterilization, each group of samples (n=5, i.e., 5 groups of samples) was immersed in 20 mL of degradation solution with a pH of 1.2; the samples were placed in a constant temperature environment of 37℃ with gentle shaking. On days 1, 2, 4, and 6 after degradation, the samples were removed, and the surface was washed with deionized water to remove residual residue and culture medium. The samples were then dried in a fume hood for at least 48 hours, and the mass of the degraded samples was weighed using a precision balance to plot a time-mass curve. Sample dimensions were measured and volume and density were calculated at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 12 hours, and time-density curves were plotted.

[0298] Figure 23 This is a graph showing the degradation amount versus time of the thermally responsive shape memory polymer cured sample under simulated gastric acid conditions, as shown in the figure. Figure 23 As shown, the PGD:PCL ratios of 2:1, 1:1, and 1:2 (mass ratio) showed decreases of 10.6%, 11.6%, and 13.7% respectively compared to the initial mass. Compared with the PGD group, the polymer-cured samples of different ratios did not show significant mass loss within one hour after gastric retention. However, as the proportion of PGD in the polymer-cured samples increased, the mass loss slightly increased. It is also evident that the degradation rate of each ratio group was significantly slower than that of the PGD group, retaining more than 50% of the initial mass after 6 hours. Among them, the 1:1 polymer-cured sample showed a degradation retention of 56.5%, which best met the design requirements.

[0299] Figure 24 This is a graph showing the density versus time of the intelligent gastric retention drug delivery system of the present invention under simulated gastric acid conditions, such as... Figure 24 As shown, the initial density of the intelligent gastric retention drug delivery system containing 200 mg Ins&GOx@ZIF-8 with a PGD:PCL ratio of 1:1 was 0.85 ± 0.22 g / cm³. 3 It can float in gastric juice; accompanied by degradation in simulated gastric juice, its density increases from the initial density to 1.08±0.15 g / cm³ after 4 hours. 3 It reached 1.16±0.30 g / cm³ at 5 hours. 3 It can achieve relatively stable floating within the normal gastric emptying time of 2-4 hours in the human body. After the stomach empties, due to the increased density, it can sink to the edge of the stomach wall, which makes it easy for the microneedles to anchor.

[0300] The main structure of this invention utilizes the shape recovery force generated by thermally induced mechanical deformation to achieve stable floating and fluid obstruction in gastric juice. Furthermore, its microneedle structure can be anchored to the stomach wall through passive or active puncture, effectively counteracting mechanical displacement caused by gastric peristalsis. Combined with the intelligent drug delivery unit, it can achieve precise drug delivery on demand, significantly improving drug delivery efficiency and reducing systemic toxicity.

[0301] Of course, the present invention may have other various embodiments, and the protection scope of this application is not limited to the above embodiments. Those skilled in the art can make various modifications or combinations based on the present invention, and these should all fall within the protection scope of the claims of the present invention.

Claims

1. A biomechanically responsive smart deforming and anchoring based gastric residence drug delivery system, characterized in that, The application relates to a capsule for drug delivery, comprising: a main body made of a thermally responsive shape memory polymer, the main body comprising a head and a plurality of tentacles, the head being a spheroid and having an opening, the plurality of tentacles being distributed around the opening; a plurality of microneedle structures arranged on the plurality of tentacles; a drug-loaded unit comprising a metal-organic framework carrier and a drug, the drug being loaded on the metal-organic framework carrier, the drug-loaded unit being distributed on the main body and / or the plurality of microneedle structures, the drug-loaded unit releasing the drug when a trigger factor occurs; and a controlled release unit for controlling the release rate of the drug in the drug-loaded unit. The application further comprises a capsule shell, the main body, the plurality of microneedle structures, the drug-loaded unit and the controlled release unit being encapsulated in the capsule shell; and / or the main body being in a contracted state in the form of a cylinder before thermal response, and being in an expanded state in the form of a jellyfish after thermal response. The thermally responsive shape memory polymer has a phase transition temperature of 35-38 DEG C; and / or the thermally responsive shape memory polymer comprises, but is not limited to, polycaprolactone, polyglycolide, polylactic acid, polylactic acid-glycolic acid copolymer, polyurethane, polyether ester polyol, copolymer of polycaprolactone-polyglycolide, polycaprolactone-polylactic acid copolymer, copolymer or blend of polycaprolactone and polylactic acid-glycolic acid. The drug-loaded unit is uniformly distributed on the main body and the plurality of microneedle structures; and / or a part of the drug-loaded unit is uniformly distributed on the main body, and the remaining part of the drug-loaded unit is uniformly distributed on the plurality of microneedle structures, wherein the ratio of the amount of the drug in the part of the drug-loaded unit to the amount of the drug in the remaining part of the drug-loaded unit is 0.01:5 to 5:0.01; and / or a part of the drug-loaded unit is distributed on the head, and the remaining part of the drug-loaded unit is distributed on the plurality of tentacles and the plurality of microneedle structures, the amount of the drug in the remaining part of the drug-loaded unit accounting for more than 70% of the total amount of the drug. The microneedle structure comprises a base and a tip, the length ratio of the base to the tip in the axial direction being 1:(1-5), the base being connected to the tentacle, a part of the drug-loaded unit being distributed on the main body and the base of the microneedle structure, and the remaining part of the drug-loaded unit being distributed on the tip of the microneedle structure, wherein the ratio of the amount of the drug in the part of the drug-loaded unit to the amount of the drug in the remaining part of the drug-loaded unit is 5:1 to 1:5, preferably the amount of the drug in the remaining part of the drug-loaded unit accounting for more than 70% of the total amount of the drug.

