CN115137963B

CN115137963B - Method for preparing microneedle patch by room-temperature 3D printing self-sustaining microneedle

Info

Publication number: CN115137963B
Application number: CN202110344161.2A
Authority: CN
Inventors: 李妍妍; 孔德圣
Original assignee: Nanjing University
Current assignee: Nanjing University
Priority date: 2021-03-31
Filing date: 2021-03-31
Publication date: 2023-08-08
Anticipated expiration: 2041-03-31
Also published as: CN115137963A

Abstract

The invention discloses a method for preparing a microneedle patch by using a room-temperature 3D printing self-sustaining microneedle, which comprises the steps of extruding a microneedle generating material from a needle head under the action of pressure, and stacking the microneedle generating material on a microneedle patch substrate; after the pressure is removed, the needle head lifts the microneedle generating material upwards to form a needle point structure of the microneedle, and the needle point structure is maintained all the time before solidification and molding; wherein the microneedle generating material is a non-newtonian fluid slurry with solid-liquid transition and shear thinning, and the creep point is greater than 100Pa. The invention can realize the requirement of printing high-precision microneedle tips at room temperature in a high-efficiency manner under the condition of no need of templates and post-treatment; the printed microneedle tip structure has self-sustaining property, and can be maintained until subsequent curing and forming under the conditions of no need of externally applied temperature field, magnetic field and crosslinking and curing.

Description

Method for preparing microneedle patch by room-temperature 3D printing self-sustaining microneedle

Technical Field

The invention belongs to the technical field of microneedle patch processing, and particularly relates to a method for preparing a microneedle patch by using a room-temperature 3D printing self-sustaining microneedle.

Background

The microneedle therapy technology has been widely focused and developed in recent years due to its characteristics of painless, small wound, safety, reliability, high therapeutic efficiency, simple operation, and the like. At present, the microneedle patch preparation technology mainly adopts a template method, and the technology is complex and tedious. The size, the shape and the number of the micro-needles of the micro-needle patch are difficult to flexibly and conveniently adjust due to the template preparation method, and the preparation requirement of personalized custom-made micro-needle patches is difficult to meet. On the other hand, since the template method is to pour the microneedle slurry loaded with the drugs into the micro-template at one time for centrifugal pouring, the microneedles based on different materials or loaded with different drugs are difficult to be integrated in the same patch conveniently, which is not beneficial to realizing the multifunctional integration in the patch.

Three-dimensional printing technology is an additive manufacturing technology which is emerging in recent years, and has revolutionary significance in the field of processing and manufacturing. The three-dimensional printing technology is based on a digital model, and the final machined part is obtained through directly manufacturing a corresponding three-dimensional structure and then subsequent curing and forming (photo-curing, high-temperature curing, drying and curing and the like), so that personalized customization is realized. The three-dimensional printing technology is adopted to prepare the microneedle patch, and the physical template does not need to be processed in advance, so that the size of the microneedle patch, the number of microneedles, the distance and other design parameters can be conveniently and flexibly controlled. One of the core challenges of three-dimensional printing microneedles is how to print out high quality needle shapes and how to maintain the shape stability of the microneedles during curing, as compared to template methods that rely on templates to determine the shape of the microneedles, which form high quality microneedles after curing of the slurry. The processing of microneedle patches has typical trans-scale features, the tip portion needs to meet the accuracy of less than 10 microns to penetrate the stratum corneum of the skin relatively easily, the height of the microneedles is typically between 500 microns and 1000 microns to meet the requirements for drug delivery or biosensing, the diameter of the microneedle chassis is typically between 200 microns and 500 microns, and the spacing between the microneedles is typically between a few hundred microns and a few millimeters, so that the accuracy and efficiency are both sufficient to produce microneedles in a 3D printing manner. If the general direct writing forming technology is adopted to print the micro-needles, the micro-needle tip structure is formed by printing the micro-needles layer by using the printing head, and the micro-needle tip structure is limited by the aperture size of the needle head, so that the high-precision micro-needle patch is difficult to prepare. If a high-precision 3D printer is used for printing the micro-needles, for example, three-dimensional printing photo-curing molding needs to use laser spots to scan point by point so as to solidify the liquid photosensitive material, although the problem of the precision of the direct-writing molding technology is solved, the molding efficiency is low, and the technical application is limited. Therefore, it is difficult to efficiently prepare high-precision microneedles by conventional 3D printing technology, researches and patents are made on the basis of the conventional 3D printing technology in combination with post-treatment process to form needle-like structures, a typical method firstly prints a columnar array, then contacts the top end of the columnar array with a glass slide and stretches to a predetermined height to generate the tips of the microneedles, thus solving the problem of low precision of conventional 3D printing, but in order to make the generated tips of the microneedles have self-sustained property before drying, the method must be immediately crosslinked and cured, and then the microneedles are continuously cured and molded by natural dehydration. Although the precision of the formed micro-needle is high, the formation of the micro-needle tip structure needs to be subjected to two steps of printing a columnar structure and stretching a glass slide, and the micro-needle tip structure before the micro-needle is dried needs to be immediately solidified by means of additional crosslinking after the micro-needle is formed, so that the process is complex and harsh, and the processing efficiency is low. Still other studies have proposed printing columnar arrays first and forming microneedle tip structures by chemical etching after the array has dried. Although the defect that the method needs to immediately crosslink and solidify to stabilize the microneedle tip structure is overcome, the precision of the microneedle tip structure formed by chemical etching is not high, and the needle body is rough. At present, the patent or research process for forming the microneedle tip structure by post-treatment is complicated and low in efficiency, and the problems of precision and efficiency of microneedle printing are not well solved, so that research and development directions for forming the microneedle tip structure by direct printing are proposed by some researches and patents. The mode of directly printing to form the micro-needle tip structure includes the low-precision direct writing forming technology and the low-efficiency light curing forming technology, and also includes hot drawing needle, cold drawing needle, magnetic drawing needle and other technological schemes. In order to solve the problems of precision and efficiency, the printer needs to be modified by the hot pull needle, the cold pull needle and the magnetic pull needle, and corresponding hardware modules are added, so that higher requirements are put forward on equipment, and meanwhile, each mode can bring new technical defects. In the hot drawing method, sucrose, PLGA and other materials suitable for preparing the micro-needle are heated to a molten state, drawing and needle drawing are carried out, and a micro-needle structure is formed under the action of temperature gradient. The mode has higher precision and higher efficiency, but the microneedle material forms a molten state due to the high temperature of hundreds of DEG C, so that the risk of influencing the performance of the medicament exists, and the mode is not suitable for loading the medicament with poor thermal stability. The cold drawing needle is designed to solve the problem that the operation temperature of the hot drawing needle is too high, the water-soluble microneedle material is prepared into an aqueous solution, the temperature of a substrate is low enough, after slurry contacts the substrate, the fluidity of the slurry is poor, the slurry is slowly transferred to a needle point, and the microneedle structure is formed by stretching. The microneedles need to be additionally frozen at low temperature to maintain the shape of the microneedles before dehydration curing and molding or the microneedle material must be crosslinked and cured to maintain the shape of the microneedles. The microneedle material of the cold-drawing needle is limited by water-soluble polymer or non-polymer pharmaceutic adjuvant, the temperature of the substrate needs to be controlled, and the problems of condensation, thermal expansion and cold contraction caused by temperature change also need to be solved. The magnetic pull needle is characterized in that magnetic particles are added into the micro needle slurry, and after the needle is pulled out, an external magnetic field is utilized to provide force to support, so that the structure of the needle body is maintained until the micro needle is slowly dried or solidified. The greatest disadvantage of magnetic pull needles is that the addition of magnetic particles is difficult to use to prepare degradable microneedles. In summary, the existing method for directly printing the microneedle structure in one step cannot print the microneedles with self-holding property at room temperature.

