Flexible substrate-hard porous microneedle patch and preparation method and application thereof

Abstract

This invention discloses a flexible substrate-rigid porous microneedle patch, its preparation method, and its application, belonging to the field of medical material preparation technology. The porous microneedle patch prepared by this invention has a substrate and needles made of different materials. It employs a flexible, bendable, or stretchable porous substrate, which offers superior liquid absorption efficiency and storage capacity compared to a solid substrate. Its flexibility allows it to adapt to the bending and deformation of the skin, improving comfort during application. Simultaneously, the rigid porous microneedle body provides sufficient mechanical strength for penetrating the epidermis. The porous microneedle patch with a flexible porous substrate is prepared using a simple process combining a one-step lifting process at room temperature with solvent precipitation. This not only enables the rapid preparation of porous microneedles of different sizes and arrays but also allows for the rapid fabrication of large quantities of porous microneedles on substrates of any material.

Description

Technical Field

[0001] This invention belongs to the field of medical material preparation technology, specifically relating to a flexible substrate-rigid porous microneedle patch and its preparation method and application. Background Technology

[0002] Monitoring biomarkers is crucial for understanding health status and early disease diagnosis. Interstitial fluid (IFF) contains rich biological information and can be considered an ultrafiltrate of plasma. The concentrations of many small molecules and ions are similar to those in blood, and ISF extraction avoids the discomfort and potential infection risks associated with traditional blood sampling. Therefore, sampling and detecting biomarkers in ISF is of great significance for minimally invasive monitoring of patient health. Microneedles are micrometer-scale structures composed of three-dimensional microarrays with heights ranging from 25 to 2000 micrometers. Initially used primarily for percutaneous drug and vaccine delivery, microneedles have recently shown great potential in ISF extraction and biomarker detection. Microneedle tips are typically much sharper than subcutaneous injection needles. This geometry allows for effective penetration of the stratum corneum to create microscale ISF extraction channels without contacting blood vessels, nerve fibers, or their terminals, significantly reducing pain during collection.

[0003] Porous polymer microneedles, made from biocompatible and biodegradable materials, can actively absorb interstitial fluid through capillary action in their porous structure, without the need for negative pressure. Currently, porous polymer microneedles are mainly fabricated using templates combined with various post-processing techniques. The template method includes master mold preparation, negative mold preparation, solution casting, and curing / demolding. Hot pressing is a relatively simple technique for fabricating porous microneedles.

[0004] Patent CN 108404286 A utilizes a hot-pressing process of polymer materials to prepare gradient porous microneedles. However, due to uneven heating, most pores are located at the tips of the microneedles, while the pore distribution at the bottom is relatively small. This method makes the porous microneedles unsuitable for extracting interstitial fluid. A porogen leaching and phase separation process combines the traditional template method, utilizing porogen removal or solvent precipitation to form pores inside the microneedles.

[0005] Patent CN 110115707 A describes the preparation of porous microneedles by directly placing a mold containing a polymer solution into a poor solvent to induce solvent precipitation. However, this method not only retains the inherent limitations of the template method but also requires consideration of the solubility of the mold material, polydimethylsiloxane, in both solvents and poor solvents. While template-based porous microneedle preparation methods can achieve high-precision microneedle fabrication, they are costly, complex, and time-consuming. In the template method, the demolding process can also lead to technical problems such as microneedle breakage and blunting of the needle tip, thereby reducing the yield of microneedle patch processing. Furthermore, if microneedle patches of different shapes, sizes, and arrays are to be prepared, corresponding microneedle molds need to be remanufactured, making personalized microneedle preparation impossible.

