A composite microneedle with microscopic shape memory properties and its preparation method

Abstract

This invention discloses a composite microneedle with microscopic shape memory properties and its preparation method. The preparation method includes: constructing a first microneedle; constructing a second microneedle; microneedle composite; hot-pressing deformation and low-temperature cooling fixation. Hot-pressing deformation is performed using a hot press to deform the composite microneedle into a target shape within a conical microporous template, followed by low-temperature cooling fixation to obtain the composite microneedle. Before puncture into tissue, this invention uses hot-pressing deformation and low-temperature cooling fixation; after entering the tissue, with the help of environmental stimuli such as body temperature, the composite microneedle recovers its complex shape using shape memory recovery properties, forming a mechanical interlock with the tissue and achieving a strong fixation effect. This overcomes the shortcomings of traditional microneedles, which rely solely on the physicochemical bonding between the material and tissue and are easily displaced and detached under external forces. The first and second microneedles are loaded with different drugs respectively, and by combining their release characteristics, controllable drug release can be achieved.

Description

Technical Field

[0001] This invention relates to the technical field of drug-loaded microneedles, and in particular to a composite microneedle with microscopic shape memory properties and its preparation method. Background Technology

[0002] Drug-loaded microneedles have gained widespread attention in recent years due to their advantages such as low cost, environmental friendliness, safety, and painlessness, particularly in transdermal drug delivery, sensor-based drug delivery, cell-based drug delivery, and even traditional Chinese medicine. In transdermal drug delivery, microneedle drug delivery systems play a crucial role. They can penetrate deep into the dermis, forming microchannels between the epidermis and dermis. Drugs diffuse through the dermal tissue fluid, resulting in higher drug utilization and more controlled release compared to traditional topical treatments like topical application and injection, leading to more significant therapeutic effects. However, several challenges remain in their application. The adhesion between traditional microneedles and tissue relies on the physicochemical bonding between the material and the tissue. As biomedical materials requiring long-term adhesion, they are prone to displacement or even detachment under external forces, which is extremely detrimental to the treatment of related diseases.

[0003] Traditional microneedles have a simple cone-shaped structure. After being inserted into the tissue, they rely solely on the physical and chemical adhesion between the material and the tissue, which does not result in a very good bond and makes them prone to detachment. Summary of the Invention

[0004] The purpose of this invention is to provide a composite microneedle with microscopic shape memory properties and its preparation method, so as to solve one or more technical problems existing in the prior art, and at least provide a beneficial option or create conditions.

[0005] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0006] This invention provides a method for preparing composite microneedles with microscopic shape memory properties, comprising:

[0007] To construct the first microneedle, a pre-crosslinked polymer A and an initiator were dissolved in an organic solvent, and drug A was added. The mixture was then cast onto a first silicon wafer template placed in a polytetrafluoroethylene culture dish. After drying at room temperature, the mixture was hot-pressed and then peeled off after cooling to room temperature to obtain the first microneedle without crosslinking and loaded with drug A.

[0008] To construct the second microneedle, the pre-crosslinked polymer B and the initiator were dissolved in an organic solvent, and drug B was added. The mixture was then poured into a second silicon wafer template placed in a polytetrafluoroethylene culture dish. After hot pressing, excess mixture on the surface of the second silicon wafer template was removed to form a highly uniform and smooth dot matrix, thus obtaining an uncrosslinked drug-loaded second microneedle.

[0009] Microneedle composite: The second microneedle and the second silicon wafer template are heated to the melting temperature of the pre-crosslinked polymer B in the second microneedle, causing the lattice surface of the second microneedle to melt and form a viscous interface. A hollow gasket is placed on the second silicon wafer template. Then, the uncrosslinked drug-loaded first microneedle is inverted on the hollow gasket with the tips of the first microneedle aligned with the center of each unit in the lattice of the second microneedle. Ultraviolet crosslinking causes the double bonds at the ends of the pre-crosslinked polymer A and the pre-crosslinked polymer B to undergo a crosslinking reaction under the action of an initiator, forming a covalent bond. The first microneedle and the second microneedle are then combined and peeled off to obtain a microneedle with a composite structure.

[0010] Hot pressing deformation and low-temperature cooling fixation: The microneedles with composite structures are inverted in a relatively large conical microporous template, with the microneedles corresponding to the conical micropores. Hot pressing deformation is performed by a hot press, so that the microneedles with composite structures are deformed into the target shape in the conical microporous template. Then, the temporary shape is fixed by low-temperature cooling to obtain composite microneedles.

[0011] This technical solution utilizes the properties of biodegradable shape memory polymers to construct complex microneedles. Before puncture into the tissue, the composite microneedles are deformed by hot pressing and fixed by low-temperature cooling, maintaining a simple shape similar to traditional microneedles for easy tissue insertion. After entering the tissue, with the help of environmental stimuli such as body temperature, the composite microneedles recover their complex shape using shape memory recovery properties, forming a mechanical interlock with the tissue to achieve a strong fixation effect. This overcomes the shortcomings of traditional microneedles, which rely solely on the physical and chemical bonding between the material and the tissue and are prone to displacement and detachment under external forces. It meets the application requirements of long-term adherent biomedical materials and is especially suitable for scenarios requiring long-term drug administration or monitoring.

[0012] This technology utilizes composite microneedles that penetrate the dermis to form microchannels, allowing medication to diffuse through dermal tissue fluid. Compared to traditional topical application and injection methods, this reduces drug loss in the epidermis and improves drug utilization. Furthermore, the first and second microneedles are loaded with different drugs, and their combined release characteristics enable controlled drug release. For example, the drug in the first microneedle takes effect quickly, while the drug in the second microneedle provides a long-lasting, sustained release. This enhances treatment outcomes for conditions requiring long-term, precise care, such as skin diseases and diabetes.