In short, existing methods either require additional post-processing steps (chemical etching, slide stretching plus cross-linking curing prior to drying curing) at both printing and curing steps, or require hardware modifications to the printer to provide additional temperature or magnetic fields. There is no suitable three-dimensional printing technology, and the high-precision microneedle tip structure can be efficiently printed at room temperature through a conventional 3D printer and a conventional 3D printing flow, namely, two steps of printing and curing and forming. In the field of microneedle patch preparation, a technology which is mild in processing conditions, simple in process, flexible in operation and strong in universality is lacking, so that the microneedle patch which is high in structural precision, personalized and customized and multifunctional can be conveniently and efficiently prepared.

Disclosure of Invention

This section is intended to outline some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section as well as in the description summary and in the title of the application, to avoid obscuring the purpose of this section, the description summary and the title of the invention, which should not be used to limit the scope of the invention.

The present invention has been made in view of the above and/or problems occurring in the prior art.

One of the purposes of the invention is to provide a method for preparing a microneedle patch by using a room-temperature 3D printing self-sustaining microneedle, which can realize the requirement of efficiently printing high-precision microneedle tips at room temperature without a template and post-treatment. The printed microneedle tip structure has self-sustaining property, and can be maintained until subsequent curing and forming under the conditions of no need of externally applied temperature field, magnetic field and crosslinking and curing.

In order to solve the technical problems, the invention provides the following technical scheme: a method for preparing a microneedle patch by using a room temperature 3D printing self-sustaining microneedle, which comprises the following steps of,

extruding the microneedle generating material from the needle head under the action of pressure, and accumulating the microneedle generating material on the microneedle patch substrate;

after the pressure is removed, the needle head lifts the microneedle generating material upwards to form a needle point structure of the microneedle, and the needle point structure is maintained all the time before solidification and molding;

wherein the microneedle generating material is a non-newtonian fluid slurry with solid-liquid transition and shear thinning, and the creep point is greater than 100Pa.

The solid-liquid transformation is characterized in that the fluid shows the solid-like rigidity characteristic without external force interference, but after the action of the external force with enough magnitude, the material is subjected to shearing stress which is larger than the yield point, and the sample shows the flowing liquid characteristic; shear thinning is characterized by a decrease in fluid viscosity with increasing shear rate.

Under the influence of air pressure, the slurry is converted from a quasi-solid state to a quasi-liquid state, the blockage is not generated when the slurry is smoothly extruded from a needle head, the air pressure is removed after printing is finished, the slurry is converted from the quasi-liquid state to the quasi-solid state, the rigidity characteristic of the solid is shown, and meanwhile, the creep point is more than 100Pa, so that the shape of the printed three-dimensional structure can be kept. When the pressure exceeds the critical pressure, the slurry is converted from solid-like to liquid so as to be smoothly extruded from the needle head. When the needle completes the discharging task, the air pressure drop is 0 (the air pressure is applied for 60-400 ms), the extruded slurry is stretched along with the lifting of the discharging needle (the lifting speed is 0.1-120 mm/s), the neck structure is formed, the slurry is finally broken at the neck structure, then the slurry is changed into quasi-solid from quasi-liquid in a very short time, and the pulled-out micro-needle base and micro-needle main structure are kept until solidification.

As a preferred embodiment of the method for preparing a microneedle patch by using a room temperature 3D printing self-sustaining microneedle according to the present invention, wherein: the microneedle generating material adjusts rheological property by adding fumed silica, and the addition amount of the fumed silica is 8-15 wt%.

As a preferred embodiment of the method for preparing a microneedle patch by using a room temperature 3D printing self-sustaining microneedle according to the present invention, wherein: the microneedle generating material is selected from one of water-soluble degradable material, slow-release degradable material and non-degradable material.

As a preferred embodiment of the method for preparing a microneedle patch by using a room temperature 3D printing self-sustaining microneedle according to the present invention, wherein: the water-soluble degradable material comprises one of a maltose/polyvinylpyrrolidone system and a sucrose/polyvinylpyrrolidone system;

the slow-release degradable material comprises one of a polylactic acid-glycolic acid copolymer system, a polylactic acid system and a polycaprolactone system;

the non-degradable material includes one of an epoxy resin system, a cellulose acetate system, and a polystyrene system.

As a preferred embodiment of the method for preparing a microneedle patch by using a room temperature 3D printing self-sustaining microneedle according to the present invention, wherein: adopting the polylactic acid-glycolic acid copolymer system, dissolving the polylactic acid-glycolic acid copolymer in a mixed solution of dimethyl sulfoxide and dioxane, and adding fumed silica to mix to form slurry;

wherein, the mass ratio of dimethyl sulfoxide to dioxane is 5:7, preparing a base material; the mass of the polylactic acid-glycolic acid copolymer is 20-50% of the total mass of dimethyl sulfoxide and dioxane; the mass of the fumed silica is 8-15% of the total mass of the polylactic acid-glycolic acid copolymer, dimethyl sulfoxide and dioxane.