[0006] 3D printing technology manufactures three-dimensional structures point-by-point or layer-by-layer through extrusion, sintering, or photopolymerization, enabling easy and flexible customization of fine structures and personalized shapes. Due to the complexity of porous structures, the fabrication of porous microneedles using 3D printing requires very high precision. Patent CN 114456334 A utilizes a conventional two-photon printer to fabricate arrayed porous microneedles by developing a novel photoinitiator. However, this method requires a long processing time, suffers from the toxicity of residual photoinitiators, and is limited to photocurable materials. Currently, various 3D printing technologies applied to microneedle fabrication struggle to balance precision and efficiency. Post-processing involves freezing, high temperatures, or external magnetic fields, which not only increases operational difficulty but may also affect the microneedle material.

[0007] Solid microneedle substrates significantly reduce the patch's absorbency; the pores of the porous microneedles alone cannot extract sufficient body fluid for testing. Most porous substrates are rigid, hindering good adhesion between the patch and the skin surface and affecting absorbency. Porous microneedle patches prepared using template-based direct phase separation typically have rigid substrates, making flexibility difficult. Patent CN 113440474 B prepared a porous microneedle patch with some flexibility; however, because the needles and substrate are made of the same material, it improves skin adhesion, but the mechanical strength of the microneedles is insufficient to penetrate the skin. Summary of the Invention

[0008] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0009] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0010] Therefore, the purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing a flexible substrate-rigid porous microneedle patch.

[0011] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a method for preparing a flexible substrate-rigid porous microneedle patch, characterized in that it includes:

[0012] Preparation of microneedle slurry: Cellulose acetate was dissolved in dimethyl sulfoxide to prepare a polymer solution. Fumed silica particles were added to the polymer solution and stirred until the silica particles were uniformly dispersed to obtain the microneedle slurry.

[0013] Printing microneedle structures: The prepared microneedle slurry is used to print microneedle structures on a flexible substrate using an automatic dispensing machine;

[0014] Preparation of porous microneedle patches: The processed microneedle structure is immersed in water and dried to prepare porous microneedle patches.

[0015] In a preferred embodiment of the preparation method described in this invention, the flexible substrate is modified filter paper or hydrophilic styrene thermoplastic elastomer.

[0016] As a preferred embodiment of the preparation method described in this invention, the modified filter paper is prepared by a method comprising:

[0017] A 15-20% (w / w) dimethyl sulfoxide solution of cellulose acetate is spin-coated onto the surface of filter paper at 1000-1500 rpm for 3-5 minutes, then immersed in water for 20-30 minutes, and finally removed and air-dried to obtain the modified filter paper.

[0018] As a preferred embodiment of the preparation method described in this invention, the hydrophilic styrene thermoplastic elastomer is prepared by a method comprising:

[0019] Prepare a toluene solution containing 15-18% by mass of styrene thermoplastic elastomer;

[0020] The toluene solution of the prepared styrene thermoplastic elastomer was mixed with salicylic acid particles at a mass ratio of 1:3, and the two were ball-milled for 3 hours to ensure thorough mixing, thus obtaining a slurry.

[0021] After the mixed slurry is coated with a scraper and dried naturally, the salicylic acid particles in the film are washed away with ethanol to obtain a styrene thermoplastic elastomer porous membrane.

[0022] Hydrophilic styrene thermoplastic elastomer was obtained by plasma treatment of porous styrene elastomer membrane for 5 minutes.

[0023] In a preferred embodiment of the preparation method described in this invention, the mass fraction of cellulose acetate in the microneedle slurry is 15-30%.

[0024] In a preferred embodiment of the preparation method described in this invention, the mass fraction of fumed silica particles in the microneedle slurry is 16-28%.

[0025] In a preferred embodiment of the preparation method described in this invention, the printed microneedle structure has a needle tube with a volume of 10 mL and an inner diameter of 0.3 mm on the automatic dispensing machine.

[0026] In a preferred embodiment of the preparation method described in this invention, the printed microneedle structure is configured with an air pressure of 400–600 kPa, a printing speed of 5–10 mm / s, and a distance of 200–400 micrometers.

[0027] Another objective of this invention is to overcome the shortcomings of the prior art and provide a flexible substrate-rigid porous microneedle patch.