[0013] As an extension of the above technical solution, the method also includes the step of preparing pre-crosslinked polymer A and / or pre-crosslinked polymer B:

[0014] Using polyethylene glycol as a primer, lactic acid, ε-caprolactone, or lactide as monomers, and stannous chloride or stannous octoate as a catalyst, a ring-opening copolymerization method is adopted. The catalyst initiates the ring-opening of the monomers, which then undergo a copolymerization reaction with the hydroxyl groups of polyethylene glycol to obtain polyethylene glycol-lactic acid copolymers, polyethylene glycol-caprolactone copolymers, or polyethylene glycol-lactide.

[0015] Double bonds are grafted onto the ends of the copolymers obtained in the above steps via esterification or alcoholysis.

[0016] The product is then precipitated by anhydrous diethyl ether and dried under vacuum to obtain polyethylene glycol-lactic acid, polyethylene glycol-caprolactone, or polyethylene glycol-lactide with double bond ends.

[0017] Vacuum drying to constant weight yields pre-crosslinked polymer A and / or pre-crosslinked polymer B.

[0018] This extended approach utilizes ring-opening copolymerization of polyethylene glycol and monomers to enable pre-crosslinked polymer A and / or pre-crosslinked polymer B to possess both the plasticity of hot-press deformation (when uncrosslinked) and the ability to recover their in vivo structure through shape memory effect (e.g., changing from a temporary conical puncture shape to a cylindrical fixed shape). Ultimately, the copolymer can be gradually degraded in vivo into non-toxic small molecules, such as CO2 and H2O, without the need for secondary surgery. By adjusting the monomer types, such as a higher proportion of caprolactone resulting in slower degradation, it can be matched to the needs of different treatment cycles, such as short-term administration or long-term fixation.

[0019] As an extension of the above technical solution, the pre-crosslinked polymer A and / or pre-crosslinked polymer B are shape memory polymers. Their molecular chains expand and recover at temperatures between 37°C and 42°C, and crystallize or fix their shape at temperatures between 0°C and 25°C. As shape memory polymers, pre-crosslinked polymer A and / or pre-crosslinked polymer B contain a stationary phase (such as crystalline regions and crosslinking points) and a reversible phase (such as amorphous regions) in their structure. At temperatures close to human body temperature (37-42°C), the reversible phase molecular chains overcome interaction energies and expand from a coiled state, driving the material to recover from a temporary shape (such as a simple cone shape for puncture) to a fixed shape (such as a complex cylindrical shape). At temperatures between 0-25°C, the movement of the reversible phase molecular chains is restricted, and the temporary shape is fixed through crystallization or glass transition, ensuring morphological stability before puncture.

[0020] As an extension of the above technical solution, the pre-crosslinked polymer A and pre-crosslinked polymer B are two polymers with different molecular weights and different degradation times, and the drug A and drug B are two drugs with different degradation times. The degradation time of pre-crosslinked polymer A and pre-crosslinked polymer B is controlled by their molecular weight difference. Polymers with higher molecular weights have more tightly wound molecular chains, making it more difficult for degrading enzymes to penetrate and resulting in slower degradation. Drug A degrades synchronously with pre-crosslinked polymer A, achieving rapid release; drug B degrades in a matched manner with pre-crosslinked polymer B, resulting in slow release over 8-12 weeks, preventing premature drug leakage or residue.

[0021] As an extension of the above technical solution, the micropores of the first silicon wafer template are conical or cylindrical, with a depth of 200-300 μm and an aperture diameter of 100-150 μm. The 200-300 μm depth design ensures that the first microneedle has sufficient length to reach the dermis while avoiding bending or breakage due to excessive length; the 100-150 μm aperture diameter of the micropores can accommodate an appropriate amount of drug, suitable for the precise delivery of small molecule drugs or biological agents.

[0022] As an extension of the above technical solution, the micropores of the second silicon wafer template are cylindrical, hemispherical, or conical, with a depth of 100-200 μm and an orifice diameter of 200-300 μm. The positions of the micropore axes of the second silicon wafer template correspond to the positions of the micropore axes of the first silicon wafer template. The micropore size of the second silicon wafer template is larger than that of the first template, so that the second microneedle and the first microneedle cross-link to form a complex shape, such as a combination of a cone and a cylinder. After the composite microneedle is inserted into the tissue, by applying heat with body temperature or a hot water bottle, the composite microneedle recovers its complex shape using shape memory recovery characteristics, forming a mechanical interlock with the tissue to achieve a strong fixation effect. This overcomes the shortcomings of traditional microneedles, which rely solely on the physical and chemical bonding between the material and the tissue and are easily displaced and detached under external force.

[0023] As an extension of the above technical solution, in the hot-pressing deformation and low-temperature cooling fixing steps, when the material of the microneedles with composite structures is an amorphous shape memory polymer, the hot-pressing temperature is 45-55℃, the pressure is set within 1-2MPa, and the pressure is maintained for 10-20 minutes. Subsequently, the pressure is maintained to allow the conical microporous template to cool down naturally. For amorphous shape memory polymers such as polyethylene glycol-lactic acid copolymer, the hot-pressing temperature is 45-55℃, which is 10-20℃ higher than its glass transition temperature, so that the material is in a highly elastic state and fits the conical template under a pressure of 1-2MPa. During the natural cooling process, the pressure is maintained until the temperature drops below 25℃, and the shape is fixed by reversible glass transition, avoiding cracking caused by internal stress.