As a preferred embodiment of the method for preparing a microneedle patch by using a room temperature 3D printing self-sustaining microneedle according to the present invention, wherein: dissolving maltose and polyvinylpyrrolidone in a mixed solution of dimethyl sulfoxide and dioxane by adopting the maltose/polyvinylpyrrolidone system, and adding fumed silica to mix to form slurry;

wherein the mass ratio of maltose to polyvinylpyrrolidone is 8:1, a step of; the mass ratio of dimethyl sulfoxide to dioxane is 5:7, preparing a base material; the mass of maltose is 40% of the total mass of dimethyl sulfoxide and dioxane; the mass of the fumed silica is 10% of the total mass of maltose, polyvinylpyrrolidone, dimethyl sulfoxide and dioxane.

As a preferred embodiment of the method for preparing a microneedle patch by using a room temperature 3D printing self-sustaining microneedle according to the present invention, wherein: uniformly mixing epoxy resin and fumed silica by adopting an epoxy resin system to obtain slurry;

wherein the mass ratio of the fumed silica to the epoxy resin is 0.15.

As a preferred embodiment of the method for preparing a microneedle patch by using a room temperature 3D printing self-sustaining microneedle according to the present invention, wherein: the microneedle generating material carries at least one bioactive or therapeutically active ingredient.

As a preferred embodiment of the method for preparing a microneedle patch by using a room temperature 3D printing self-sustaining microneedle according to the present invention, wherein: the needles may be one or more, and the needles are controlled by an operating program that determines the shape of the microneedles by adjusting the pressure and the stretching speed.

As a preferred embodiment of the method for preparing a microneedle patch by using a room temperature 3D printing self-sustaining microneedle according to the present invention, wherein: the extrusion operation may be performed two or more times, sequentially over the previous needle printed dot matrix, to form layered microneedles.

As a preferred embodiment of the method for preparing a microneedle patch by using a room temperature 3D printing self-sustaining microneedle according to the present invention, wherein: also included is a method of manufacturing a semiconductor device,

solidifying and molding the needle point structure formed by printing;

the curing and forming comprises one or more of natural volatilization, photo-curing and high-temperature curing.

Another object of the present invention is to provide a microneedle patch manufactured by the method for manufacturing a microneedle patch using a room temperature 3D printing self-sustaining microneedle as described above.

Compared with the prior art, the invention has the following beneficial effects:

the invention prepares the slurry with the characteristics of shear thinning and solid-liquid transformation by adding fumed silica into the slurry as a rheology modifier, and the creep point is more than 100Pa. The printing head is used for extruding the sizing agent, the sizing agent is lifted in the z direction of the printing head to stretch and draw silk, the micro-needle tip structure is formed at room temperature in one step and has self-sustaining property, no external force support is needed, and the tip structure of the liquid micro-needle can be always kept. The high-precision microneedle tips can be formed by one-step printing at room temperature without the need for templates and post-processing. After the end of the drawing, when the microneedle is still in a liquid state, the unique gas phase silicon dioxide proportion (8-15 wt%) of the invention can enable the liquid microneedle to have self-holding property under the conditions of no need of an external temperature field (a cold field or a hot field) and cross-linking curing, and the needle point structure of the microneedle can be kept until other drying and curing forming modes are adopted to form the final microneedle patch, so that the complexity of a processing system is greatly reduced.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the description of the embodiments will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art. Wherein:

FIG. 1 is a graph showing the results of a rheological test of a microneedle-generating material according to example 1 of the present invention; wherein, (a) is the viscosity as a function of shear rate and (b) is the storage modulus G 'and loss modulus G' as a function of shear stress.

FIG. 2 is a 3D printing process of embodiment 1 of the present invention; wherein, (a) is extrusion slurry, (b) is stretching to form a neck structure, (c) is breaking to form a microneedle, and (d) is curing and forming.

FIG. 3 is a graph showing the effect of printing conditions on the shape of microneedles in example 1 of the present invention; wherein, (a) is the shape of the microneedle printed when the air pressure is reduced from 600kPa to 300kPa at a printing speed of 5 mm/s; (b) At an air pressure of 500kPa, the printing speed was reduced from 10mm/s to 0.5mm/s, which was the shape of the microneedle printed.

FIG. 4 is a graph showing the shape of the microneedle prepared in example 2 of the present invention at a printing speed of 5mm/s and a printing air pressure of 300 kPa; wherein, (a) is a macro photograph of the shape of the micro needle, and (b) is a micro electron microscope photograph of the shape of the micro needle.

FIG. 5 is a graph showing the shape of the microneedle produced in example 2 of the present invention at a printing speed of 100mm/s and a printing air pressure of 300 kPa.

FIG. 6 is a graph showing the results of a rheological test of the microneedle generating material of example 2 of the present invention; wherein, (a) is the viscosity as a function of shear rate and (b) is the storage modulus G 'and loss modulus G' as a function of shear stress.

FIG. 7 is a graph showing the results of a rheological test of the microneedle generating material of example 3 of the present invention; wherein, (a) is the viscosity as a function of shear rate and (b) is the storage modulus G 'and loss modulus G' as a function of shear stress.

FIG. 8 is a graph showing the shape of the microneedle prepared in example 3 of the present invention.

FIG. 9 is a graphical representation of the shape of drug-loaded microneedles prepared in example 4 of the present invention.

Fig. 10 shows the mechanical test results of the drug-loaded microneedle patch and the drug-free patch prepared in example 4 of the present invention.

Fig. 11 is a release profile of a drug-loaded microneedle patch prepared according to example 4 of the present invention.

FIG. 12 is a shape chart of a water-soluble microneedle prepared in example 5 of the present invention.

FIG. 13 is a graph showing the results of a rheology test of the microneedle generating material of example 5 of the present invention; wherein, (a) is the viscosity as a function of shear rate and (b) is the storage modulus G 'and loss modulus G' as a function of shear stress.

FIG. 14 is a diagram of the shape of a vertically segmented microneedle prepared according to example 6 of the present invention.

FIG. 15 is a diagram showing the shape of an integrated microneedle patch according to example 7 of the present invention; wherein, (a) is an integrated microneedle patch shape diagram after printing is finished, and (b) is an integrated microneedle patch shape diagram after curing and forming.

FIG. 16 is a shape chart of a microneedle patch prepared in example 8 of the present invention.