2. The biomechanically responsive smart deforming and anchoring based gastric residence drug delivery system of claim 1, wherein, ​ 3. The biomechanically responsive smart deforming and anchoring based gastric residence drug delivery system of claim 1, wherein, ​ 4. The biomechanically responsive smart deforming and anchoring based gastric residence drug delivery system of claim 1, wherein, ​ 5. The biomechanically responsive smart deforming and anchoring based gastric residence drug delivery system of claim 1, wherein, ​ 6. The biomechanically responsive smart deforming and anchoring based gastric residence drug delivery system of claim 1, wherein, The drug-loaded unit further comprises a stimulus-responsive factor, which is loaded on the metal-organic framework (MOF) carrier; the metal-organic framework carrier includes but is not limited to at least one of a zinc-based MOF, an iron-based MOF, a zirconium-based MOF, and a copper-based MOF; the zinc-based MOF includes but is not limited to ZIF-8, ZIF-90, MOF-5, and MOF-74; the iron-based MOF includes but is not limited to MIL-100(Fe), MIL-101(Fe), and MIL-88B(Fe); the zirconium-based MOF includes but is not limited to UiO-66, UiO-67, and NU-1000; the copper-based MOF includes but is not limited to HKUST-1, Cu-BTC, and MOF-199; the stimulus-responsive factor includes but is not limited to a pH-responsive factor, a glucose-responsive factor, a redox-responsive factor, a magnetic-responsive factor, or a light-responsive factor.

7. The biomechanically responsive smart deforming and anchoring based gastric residence drug delivery system of claim 1, wherein, The controlled-release unit is a slow-release coating layer coated on the surface of the main body and the microneedle structure, and the slow-release coating layer is provided with a microchannel at the microneedle structure.

8. The biomechanically responsive smart deforming and anchoring based gastric residence drug delivery system of claim 1, wherein, The microneedle structure is a needle-shaped structure with a length of 0.5-2 mm and an apex angle of 10-65°, and the density of the microneedle structure arranged on the antenna is 5-20 needles / mm 2 ; and / or, the apex angle of the microneedle structure is provided with a barb structure with an axial depth of 50-1000 μm.

9. A process for the preparation of a biomechanically responsive smart deforming and anchoring based gastric residence drug delivery system as claimed in any of claims 1 to 8, characterized in that, The method comprises the following steps: Step 1: loading a drug on a metal-organic framework carrier to obtain a drug-loaded unit; Step 2: mixing a thermal-responsive shape memory polymer and the drug-loaded unit to prepare a main body and a microneedle structure; Step 3: coating a slow-release coating layer on the main body and the microneedle structure, and providing a microchannel at the microneedle structure to obtain a controlled-release unit; When a trigger factor appears, the drug-loaded unit releases the drug.

10. A process for the preparation of a gastro retentive drug delivery system based on intelligent deformation and anchoring in response to biomechanical response as claimed in claim 9, wherein, The method for loading a drug on a metal-organic framework carrier includes but is not limited to at least one of in-situ encapsulation, post-dipping, surface modification, and core-shell structure; the trigger factor includes but is not limited to pH triggering, biomarker triggering, redox triggering, or external stimulus factor triggering.

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