[0024] As an extension of the above technical solution, in the hot-pressing deformation and low-temperature cooling fixation steps, when the material of the microneedles with composite structures is a semi-crystalline shape memory polymer, the hot-pressing temperature is 50-70℃, allowing the material to flow and fill the conical microporous template after the crystals melt. The pressure is set within 1-2 MPa and maintained for 10-20 minutes, followed by cooling fixation at a temperature of 0-25℃. For semi-crystalline polymers such as polyethylene glycol-caprolactone copolymer, a hot-pressing temperature of 50-70℃, which is 5-10℃ higher than its melting temperature, allows the crystals to melt, improving material fluidity and ensuring detailed filling of the template. During cooling at 0-25℃, the crystals recrystallize, and the shape is fixed through crystallization, improving structural stability. Furthermore, the 0-25℃ fixation temperature facilitates storage and transportation, lowering the threshold for clinical use.

[0025] On the other hand, the present invention also provides a composite microneedle prepared using the method described above for a composite microneedle with microscopic shape memory properties. The composite microneedle possesses microscopic shape memory properties, and its mechanical interlocking structure after shape recovery significantly enhances its adhesion to tissues. It is suitable for drug delivery or monitoring in moving areas, such as joints and skin folds, thus solving the problem of microneedles easily detaching in wearable devices.

[0026] As an extension of the above technical solution: the composite microneedles are heated to 38-42℃ during use to trigger microscopic shape recovery. The recovery temperature of 38-42℃ matches the human body environment, allowing for shape recovery within the body without surgery or equipment intervention, simplifying the operation process. Alternatively, conventional heating methods can be used to trigger the composite microneedles' recovery, such as using a hairdryer to heat the microneedle area or applying a hot water bottle. Attached Figure Description

[0027] The present invention will be further described below with reference to the accompanying drawings and embodiments;

[0028] Figure 1 This is a schematic diagram of the structure of the first microneedle and the first silicon wafer template in the embodiment;

[0029] Figure 2 This is a schematic diagram of the structure of the second microneedle and the second silicon wafer template in the embodiment;

[0030] Figure 3 This is a schematic diagram of the structure when the first and second microneedles are combined in an embodiment;

[0031] Figure 4 This is a schematic diagram of the composite structure of the microneedles and the conical microporous template in the embodiment.

[0032] Figure 5 This is a schematic diagram of the composite microneedles in the embodiment, which are fixed by low-temperature cooling.

[0033] In the attached figures: 10: first microneedle, 100: first silicon wafer template, 20: second microneedle, 200: second silicon wafer template, 30: microneedle with composite structure, 300: hollow gasket, 40: composite microneedle, 400: conical microporous template. Detailed Implementation

[0034] This section will describe in detail specific embodiments of the present invention. Preferred embodiments of the present invention are shown in the accompanying drawings. The purpose of the drawings is to supplement the textual description with graphics, so that people can intuitively and vividly understand each technical feature and overall technical solution of the present invention, but they should not be construed as limiting the scope of protection of the present invention.

[0035] In the description of this invention, it should be understood that the orientation descriptions, such as up, down, front, back, left, right, etc., are based on the orientation or positional relationship shown in the accompanying drawings. They are only for the convenience of describing this invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limiting this invention.

[0036] In the description of this invention, if there are words such as "several", they mean one or more, "multiple" means two or more, "greater than", "less than", "exceeding" etc. are understood to exclude the number itself, and "above", "below", "within" etc. are understood to include the number itself.

[0037] In the description of this invention, unless otherwise explicitly defined, terms such as "set up," "install," and "connect" should be interpreted broadly, and those skilled in the art can reasonably determine the specific meaning of the above terms in this invention in conjunction with the specific content of the technical solution.

[0038] Reference Figures 1 to 5 The following are several embodiments of a composite microneedle with microscopic shape memory properties and its preparation method according to the present invention.

[0039] like Figures 1 to 5 As shown, an embodiment of the present invention provides a method for preparing a composite microneedle with microscopic shape memory properties, comprising:

[0040] To construct the first microneedle 10, a pre-crosslinked polymer A and an initiator were dissolved in an organic solvent, and drug A was added. The mixture was then poured into a first silicon wafer template 100 placed in a polytetrafluoroethylene culture dish. After drying at room temperature, the mixture was hot-pressed and then peeled off after cooling to room temperature to obtain the first microneedle 10 without crosslinking and loaded with drug A.

[0041] To construct the second microneedle 20, the pre-crosslinked polymer B and the initiator were dissolved in an organic solvent, and drug B was added. Then, the mixture was poured into the second silicon wafer template 200 placed in a polytetrafluoroethylene culture dish. After hot pressing, the excess mixture on the surface of the second silicon wafer template was removed to form a highly uniform and smooth dot matrix, thus obtaining the uncrosslinked drug-loaded second microneedle 20.

[0042] Microneedle composite: The second microneedle 20 and the second silicon wafer template 200 are heated to the melting temperature of the pre-crosslinked polymer B in the second microneedle 20, causing the lattice surface of the second microneedle 20 to melt and form a viscous interface. A hollow spacer 300 is placed on the second silicon wafer template 200. Then, the uncrosslinked drug-loaded first microneedle 10 is inverted on the hollow spacer 300 with each needle tip aligned with the center of each unit in the lattice of the second microneedle 20. Ultraviolet crosslinking causes the double bonds at the ends of the pre-crosslinked polymer A and the pre-crosslinked polymer B to undergo a crosslinking reaction under the action of an initiator, forming a covalent bond. The first microneedle 10 and the second microneedle 20 are then combined and peeled off to obtain a microneedle 30 with a composite structure.