FIG. 17 is a shape chart of a microneedle patch prepared in example 9 of the present invention.

FIG. 18 is a diagram showing the shape of the microneedle patches prepared in examples 10-13 of the present invention; wherein, (i) is the microneedle patch shape prepared in example 10, (ii) is the microneedle patch shape prepared in example 11, (iii) is the microneedle patch shape prepared in example 12, and (iv) is the microneedle patch shape prepared in example 13.

Detailed Description

In order that the above-recited objects, features and advantages of the present invention will become more apparent, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings.

In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.

Further, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic can be included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.

The invention provides a processing method for preparing a microneedle patch by utilizing three-dimensional printing, which is characterized in that slurry is extruded through a printing head, the slurry is stretched and drawn by lifting the printing head in the z direction, and the requirement of high-efficiency printing of high-precision microneedle tips at room temperature can be met under the condition that a template and post-treatment are not needed. The printed microneedle tip structure has self-sustaining property, and can be maintained until subsequent curing and forming under the conditions of no need of externally applied temperature field, magnetic field and crosslinking and curing. Meanwhile, the size of the microneedle patch can be flexibly and rapidly changed according to actual requirements, and the distance between the microneedles and the quantity of the microneedles can be used for preparing the personalized microneedle patch. In addition, the invention combines a multi-head printer, can efficiently and conveniently integrate the micro-needles with different materials and different medicines into the same micro-needle patch to prepare the multifunctional integrated micro-needle patch. The invention has wide applicability, can be used for printing water-soluble microneedles, degradable microneedles and nondegradable microneedles, and the subsequent curing process comprises natural volatilization, photo-curing and high-temperature curing. The printed microneedle patch has a double-layer needle structure in the vertical direction, and is divided into a microneedle base without medicine loading and a microneedle body part with medicine loading, so that the waste of medicine is reduced, and the medicine feeding efficiency is improved.

The length and width of the microneedle patch substrate are selected to be 8mm by 0.2mm (the length and width parameters of the microneedle substrate are adjustable), the diameter of the microneedle chassis is selected to be 300-500 micrometers, the height of the microneedle is selected to be 500-1200 micrometers, and the center-to-center distance of the microneedle is selected to be 500-1000 micrometers (the parameters of the microneedle array are also adjustable).

Example 1

(1) Preparing a microneedle generating material: PLGA (polylactic acid-glycolic acid copolymer) is dissolved in the mixed solution of dimethyl sulfoxide and dioxane, and is magnetically stirred for half an hour to form a uniform solution; wherein m (dimethyl sulfoxide): m (dioxane) =5: 7, m (PLGA): m (dimethyl sulfoxide+dioxane) =0.4; adding fumed silica serving as a rheology modifier into the solution, and forming uniform slurry by rotating for 5 minutes through a planetary mixer, namely generating a material by micro needles; wherein m (fumed silica): m (plga+dimethyl sulfoxide+dioxane) =0.1.

Through rheological tests, as shown in fig. 1, the shear speed is increased from 0.01/s to 200/s, and the viscosity is reduced from 830Pa.s to 0.024668 Pa.s, which means that the slurry has obvious shear thinning property, so that the viscosity of the slurry is rapidly reduced when the slurry is externally applied with air pressure, and the slurry can be smoothly extruded from a needle head under relatively small air pressure without blockage. Through rheological tests, the creep point is 360Pa, below which the storage modulus curve is above the loss modulus curve, indicating that the slurry is now in a solid-like form without fluidity, and above which the storage modulus curve is below the loss modulus curve, indicating that the slurry is now in a liquid-like form, can be extruded from the needle and pulled.

(2) 3D prints microneedle structure: transferring the slurry to a 10ml dispensing syringe, and placing the dispensing syringe at a No. 1 printing position for printing the micro-needle; inputting program parameters, setting printing speed and printing air pressure, printing micro-needles on a PVP/PVA flexible substrate by using an extrusion type 3D printer (dispensing machine), taking down a dispensing needle cylinder after printing, and reserving a printing position;

wherein the air pressure is adjusted to increase from 300kPa to 600kPa at a speed of 5 mm/s; at an air pressure of 500kPa, the adjustment speed was increased from 0.5mm/s to 10mm/s, and the effect of the printing conditions on the microneedle shape was examined.

As shown in fig. 2, the printing process may be subdivided into (a) extruding the slurry, extruding the microneedle generating material from the needle under the action of the printing air pressure, and stacking the microneedle generating material on the microneedle patch substrate; (b) Stretching to form a neck structure, and lifting the microneedle generating material upwards by the needle head according to the printing speed to form the neck structure; (c) Breaking to form a microneedle, and breaking the microneedle generating material at the neck structure to form a needle point structure of the microneedle; the method has the advantages that no post-treatment is needed in the microneedle forming process, no additional slide glass stretching is needed, no additional chemical etching is needed, the microneedle structure is formed in one step, no additional crosslinking curing is needed before the microneedle is cured and molded, no additional temperature field is needed, and the microneedle shape can be maintained until the subsequent curing and molding of (d) is performed.

As shown in fig. 3, when the printing speed is 5mm/s, fig. 3 (a) shows the shape of the microneedle printed when the air pressure is reduced from 600kPa to 300kPa from left to right, and it can be seen that the diameter of the microneedle base becomes smaller as the printing air pressure is reduced; in FIG. 3 (b), the air pressure was 500kPa, and the shape of the microneedles printed when the printing speed was reduced from 10mm/s to 0.5mm/s from left to right, it was found that the height of the microneedles increased as the printing speed increased.

(3) And (5) placing the printed microneedle patch into a vacuum drying barrel for drying for 48 hours, and transferring the microneedle patch into a drying cabinet for storage. As shown in fig. 2 (d) and 3, the size of the micro-needle is further reduced and the precision is further improved along with the evaporation of the solvent in the process of curing and drying the micro-needle, but the shape of the micro-needle is basically maintained.

Example 2

(1) Preparing a microneedle generating material: PLGA (polylactic acid-glycolic acid copolymer) is dissolved in the mixed solution of dimethyl sulfoxide and dioxane, and is magnetically stirred for half an hour to form a uniform solution; wherein m (dimethyl sulfoxide): m (dioxane) =5: 7, m (PLGA): m (dimethyl sulfoxide+dioxane) =0.2 to 0.5; adding fumed silica serving as a rheology modifier into the solution, and rotating for 5 minutes by a planetary mixer to form uniform slurry, namely a microneedle generating material, wherein 0.01 weight percent of Sudan dye is additionally added into the slurry for facilitating photographing and observation; wherein m (fumed silica): m (plga+dimethyl sulfoxide+dioxane) =0.05.

(2) 3D prints microneedle structure: transferring the slurry to a 10ml dispensing syringe, and placing the dispensing syringe at a No. 1 printing position for printing the micro-needle; inputting program parameters, setting printing speed and printing air pressure, printing micro-needles on the PVP/PVA flexible substrate by using an extrusion type 3D printer (dispensing machine), taking down a dispensing needle cylinder after printing, and leaving a printing position.

Through researches, the printing parameters are traversed, the printing speed (0.1 mm/s-120 mm/s) and the printing air pressure (0-600 kPa) are set, finally, the printing parameters of the sample in the figure 4 are the printing speed of 5mm/s and the printing air pressure of 300kPa, the printing parameters of the sample in the figure 5 are the printing speed of 120mm/s and the printing air pressure of 300kPa, and the high-precision micro-needles are difficult to print on the PVP/PVA flexible substrate.

Although the shape of the micro needle can be printed, the self-sustaining property is insufficient due to insufficient addition of the rheology regulator, after the slow needle drawing is finished, the micro needle is seriously contracted under the action of surface tension, so that the diameter of the tip of the micro needle is enlarged, the tip of the micro needle becomes blunt, and the requirement that the tip of the micro needle is below 10 microns is difficult to meet. After the quick needle pulling is finished, the formed micro needle is longer, and the needle point is bent and cannot stand upright. Through rheological tests, as shown in fig. 6, the shearing speed is increased from 0.01/s to 200/s, and the viscosity is reduced from 3907Pa.s to 200Pa.s, which means that the slurry has obvious shearing and thinning properties, so that the viscosity of the slurry is rapidly reduced when the slurry is externally applied with air pressure, and the slurry can be smoothly extruded from a needle head under relatively small air pressure without blocking. Through rheological tests, the creep point is 45Pa, below the creep point, the storage modulus curve is above the loss modulus curve, which indicates that the slurry is in a solid-like form and has no fluidity, above the creep point, the storage modulus curve is below the loss modulus curve, which indicates that the slurry is in a liquid-like form and can be extruded from a needle and stretched for needle drawing, but the creep point is too low, the printed micro needle has no self-holding property and can retract under the action of surface tension, so that the needle becomes dull or the needle bends.

Example 3

(1) Preparing a microneedle generating material: PLGA (polylactic acid-glycolic acid copolymer) is dissolved in the mixed solution of dimethyl sulfoxide and dioxane, and is magnetically stirred for half an hour to form a uniform solution; wherein m (dimethyl sulfoxide): m (dioxane) =5: 7, m (PLGA): m (dimethyl sulfoxide+dioxane) =0.4.

Through researches, traversing printing parameters, setting printing speed (0.1 mm/s-120 mm/s) and printing air pressure (0-600 kPa), and printing micro-needles on PVP/PVA flexible substrates, wherein high-precision micro-needles are difficult to print.

The shear rate increases from 0.01/s to 200/s and the viscosity decreases from 12.28pa.s to 6.4pa.s, as shown in fig. 7, and it is believed that the slurry does not have the property of shear thinning, the slurry is always in a low viscosity state, the air pressure required for printing is very small, 30kPa can be extruded from the needle, the printed structure can easily flow, and the storage modulus curve is always below the loss modulus curve, as shown in fig. 8, through the rheological test, without creep point, which means that the slurry is always in a liquid form, although the slurry can be extruded from the needle and drawn by drawing, but without creep point, the printed microneedle has no self-holding property and can be retracted rapidly and seriously under the action of surface tension to become a hemisphere, as shown in fig. 8.

Example 4

(1) Preparing a microneedle generating material: PLGA (polylactic acid-glycolic acid copolymer) and DOX (doxorubicin hydrochloride) are dissolved in a mixed solution of dimethyl sulfoxide and dioxane, and the mixed solution is magnetically stirred for half an hour to form a uniform solution; wherein m (dimethyl sulfoxide): m (dioxane) =5: 7, m (PLGA): m (dimethyl sulfoxide+dioxane) =0.4, m (DOX): m (PLGA) =0.25; adding fumed silica serving as a rheology modifier into the solution, and forming uniform slurry by rotating for 5 minutes through a planetary mixer, namely generating a material by micro needles; wherein m (fumed silica): m (plga+dimethyl sulfoxide+dioxane) =0.1.

(2) 3D prints microneedle structure: transferring the slurry to a 10ml dispensing syringe, and placing the dispensing syringe at a No. 1 printing position for printing the micro-needle; inputting program parameters, setting printing speed of 5mm/s and printing air pressure of 500kPa, printing micro-needles on a PVP/PVA flexible substrate by using an extrusion type 3D printer (dispensing machine), taking down a dispensing needle cylinder after printing, and leaving a printing position.

As shown in fig. 9, DOX was added as a simulated drug to print out high-precision microneedles.

(3) And (5) placing the printed microneedle patch into a vacuum drying barrel for drying for 48 hours, transferring to a drying cabinet for storage, and taking the microneedle patch when needed.

The mechanical tests of the drug-loaded microneedle patch and the drug-unloaded patch are respectively carried out, as shown in fig. 10, and the results show that the mechanical properties of the microneedles are reduced after the drugs are added, but the requirements of more than 0.03N/needle are met. Drug loaded microneedles were placed in PBST buffer and the release profile measured. As shown in fig. 11, the slow release period was 15 days.

Example 5

(1) Preparing a microneedle generating material: dissolving maltose and PVP (polyvinylpyrrolidone) in a mixed solution of dimethyl sulfoxide and dioxane, and magnetically stirring for half an hour to form a uniform solution; wherein m (maltose): m (PVP) =8: 1, m (dimethyl sulfoxide): m (dioxane) =5: 7, m (maltose): m (dimethyl sulfoxide+dioxane) =0.4; adding fumed silica as a rheology modifier, and rotating a planetary mixer for 5 minutes to form uniform slurry, namely a microneedle generating material; wherein m (fumed silica): m (maltose+pvp+dimethyl sulfoxide+dioxane) =0.1.