[0043] Hot pressing deformation and low-temperature cooling fixation: The microneedle 30 with composite structure is inverted in a relatively large conical microporous template 400, so that the microneedle corresponds to the conical micropore. Hot pressing deformation is performed by a hot press, so that the microneedle 30 with composite structure is deformed into the target shape in the conical microporous template 400. Then, the temporary shape is fixed by low-temperature cooling to obtain the composite microneedle 40.

[0044] In this embodiment, the pre-crosslinked polymer A has good needle-forming properties and mechanical strength, such as the polyethylene glycol-lactic acid copolymer with double bonds at the ends in the optional embodiment below. Its molecular weight and flowability before crosslinking are adapted to the micropore filling of the first silicon wafer template. The pre-crosslinked polymer B can be combined with the pre-crosslinked polymer A through a crosslinking reaction. For example, it also contains double bonds, but its mechanical properties are more flexible or its degradation rate is different. It is suitable as a substrate. Its flowability is adapted to the micropore filling of the second silicon wafer template. Its molecular weight may be higher than that of the pre-crosslinked polymer A.

[0045] Drug A is a small molecule drug or bioactive substance that requires deep delivery, such as vaccines or proteins. The dosage is adjusted according to the drug loading requirements and is usually 5%-20% of the mass of the pre-crosslinked polymer A. It is stable in organic solvents and does not degrade or precipitate. Drug B is a drug that requires sustained release or surface delivery, such as anti-inflammatory drugs or local analgesics. It has high stability and can withstand the subsequent hot pressing process. The dosage is usually 10%-30% of the mass of the pre-crosslinked polymer B. This embodiment does not impose any restrictions on the specific drugs of Drug A and Drug B.

[0046] The initiator is benzophenone or a photoinitiator, such as Igace 2959. The organic solvent can dissolve both the initiator and the pre-crosslinked polymer A or B, and has good compatibility with both drug A and drug B, such as dichloromethane or ethyl acetate.

[0047] In this embodiment, the pre-crosslinked polymer A and the initiator are dissolved in an organic solvent, and drug A is added. The mixture is stirred evenly at 300-500 rpm for 10-20 minutes to ensure uniform drug dispersion. Then, it is slowly poured into a first silicon wafer template, or a PDMS template can be used. The first silicon wafer template is made of silicon wafer and is prepared by photolithography etching. The pore depth is usually 200-300 μm. The first silicon wafer template is placed in a polytetrafluoroethylene (PTFE) petri dish. The non-stick properties of PTFE are used to prevent solution leakage. At the same time, the first silicon wafer template is gently shaken with an amplitude of 5-10 mm to remove air bubbles in the solution and ensure that the micropores are completely filled. Then, it is placed in a ventilated environment at 25-30℃ for 6-12 hours to allow the organic solvent to evaporate slowly and avoid rapid drying that could cause cracks or bubbles on the surface of the microneedles. After drying, the pre-crosslinked polymer A forms a solid structure with a certain strength, but it is not crosslinked, thus maintaining its processability. The dried first silicon wafer template is placed in a hot press, with the temperature set 10-20°C above the glass transition temperature of the pre-crosslinked polymer A, typically 40-60°C, and the pressure set at 1-5 MPa. The press is held for 5-10 minutes to ensure that the material fully adheres to the first silicon wafer template within the micropores. After cooling to room temperature, the first silicon wafer template is gently peeled off using the low surface energy characteristics of the PTFE culture dish to obtain the first microneedle loaded with uncrosslinked drug A.

[0048] The construction of the second microneedle is similar to that of the first microneedle, except that hot pressing is performed directly after casting, without the need for prior drying to a completely solid state at room temperature. The purpose is to promote solvent evaporation and allow the pre-crosslinked polymer B to initially take shape through heating. The hot pressing temperature is typically 50-70℃, higher than the glass transition temperature of the pre-crosslinked polymer B, with a pressure of 1-5 MPa and a holding time of 10-15 minutes, allowing the material to solidify within the micropores and bond tightly with the second silicon wafer template. After hot pressing, excess mixture that has not entered the micropores may remain on the surface of the second silicon wafer template. Before the material is completely hardened (when cooled to 40-50℃ after hot pressing), it is scraped parallel to the surface of the second silicon wafer template with a scraper to ensure that only the material remains within the micropores, forming a highly consistent and smooth lattice. This operation ensures the structural alignment accuracy when subsequently composited with the first microneedle. The resulting uncrosslinked drug-loaded second microneedle serves as the substrate for the composite structure.

[0049] The second microneedle and the second silicon wafer template are placed together in an oven or heating table and heated. The heating temperature is set to the melting temperature of the pre-crosslinked polymer B in the second microneedle, usually 60-80℃. The temperature is maintained for 5-10 minutes, so that the lattice surface of the second microneedle melts to form a viscous interface, which facilitates bonding with the first microneedle. A hollow spacer is placed on the second silicon wafer template. The hollow spacer is usually made of silicone or PTFE and has a thickness of 50-100μm. The spacer is placed to control the bonding thickness between the first and second microneedles, avoid excessive contact that would cause the first microneedle structure to be covered by the molten lattice material, and also to form a physical gap and assist in positioning. Subsequently, the first microneedle, uncrosslinked and loaded with drug A, is placed upside down on a hollow gasket with the tips of each microneedle aligned with the center of each unit in the lattice of the second microneedle. The composite structure is then fixed by ultraviolet crosslinking. A UV lamp with a wavelength of 254-365 nm can be used, with an irradiation distance of 10-20 cm and an irradiation time of 5-30 min, which can be adjusted according to the type and concentration of the initiator. The UV crosslinking causes the double bonds at the ends of the pre-crosslinked polymer A and the pre-crosslinked polymer B to undergo a crosslinking reaction under the action of the initiator, forming a covalent bond. The first microneedle is then combined with the second microneedle. After crosslinking, the mixture is cooled to room temperature. The template is first peeled off, and then the composite structure is completely removed using the non-stick properties of the PTFE culture dish, resulting in a microneedle with a composite structure.