(2) 3D prints microneedle structure: transferring the slurry to a 10ml dispensing syringe, and placing the dispensing syringe at a No. 1 printing position for printing the micro-needle; inputting program parameters, setting printing speed of 2mm/s and printing air pressure of 550kPa, printing micro-needles on a PVP/PVA flexible substrate by using an extrusion type 3D printer (dispensing machine), taking down a dispensing needle cylinder after printing, and leaving a printing position.

As shown in fig. 12, high-precision water-soluble microneedles were printed.

Through rheological tests, as shown in FIG. 13, the shearing speed is increased from 0.01/s to 200/s, and the viscosity is reduced from 82290Pa.s to 200Pa.s, which means that the slurry has obvious shearing and thinning properties, so that the viscosity of the slurry is rapidly reduced when the slurry is externally applied with air pressure, and the slurry can be smoothly extruded from a needle head under relatively small air pressure without blocking. Through rheological tests, the creep point is 1113Pa, below the creep point, the storage modulus curve is above the loss modulus curve, the slurry is in a solid-like form and has no fluidity, above the creep point, the storage modulus curve is below the loss modulus curve, the slurry is in a liquid form, the slurry can be extruded from a needle head and drawn into the needle, the creep point reaches 1113Pa, and the printed micro needle has self-sustaining property.

Example 6

(1) Preparing a microneedle base generating material: dissolving maltose and PVP (polyvinylpyrrolidone) in a mixed solution of dimethyl sulfoxide and dioxane, adding fumed silica as a rheology modifier, and rotating a planetary stirrer for 5 minutes to form uniform slurry, namely a microneedle base generating material; wherein m (maltose): m (PVP) =8: 1, m (dimethyl sulfoxide): m (dioxane) =5: 7, m (maltose): m (dimethyl sulfoxide+dioxane) =0.4, m (fumed silica): m (maltose+pvp+dimethyl sulfoxide+dioxane) =0.1.

(2) Preparing a microneedle generating material: dissolving PLGA (polylactic acid-glycolic acid copolymer) in a mixed solution of dimethyl sulfoxide and dioxane, adding fumed silica as a rheology regulator, adding DOX (doxorubicin) with a certain proportion as a model drug, and rotating for 5 minutes by a planetary mixer to form uniform slurry, namely a microneedle generating material; wherein m (dimethyl sulfoxide): m (dioxane) =5: 7, m (PLGA): m (dimethyl sulfoxide+dioxane) =0.4 m (fumed silica): m (plga+dimethyl sulfoxide+dioxane) =0.1.

(3) 3D prints microneedle base: transferring the microneedle base generating material into a 10ml dispensing syringe, and placing the dispensing syringe at a No. 1 printing position for printing the microneedle base; program parameters are input, the printing speed is set to be 1mm/s, the printing air pressure is set to be 550kPa, and a microneedle base without medicine carrying is printed on a PVP/PVA flexible substrate by using an extrusion type multi-head 3D printer (multi-head dispensing machine).

(4) 3D printing microneedle: transferring the microneedle generating material into a 10ml dispensing needle cylinder, placing the dispensing needle cylinder at a No. 2 printing position, inputting program parameters, setting the printing speed of 5mm/s and the printing air pressure of 550kPa, calibrating the coordinates of each printing position by utilizing a microscope alignment technology, and continuously printing the microneedle bodies loaded with the medicaments on a microneedle base without carrying the medicaments by utilizing an extrusion type multi-head 3D printer (multi-head dispensing machine) at the No. 2 position.

As shown in fig. 14, high precision vertically segmented microneedles were printed.

(5) And (5) placing the printed microneedle patch into a vacuum drying barrel for drying for 48 hours, transferring to a drying cabinet for storage, and taking the microneedle patch when needed.

Example 7

(2) Preparing a microneedle generating material: dissolving PLGA (polylactic acid-glycolic acid copolymer) in a mixed solution of dimethyl sulfoxide and dioxane, adding fumed silica as a rheology regulator, adding DOX (doxorubicin) as a model drug I, and rotating for 5 minutes by a planetary mixer to form uniform slurry, namely a drug I microneedle generating material; wherein m (dimethyl sulfoxide): m (dioxane) =5: 7, m (PLGA): m (dimethyl sulfoxide+dioxane) =0.4, m (fumed silica): m (plga+dimethyl sulfoxide+dioxane) =0.1.

(3) Preparing a microneedle generating material: dissolving maltose and PVP (polyvinylpyrrolidone) in a mixed solution of dimethyl sulfoxide and dioxane, adding fumed silica as a rheology regulator, adding ICG (indocyanine green) as a model drug II, and rotating a planetary mixer for 5 minutes to form uniform slurry, namely a drug II microneedle generating material; wherein m (maltose): m (PVP) =8: 1, m (dimethyl sulfoxide): m (dioxane) =5: 7, m (maltose): m (dimethyl sulfoxide+dioxane) =0.4, m (fumed silica): m (maltose+pvp+dimethyl sulfoxide+dioxane) =0.1.

(4) 3D prints microneedle base: transferring the microneedle base generating material into a 10ml dispensing syringe, and placing the dispensing syringe at a No. 1 printing position for printing the microneedle base; inputting program parameters, setting printing speed to be 1mm/s and printing air pressure to be 550kPa, and printing a microneedle base without medicine carrying on a PVP/PVA flexible substrate by using an extrusion type multi-head 3D printer (multi-head dispensing machine).

(5) 3D printing microneedle: transferring the micro-needle generating material of the medicine I into a 10ml dispensing syringe, and placing the dispensing syringe at a No. 2 printing position; transferring the drug II microneedle generating material into a 10ml dispensing syringe, and placing the dispensing syringe at a number 3 printing position; program parameters are input, the printing speed is set to be 5mm/s, the printing air pressure is set to be 550kPa, the coordinate of each printing position is calibrated by utilizing a microscope alignment technology, and the 2-bit and 3-bit microneedle bodies loaded with the medicines are continuously printed on the microneedle bases without the medicines by utilizing an extrusion type multi-head 3D printer (multi-head dispensing machine).

As shown in fig. 15, an integrated microneedle patch was printed, and it can be seen that microneedles of two drugs were integrated on one microneedle patch, the types of microneedles were slow release and fast dissolving microneedles, respectively, while each of the needles had a vertically segmented structure, divided into a base portion not carrying a drug and a microneedle portion carrying a drug.

(6) And (5) placing the printed microneedle patch into a vacuum drying barrel for drying for 48 hours, transferring to a drying cabinet for storage, and taking the microneedle patch when needed.

Example 8

(1) Preparing a microneedle generating material: uniformly mixing VP (1-vinyl-2-pyrrolidone), a free radical initiator (azodiisobutyronitrile) and fumed silica, and rotating a planetary mixer for 5 minutes to form uniform slurry, namely a microneedle generating material; wherein m (fumed silica): m (VP) =0.1, m (radical initiator): m (VP) =0.01.

(2) 3D printing microneedle: transferring the microneedle generating material into a 10ml dispensing syringe, placing the dispensing syringe at a No. 1 printing position, inputting program parameters, setting printing speed of 5mm/s and printing air pressure of 450kPa, and printing the microneedles on a PVP/PVA flexible substrate at room temperature by using an extrusion type 3D printer (dispensing machine). And after printing, the dispensing needle cylinder is taken down, and a printing position is left.

(3) Irradiating with ultraviolet lamp at room temperature for half an hour to solidify the microneedle, transferring to a drying cabinet, and storing for use when required.

As shown in fig. 16, the overall morphology of the microneedle array and the morphology of individual microneedles were observed. The result shows that the microneedle patch prepared by 3D printing has complete appearance, conical microneedle, smooth appearance, complete structure and about 800 microns in height. Mechanical tests were performed and the results showed that the requirements of greater than 0.03N/needle were met.

Example 9

(1) Preparing a microneedle generating material: uniformly mixing epoxy resin and fumed silica, and rotating a planetary stirrer for 5 minutes to form uniform slurry, namely a microneedle generating material; wherein m (fumed silica): m (epoxy) =0.15.

(2) 3D printing microneedle: transferring the microneedle generating material into a 10ml dispensing syringe, placing the dispensing syringe at a No. 1 printing position, inputting program parameters, setting printing speed of 5mm/s and printing air pressure of 550kPa, and printing the microneedles on a PVP/PVA flexible substrate at room temperature by using an extrusion type 3D printer (dispensing machine). And after printing, the dispensing needle cylinder is taken down, and a printing position is left.

(3) Heating the oven at 180 ℃ for 2 hours to solidify the micro-needles, transferring the micro-needles into a drying cabinet for storage, and taking the micro-needles when needed.

As shown in fig. 17, the overall morphology of the microneedle array and the morphology of individual microneedles were observed. The result shows that the microneedle patch prepared by 3D printing has complete appearance, conical microneedle, smooth appearance, complete structure and about 500 microns in height. Mechanical tests were performed and the results showed that the requirements of greater than 0.03N/needle were met.

Example 10

(1) Preparing a microneedle generating material: dissolving PLA (polylactic acid) in a mixed solution of dimethyl sulfoxide and dioxane, and magnetically stirring for half an hour to form a uniform solution; wherein m (dimethyl sulfoxide): m (dioxane) =7: 5, m (PLA): m (dimethyl sulfoxide+dioxane) =0.4; adding fumed silica as a rheology modifier, and rotating a planetary mixer for 5 minutes to form uniform slurry, namely a microneedle generating material; wherein m (fumed silica): m (pla+dimethyl sulfoxide+dioxane) =0.12.

(2) 3D prints microneedle structure: transferring the slurry to a 10ml dispensing syringe, and placing the dispensing syringe at a No. 1 printing position for printing the micro-needle; inputting program parameters, setting printing speed of 20mm/s and printing air pressure of 400kPa, printing micro-needles on a PVP/PVA flexible substrate by using an extrusion type 3D printer (dispensing machine), taking down a dispensing needle cylinder after printing, and leaving a printing position.

As shown in fig. 18 (i), the overall morphology of the microneedle array and the morphology of individual microneedles were observed. The result shows that the microneedle patch prepared by 3D printing has complete appearance, conical microneedle, smooth appearance, complete structure and about 500 microns in height. Mechanical tests were performed and the results showed that the requirements of greater than 0.03N/needle were met.

Example 11

(1) Preparing a microneedle generating material: dissolving PCL (polycaprolactone) in a mixed solution of DMF (N, N-dimethylformamide) and dioxane, and magnetically stirring for half an hour to form a uniform solution; wherein m (DMF): m (dioxane) =7: 5, m (PCL): m (dmf+dioxane) =0.3: 1, a step of; adding fumed silica as a rheology modifier, and rotating a planetary mixer for 5 minutes to form uniform slurry, namely a microneedle generating material; wherein m (fumed silica): m (pcl+dmf+dioxane) =0.12.

(2) 3D prints microneedle structure: transferring the slurry to a 10ml dispensing syringe, and placing the dispensing syringe at a No. 1 printing position for printing the micro-needle; inputting program parameters, setting printing speed to 10mm/s and printing air pressure to 350kPa, printing micro-needles on a PVP/PVA flexible substrate by using an extrusion type 3D printer (dispensing machine), taking down a dispensing needle cylinder after printing, and leaving a printing position.

As shown in fig. 18 (ii), the overall morphology of the microneedle array and the morphology of individual microneedles were observed. The result shows that the microneedle patch prepared by 3D printing has complete appearance, conical microneedle, smooth appearance, complete structure and about 500 microns in height. Mechanical tests were performed and the results showed that the requirements of greater than 0.03N/needle were met.

Example 12

(1) Preparing a microneedle generating material: dissolving CA (cellulose acetate) in a mixed solution of dimethyl sulfoxide and dioxane, and magnetically stirring for half an hour to form a uniform solution; wherein m (dimethyl sulfoxide): m (dioxane) =7: 5, m (CA): m (dimethyl sulfoxide+dioxane) =0.3: 1, a step of; adding fumed silica as a rheology modifier, and rotating a planetary mixer for 5 minutes to form uniform slurry, namely a microneedle generating material; wherein m (fumed silica): m (ca+dimethyl sulfoxide+dioxane) =0.12.

(2) 3D prints microneedle structure: transferring the slurry to a 10ml dispensing syringe, and placing the dispensing syringe at a No. 1 printing position for printing the micro-needle; inputting program parameters, setting printing speed to be 10mm/s and printing air pressure to be 550kPa, printing micro-needles on a PVP/PVA flexible substrate by using an extrusion type 3D printer (dispensing machine), taking down a dispensing needle cylinder after printing, and leaving a printing position.