[0050] Hot pressing deformation and low-temperature cooling fixation: The microneedles with composite structures are inverted in a relatively large conical microporous template, with the microneedles corresponding to the conical micropores. Hot pressing deformation is performed by a hot press, so that the microneedles with composite structures are deformed into the target shape in the conical microporous template. Then, the temporary shape is fixed by low-temperature cooling to obtain composite microneedles.

[0051] This embodiment utilizes the properties of biodegradable shape memory polymers to construct complex microneedles. Before puncture into the tissue, the composite microneedles are deformed by hot pressing and fixed by low-temperature cooling, so that the temporary shape of the composite microneedles remains similar to that of traditional microneedles, facilitating smooth insertion into the tissue. After entering the tissue, with the help of environmental stimuli such as body temperature, the composite microneedles recover their complex shape by utilizing the shape memory recovery properties, forming a mechanical interlock with the tissue to achieve a strong fixation effect. This overcomes the shortcomings of traditional microneedles, which rely solely on the physical and chemical bonding between the material and the tissue and are prone to displacement and detachment under external forces. It meets the application requirements of long-term adherent biomedical materials and is especially suitable for scenarios requiring long-term drug administration or monitoring.

[0052] The composite microneedles of this embodiment can penetrate the dermis to form microchannels, allowing medication to diffuse through the dermal tissue fluid. Compared to traditional topical application and injection methods, this reduces drug loss in the epidermis and improves drug utilization. Simultaneously, the first and second microneedles are loaded with different drugs, and by combining their release characteristics, controlled drug release can be achieved. For example, the drug in the first microneedle has a rapid onset of action, while the drug in the second microneedle has a long-lasting, sustained release. This enhances treatment efficacy for conditions requiring long-term and precise treatment, such as skin-related diseases and diabetes.

[0053] In an optional embodiment, based on the above preparation method, the method further includes the step of preparing pre-crosslinked polymer A and / or pre-crosslinked polymer B:

[0054] Using polyethylene glycol as a primer, lactic acid, ε-caprolactone, or lactide as monomers, and stannous chloride or stannous octoate as a catalyst, a ring-opening copolymerization method is adopted. The catalyst initiates the ring-opening of the monomers, which then undergo a copolymerization reaction with the hydroxyl groups of polyethylene glycol to obtain polyethylene glycol-lactic acid copolymers, polyethylene glycol-caprolactone copolymers, or polyethylene glycol-lactide.

[0055] Double bonds are grafted onto the ends of the copolymers obtained in the above steps via esterification or alcoholysis.

[0056] The copolymer is then precipitated by anhydrous diethyl ether and dried under vacuum. An excess of anhydrous diethyl ether is slowly added dropwise to the reaction solution. Taking advantage of the extremely low solubility of the copolymer in diethyl ether, it precipitates as solid particles. Unreacted monomers, catalysts, and other impurities dissolve in the diethyl ether, achieving separation. After washing with diethyl ether 3-5 times, the copolymer is first air-dried in a fume hood to remove most of the diethyl ether. Then it is transferred to a vacuum drying oven and dried at 30-50℃ and a vacuum degree <100Pa for 8-12 hours to initially remove residual solvent, yielding polyethylene glycol-lactic acid, polyethylene glycol-caprolactone, or polyethylene glycol-lactide with double bond ends.

[0057] Then, vacuum drying is performed to constant weight to obtain pre-crosslinked polymer A and / or pre-crosslinked polymer B.

[0058] In this embodiment, polyethylene glycol (PEG) serves as a hydrophilic primer, with its terminal hydroxyl group (-OH) providing an active site for the copolymerization reaction. Lactic acid, ε-caprolactone, or lactide serves as monomers, providing hydrophobic segments that determine the degradation rate and mechanical strength of the copolymer. For example, lactic acid-derived segments degrade quickly and are suitable for short-term applications, while ε-caprolactone-derived segments degrade slowly and are suitable for long-term fixation. Lactide (a cyclic dimer of lactic acid) exhibits higher ring-opening polymerization activity, making it easier to control the reaction rate. The amount of catalyst used is generally 0.01%-0.1% of the monomer mass, initiating the ring-opening of the cyclic monomer through coordination and simultaneously promoting copolymerization with the PEG hydroxyl group. Ring-opening copolymerization should be carried out under anhydrous and oxygen-free conditions (nitrogen atmosphere) to avoid catalyst deactivation or polymer chain breakage caused by moisture. The preferred reaction temperature is 100-160℃, such as 120-160℃ for lactide polymerization and 100-140℃ for ε-caprolactone polymerization. Too high a temperature will lead to thermal degradation of PEG, while too low a temperature will result in incomplete reaction. The endpoint is determined by monitoring the monomer conversion rate, such as by tracking the changes in characteristic peaks in 1H NMR spectroscopy to form block or random copolymers, such as polyethylene glycol-lactic acid. The glass transition temperature (Tg) or melting temperature (Tm) can be controlled by the ratio of PEG to monomer. The higher the PEG content, the lower the Tg, which lays the foundation for subsequent shape memory properties.