As shown in fig. 18 (iii), the overall morphology of the microneedle array and the morphology of individual microneedles were observed. The result shows that the microneedle patch prepared by 3D printing has complete appearance, conical microneedle, smooth appearance, complete structure and about 500 microns in height. Mechanical tests were performed and the results showed that the requirements of greater than 0.03N/needle were met.

Example 13

(1) Preparing a microneedle generating material: PS (polystyrene) is dissolved in DMF (N, N-dimethylformamide) solution and stirred magnetically for half an hour to form a uniform solution; wherein m (PS): m (DMF) =0.3: 1, a step of; adding fumed silica as a rheology modifier, and rotating a planetary mixer for 5 minutes to form uniform slurry, namely a microneedle generating material; wherein m (fumed silica): m (ps+dmf) =0.12.

(2) 3D prints microneedle structure: transferring the slurry to a 10ml dispensing syringe, and placing the dispensing syringe at a No. 1 printing position for printing the micro-needle; inputting program parameters, setting printing speed of 120mm/s and printing air pressure of 300kPa, printing micro-needles on a PVP/PVA flexible substrate by using an extrusion type 3D printer (dispensing machine), taking down a dispensing needle cylinder after printing, and leaving a printing position.

As shown in fig. 18 (iv), the overall morphology of the microneedle array and the morphology of individual microneedles were observed. The result shows that the microneedle patch prepared by 3D printing has complete appearance, conical microneedle, smooth appearance, complete structure and about 500 microns in height. Mechanical tests were performed and the results showed that the requirements of greater than 0.03N/needle were met.

The invention has wide applicability, can be used for printing water-soluble microneedles, slow-release degradable microneedles and nondegradable microneedles, and the subsequent curing and forming process comprises natural volatilization, photo-curing and high-temperature curing. The printing condition is mild, the operation is simple and flexible and convenient, and the requirement of conveniently and flexibly printing biodegradable or dissolvable microneedle patches at room temperature can be met.

The microneedle patch preparation technology is mainly a template method, and the process is complex and tedious. Limited by template preparation, the size of the microneedle patch, and the shape and number of microneedles are difficult to flexibly and conveniently modify, and it is difficult to prepare personalized custom-made microneedle patches. The invention provides a processing method for preparing a microneedle patch by using a 3D direct-writing printer, which can flexibly and freely change the parameters of a program under the condition of not needing a template, thereby adjusting the distance between needles in the microneedle patch, the size of the whole microneedle patch, the total number of microneedles in the whole microneedle array and the proportion of different types of microneedles. The shape of the micro needle can be controlled within a certain range by controlling the printing air pressure and the printing speed, and the personalized and customized micro needle medicine carrying patch can be printed in time according to the treatment requirement of a patient.

The template method is to pour the microneedle slurry loaded with the drugs into a micro template for centrifugal pouring at one time, so that the microneedles of different materials loaded with different drugs are difficult to be integrated into the same microneedle patch efficiently and conveniently, and the multifunctional integrated microneedle patch is prepared. The invention can print the microneedles with different medicines made of the same material in the same microneedle patch by utilizing the multi-head direct-writing type 3D printer, and can also realize the printing of the microneedles with different materials, including water-soluble microneedles, slow-release degradable microneedles and non-degradable microneedles. Therefore, the types of medicines in the microneedle patch and the types of medicine release can be timely adjusted according to the treatment requirements of different patients in actual life, and the multifunctional integrated patch is prepared, so that great convenience is brought to the life of the patients.

According to the invention, the biocompatible material is dissolved in the solvent, the rheological property is controlled by utilizing the biodegradable fumed silica particles, the slurry is extruded, and the slurry is drawn and spun in one step to form the micro-needle, in addition, the diameter of the tip of the micro-needle is further reduced in the subsequent solvent drying process, so that the diameter of the tip of the prepared micro-needle is one order of magnitude smaller than the diameter of a printing head, the defect of insufficient precision of the tip of the traditional direct-writing 3D printing micro-needle is overcome, the trans-scale manufacturing is realized, and the painless minimally invasive drug delivery treatment by the micro-needle patch is facilitated.

The printed microneedle patch has a double-layer needle structure in the vertical direction, and is divided into a microneedle base without medicine loading and a microneedle body part with medicine loading, so that the waste of medicine is reduced, and the medicine feeding efficiency is improved.

It should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered in the scope of the claims of the present invention.

Claims

1. A method for preparing a microneedle patch by using a room temperature 3D printing self-sustaining microneedle, which is characterized by comprising the following steps: comprising the steps of (a) a step of,

the microneedle generating material adjusts rheological property by adding fumed silica, wherein the addition amount of the fumed silica is 8-15 wt%;

2. The method for preparing the microneedle patch by using the room temperature 3D printing self-sustaining microneedle according to claim 1, wherein: the microneedle generating material is selected from one of water-soluble degradable material, slow-release degradable material and non-degradable material.

3. The method for preparing the microneedle patch by using the room temperature 3D printing self-sustaining microneedle according to claim 2, wherein: the water-soluble degradable material comprises one of a maltose/polyvinylpyrrolidone system and a sucrose/polyvinylpyrrolidone system;

4. A method of preparing a microneedle patch with room temperature 3D printing self-sustaining microneedle according to claim 3, wherein: adopting the polylactic acid-glycolic acid copolymer system, dissolving the polylactic acid-glycolic acid copolymer in a mixed solution of dimethyl sulfoxide and dioxane, and adding fumed silica to mix to form slurry;

5. The method for preparing the microneedle patch by using the room temperature 3D printing self-sustaining microneedle according to claim 4, wherein: the microneedle generating material carries at least one bioactive or therapeutically active ingredient.

6. The method for preparing the microneedle patch by using the room temperature 3D printing self-sustaining microneedle according to any one of claims 1, 3, 4, wherein: the needles may be one or more, and the needles are controlled by an operating program that determines the shape of the microneedles by adjusting the pressure and the stretching speed.

7. The method for preparing the microneedle patch by using the room temperature 3D printing self-sustaining microneedle according to claim 1, wherein: the extrusion operation may be performed two or more times, sequentially over the previous needle printed dot matrix, to form layered microneedles.

8. A method of preparing a microneedle patch with room temperature 3D printing self-sustaining microneedle as defined in claim 1, wherein: also included is a method of manufacturing a semiconductor device,

solidifying and molding the needle point structure formed by printing;

9. A microneedle patch made by the method of making a microneedle patch using room temperature 3D printing self-sustaining microneedles according to any one of claims 1-8.