[0059] In the grafting of double bonds at the ends of copolymers, the choice between esterification or alcoholysis depends on the specific circumstances. If the copolymer ends are predominantly hydroxyl (-OH), such as at the ends of PEG chains, esterification is preferred: reacting with carboxylic acids containing double bonds, such as acrylic acid and methacrylic acid, under the action of a dehydrating agent (DCC) and a catalyst (DMAP), to form ester bonds (-COO-) and graft double bonds (such as -CH=CH2). If the copolymer ends contain ester groups (-COO-), such as at the ends of polyethylene glycol-lactic acid or polyethylene glycol-caprolactone chains, alcoholysis is used: reacting with alcohols containing double bonds, such as allyl alcohol and hydroxyethyl methacrylate, under the action of an organotin catalyst (dibutyltin dilaurate), to break the original ester bonds and form new ester bonds, thus achieving double bond grafting. The double bond grafting rate of esterification or alcoholysis reaction is high and the double bond stability is good. It is not easy to break during storage and processing, which ensures that the pre-crosslinked polymer A and / or pre-crosslinked polymer B can form a strong covalent bond connection during subsequent UV crosslinking, thus avoiding the delamination of the composite microneedles when used in vivo.

[0060] This embodiment utilizes ring-opening copolymerization of polyethylene glycol and monomers to enable pre-crosslinked polymer A and / or pre-crosslinked polymer B to possess both the plasticity of hot-press deformation (when not crosslinked) and the ability to achieve in vivo structural recovery through shape memory effect (e.g., changing from a temporary conical puncture shape to a cylindrical fixed shape). Ultimately, the copolymer can be gradually degraded in vivo into non-toxic small molecules, such as CO2 and H2O, without the need for secondary surgery for removal. By adjusting the monomer types, such as a higher proportion of caprolactone resulting in slower degradation, it is possible to match the needs of different treatment cycles, such as short-term administration or long-term fixation.

[0061] In an optional embodiment, the pre-crosslinked polymer A and / or pre-crosslinked polymer B are shape memory polymers, which expand and recover their shape at a temperature of 37°C-42°C and crystallize or fix their shape at a temperature of 0-25°C.

[0062] In this embodiment, pre-crosslinked polymer A and / or pre-crosslinked polymer B are shape memory polymers, whose structures include a stationary phase (such as crystalline regions and crosslinking points) and a reversible phase (such as amorphous regions). At temperatures close to human body temperature (37-42°C), the reversible phase molecular chains overcome interaction energies and unfold from a coiled state, driving the material to return from a temporary shape (such as a simple cone shape for puncture) to a fixed shape (such as a complex cylindrical shape). It can also be heated by conventional heating methods, such as using a hot water bottle or a hair dryer. At temperatures of 0-25°C, the movement of the reversible phase molecular chains is restricted, and the temporary shape is fixed through crystallization or glass transition, ensuring morphological stability before puncture.

[0063] In an optional embodiment, the pre-crosslinked polymer A and pre-crosslinked polymer B are two polymers with different molecular weights and different degradation times, and the drug A and drug B are two drugs with different degradation times. The degradation time of pre-crosslinked polymer A and pre-crosslinked polymer B is controlled by their molecular weight difference. For example, pre-crosslinked polymer A has a molecular weight of 5000-10000 and a degradation cycle of 2-4 weeks; pre-crosslinked polymer B has a molecular weight of 20000-30000 and a degradation cycle of 8-12 weeks. Polymers with higher molecular weights have more tightly wound molecular chains, making it more difficult for degrading enzymes to penetrate and resulting in slower degradation. Drug A degrades synchronously with pre-crosslinked polymer A, achieving rapid release; drug B degrades in sync with pre-crosslinked polymer B, resulting in slow, continuous release over 8-12 weeks, avoiding premature drug leakage or residue.

[0064] In an optional embodiment, the micropores of the first silicon wafer template are conical or cylindrical, with a depth of 200-300 μm and an aperture diameter of 100-150 μm. The 200-300 μm depth design ensures that the first microneedle is long enough to reach the dermis while avoiding bending or breakage due to excessive length; the 100-150 μm aperture diameter of the micropores can accommodate an appropriate amount of drug, suitable for the precise delivery of small molecule drugs or biologics.

[0065] In an optional embodiment, the micropores of the second silicon wafer template are cylindrical, hemispherical, or conical, with a depth of 100-200 μm and an orifice diameter of 200-300 μm. The positions of the micropore axes of the second silicon wafer template correspond to the positions of the micropore axes of the first silicon wafer template. The micropore size of the second silicon wafer template is larger than that of the first template, allowing the second microneedle to cross-link with the first microneedle to form a complex shape, such as a combination of a cone and a cylinder. After the composite microneedle is inserted into the tissue, body temperature or a hot water bottle is applied, and the shape memory recovery property is utilized to restore the composite microneedle to its complex shape, forming a mechanical interlock with the tissue and achieving a strong fixation effect. This overcomes the shortcomings of traditional microneedles, which rely solely on the physical and chemical bonding between the material and the tissue and are easily displaced and detached under external force.

[0066] In an optional embodiment, during the hot-pressing deformation and low-temperature cooling fixing steps, when the material of the microneedles with the composite structure is an amorphous shape memory polymer, the hot-pressing temperature is 45-55°C, the pressure is set to 1-2 MPa, and the pressure is maintained for 10-20 minutes. Subsequently, the pressure is maintained while allowing the conical microporous template to cool naturally. For amorphous shape memory polymers such as polyethylene glycol-lactic acid copolymers, a hot-pressing temperature of 45-55°C, 10-20°C higher than their glass transition temperature, keeps the material in a highly elastic state, allowing it to adhere to the conical template under a pressure of 1-2 MPa. During the natural cooling process, the pressure is maintained until the temperature drops below 25°C, reversibly glassizing and fixing the shape, thus preventing cracking caused by internal stress.

[0067] In an optional embodiment, during the hot-pressing deformation and low-temperature cooling fixation steps, when the material of the microneedles with the composite structure is a semi-crystalline shape memory polymer, the hot-pressing temperature is 50-70°C, allowing the material to flow and fill the conical microporous template after the crystals melt. The pressure is set within 1-2 MPa and maintained for 10-20 minutes, followed by cooling fixation at a temperature of 0-25°C. For semi-crystalline polymers such as polyethylene glycol-caprolactone copolymer, a hot-pressing temperature of 50-70°C, which is 5-10°C higher than their melting temperature, allows the crystals to melt, improving material fluidity and ensuring detailed filling of the template. During cooling at 0-25°C, the crystals recrystallize, and the shape is fixed through crystallization, improving structural stability. Furthermore, the fixation temperature of 0-25°C facilitates storage and transportation, lowering the threshold for clinical use.

[0068] On the other hand, another embodiment of the present invention provides a composite microneedle prepared using one or more of the above-described alternative embodiments. The composite microneedle possesses microscopic shape memory properties, and its mechanical interlocking structure after shape recovery significantly enhances its adhesion to tissues. It is suitable for drug delivery or monitoring in moving areas, such as joints and skin folds, thus solving the problem of microneedles easily detaching in wearable devices.

[0069] In an optional embodiment, the composite microneedles are heated to 38-42°C after use to trigger microscopic shape recovery.

[0070] In this embodiment, the recovery temperature of 38-42°C matches the human body environment, and the shape can be restored in the body without surgery or equipment intervention, simplifying the operation process. At the same time, conventional heating methods can be used to trigger the composite microneedle recovery, such as using a hair dryer to blow hot air on the microneedle site or using a hot water bottle for hot compress.

[0071] The following examples further illustrate the present invention in detail. It should also be understood that the following examples are only for further explanation of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the above description of the present invention are within the scope of protection of the present invention. The specific process parameters, etc., in the following examples are merely examples within a suitable range; that is, those skilled in the art can make appropriate selections within the appropriate range based on the description herein, and are not intended to be limited to the specific values ​​in the examples below.

[0072] Example 1:

[0073] This invention discloses a method for preparing composite microneedles with microscopic shape memory properties, comprising the following steps:

[0074] 1) Weigh 10g of polyethylene glycol-lactic acid-propylene, a certain amount of drug A and 0.5g of benzophenone, dissolve them in 10mL of dichloromethane, and dry to constant weight; then place the first silicon wafer template at the bottom, cover the first silicon wafer template with the obtained mixture, and place the whole thing in a hot press mold. The temperature of the hot press is increased to 50℃, the pressure is increased to 1MPa, and it is maintained for 10 minutes to allow the polymer material to penetrate into the first silicon wafer template; after the temperature drops to room temperature, peel the polymer film with micro-patterns on the surface from the surface of the first silicon wafer template to obtain the first microneedle;

[0075] 2) Weigh 1g of polyethylene glycol-lactic acid-propylene, a certain amount of drug B and 0.05g of benzophenone, dissolve them in 2mL of dichloromethane, and dry to constant weight; then place the second silicon wafer template at the bottom, cover the template with the obtained mixture, and place the whole thing in a hot press mold. Raise the temperature of the hot press to 50℃, raise the pressure to 1MPa, and maintain it for 10 minutes to allow the polymer material to penetrate into the silicon wafer template; after the temperature drops to room temperature, scrape off the excess polymer on the surface to obtain the second microneedle.

[0076] 3) Heat the second microneedle loaded with drug B and the second silicon wafer template to a molten state, and add a hollow spacer of a certain thickness on the second silicon wafer template; then, place the uncrosslinked first microneedle loaded with drug A upside down on the hollow spacer, with the tip of the first microneedle corresponding to the center of each unit of the lattice of the second silicon wafer template. After ultraviolet crosslinking, peel it off to obtain the composite microneedle.

[0077] 4) The obtained composite microneedles are upside down and placed on a relatively large conical microporous template, ensuring that they correspond one-to-one; they are then hot-pressed and deformed using a hot press, and then cooled at low temperature to fix the temporary shape, thereby obtaining composite microneedles with microscopic shape memory properties.

[0078] In this embodiment, the semi-crystalline polymer can also be polyethylene glycol-caprolactone or polyethylene glycol-urethane.

[0079] Example 2:

[0080] Similar to Example 1, except that the micropore depth and orifice diameter of the first and second silicon wafer templates are different, and the micropores of the first silicon wafer template are conical micropores, while the micropores of the second silicon wafer template are hemispherical micropores, thus preparing composite microneedles with different patterns, micropore depths and orifice diameters.

[0081] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the embodiments described. Those skilled in the art can make various equivalent modifications or substitutions without departing from the spirit of the present invention, and these equivalent modifications or substitutions are all included within the scope defined by the claims of this application.

Claims

1. A method for preparing composite microneedles with microscopic shape memory properties, characterized in that, include: To construct the first microneedle (10), the pre-crosslinked polymer A and the initiator were dissolved in an organic solvent and drug A was added. Then, the mixture was poured into the first silicon wafer template (100) placed in a polytetrafluoroethylene culture dish. After drying at room temperature, it was hot-pressed and then peeled off after cooling to room temperature to obtain the first microneedle (10) without crosslinking and loaded with drug A. To construct the second microneedle (20), the pre-crosslinked polymer B and the initiator were dissolved in an organic solvent and drug B was added. Then, the mixture was poured into the second silicon wafer template (200) placed in a polytetrafluoroethylene culture dish. After hot pressing, the excess mixture on the surface of the second silicon wafer template (200) was removed to form a highly consistent and smooth dot matrix, thus obtaining the uncrosslinked drug-loaded second microneedle (20). Microneedle composite: The second microneedle (20) and the second silicon wafer template (200) are heated. The heating temperature is set to the melting temperature of the pre-crosslinked polymer B in the second microneedle (20), so that the lattice surface of the second microneedle (20) melts to form a viscous interface. A hollow gasket (300) is placed on the second silicon wafer template (200). Then, the uncrosslinked drug-loaded first microneedle (10) is inverted on the hollow gasket and each needle tip of the first microneedle (10) is aligned with the center of each unit in the lattice of the second microneedle (20). Ultraviolet crosslinking causes the double bonds at the ends of the pre-crosslinked polymer A and the pre-crosslinked polymer B to undergo a crosslinking reaction under the action of an initiator, forming a covalent bond connection. The first microneedle (10) and the second microneedle (20) are combined and peeled off to obtain a microneedle (30) with a composite structure. Hot pressing deformation and low temperature cooling fixation: The microneedle (30) with composite structure is upside down in a relatively large conical microporous template (400) and its microneedle corresponds to the conical micropore. The microneedle is hot pressed and deformed by a hot press, so that the microneedle (30) with composite structure is deformed into the target shape in the conical microporous template (400). Then, the temporary shape is fixed by low temperature cooling to obtain the composite microneedle (40). The pre-crosslinked polymer A and / or pre-crosslinked polymer B are shape memory polymers, which expand and recover their shape when the molecular chains are at a temperature of 37℃-42℃, and crystallize or fix their shape when the temperature is 0-25℃.

2. The method for preparing a composite microneedle with microscopic shape memory properties according to claim 1, characterized in that, It also includes the steps of preparing pre-crosslinked polymer A and / or pre-crosslinked polymer B: Using polyethylene glycol as a primer, lactic acid, ε-caprolactone, or lactide as monomers, and stannous chloride or stannous octoate as a catalyst, a ring-opening copolymerization method is adopted. The catalyst initiates the ring-opening of the monomers, which then undergo a copolymerization reaction with the hydroxyl groups of polyethylene glycol to obtain polyethylene glycol-lactic acid copolymers, polyethylene glycol-caprolactone copolymers, or polyethylene glycol-lactide. Double bonds are grafted onto the ends of the copolymers obtained in the above steps via esterification or alcoholysis. The product is then precipitated by anhydrous diethyl ether and dried under vacuum to obtain polyethylene glycol-lactic acid, polyethylene glycol-caprolactone, or polyethylene glycol-lactide with double bond ends. Vacuum drying to constant weight yields pre-crosslinked polymer A and / or pre-crosslinked polymer B.

3. The method for preparing a composite microneedle with microscopic shape memory properties according to claim 1, characterized in that: The pre-crosslinked polymer A and pre-crosslinked polymer B are two polymers with different molecular weights and different degradation times, and the drug A and drug B are two drugs with different degradation times.

4. The method for preparing a composite microneedle with microscopic shape memory properties according to claim 1, characterized in that: The micropores of the first silicon wafer template (100) are conical or cylindrical, with a depth of 200-300 μm and an orifice diameter of 100-150 μm.

5. The method for preparing a composite microneedle with microscopic shape memory properties according to claim 4, characterized in that: The micropores of the second silicon wafer template (200) are cylindrical, hemispherical, or conical, with a depth of 100-200 μm and an orifice diameter of 200-300 μm. The positions of the micropore axes of the second silicon wafer template (200) correspond to the positions of the micropore axes of the first silicon wafer template (100).

6. The method for preparing a composite microneedle with microscopic shape memory properties according to claim 1, characterized in that: In the hot pressing deformation and low temperature cooling fixation steps, when the material of the microneedle (30) with composite structure is an amorphous shape memory polymer, the hot pressing temperature is 45-55℃, the pressure is set to 1-2MPa, the pressure is maintained for 10-20min, and then the pressure is maintained to allow the conical microporous template (400) to cool down naturally.

7. The method for preparing a composite microneedle with microscopic shape memory properties according to claim 1, characterized in that: In the hot pressing deformation and low temperature cooling and fixing steps, when the material of the microneedles (30) with composite structure is a semi-crystalline shape memory polymer, the hot pressing temperature is 50-70℃, so that after the crystal melts, the material flows and fills the conical microporous template (400), the pressure is set to 1-2MPa, the pressure is maintained for 10-20min, and then it is cooled and fixed at a temperature of 0-25℃.

8. A composite microneedle prepared by the method for preparing a composite microneedle with microscopic shape memory properties as described in any one of claims 1-7.

9. A composite microneedle according to claim 8, characterized in that: The composite microneedle (40) is heated to 38-42°C after use to trigger the microstructure recovery of the composite microneedle (40).

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