[0028] Another objective of this invention is to overcome the shortcomings of the prior art and provide an application of microneedle patches in collecting interstitial fluid from organisms or in transdermal drug delivery.

[0029] Beneficial effects of this invention:

[0030] (1) The porous microneedle patch prepared in this invention has a base and needles made of different materials. The highly porous, flexible, bendable or stretchable base has capillary action and can spontaneously absorb liquid. This not only provides the porous microneedle patch with more liquid absorption and storage capacity, but also its flexible characteristics can better fit the skin surface, allowing more microneedles to penetrate the skin. At the same time, the rigid porous microneedles are beneficial to enhance the mechanical strength of the needles, thereby improving the ability to penetrate the stratum corneum of the epidermis. The rigid porous microneedles with high precision tips combined with the flexible base in this invention can largely avoid the incomplete penetration of the microneedle patch into the skin.

[0031] (2) This invention uses biocompatible polymer materials and a simple one-step vertical extrusion pulling process to form a microneedle structure with self-sustaining properties and sharp tips. By precipitating the solvent in the microneedle body, this simple and mild pore-forming technology can quickly form porous microneedles. Any flexible porous material can be used as a microneedle substrate after simple modification treatment, which greatly shortens the preparation process and time of porous polymer microneedles. It allows for the rapid production of a large number of porous microneedles without templates, thus eliminating the need for demolding, simplifying the process and improving the yield. This invention can quickly prepare flexible porous microneedle patches of different sizes and arrays through simple parameter adjustment, thereby adapting to the actual needs of the skin layer. Attached Figure Description

[0032] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein:

[0033] Figure 1 This is an optical micrograph of the modified filter paper substrate in Example 1 of the present invention.

[0034] Figure 2 This is a diagram of the microneedle patch that has just been printed in Embodiment 1 of the present invention.

[0035] Figure 3 This is an image of the porous microneedle patch prepared in Example 1 of the present invention.

[0036] Figure 4 This is a flexible display diagram of the porous microneedle patch prepared in Example 1 of the present invention.

[0037] Figure 5 This is a scanning electron microscope image of the cross-section of the porous microneedles prepared in Example 1 of the present invention.

[0038] Figure 6 This is a diagram of the microneedle shape that has just been printed in Embodiment 3 of the present invention.

[0039] Figure 7 This is a shape diagram of the porous microneedles prepared in Example 3 of the present invention.

[0040] Figure 8 This is a tensile photograph of the porous microneedle patch prepared in Example 3 of the present invention.

[0041] Figure 9 This is an optical image of Rhodamine B penetrating into pigskin after the porous microneedle patch was removed in Embodiment 4 of the present invention.

[0042] Figure 10 This is a graph showing the change in the amount of liquid extracted from agarose hydrogel by the porous microneedle patch in Example 5 of the present invention over time.

[0043] Figure 11 Figure 1 shows the liquid absorption volume of the porous polymer microneedles in Comparative Example 1 after 10 minutes.

[0044] Figure 12 This is a graph showing the change in liquid absorption volume of the microneedle patch over time in Comparative Example 2. Detailed Implementation

[0045] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0046] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0047] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0048] This invention provides a method for preparing a rigid porous polymer microneedle patch on a flexible substrate and its application. The porous polymer microneedle patch utilizes a flexible porous substrate and rigid porous microneedles, possessing not only sufficient mechanical strength but also excellent skin adhesion. The porous structure of the substrate significantly improves the overall liquid absorption capacity and efficiency of the patch. Rapid and personalized porous microneedle patch preparation is achieved through a simple one-step lifting process to fabricate the microneedle structure and a gentle solvent precipitation process. When the microneedle patch is immersed in a non-solvent miscible with the solvent, stratification occurs in the coagulation bath, disrupting the thermodynamic equilibrium of the polymer microneedles and transforming the single phase into a two-phase mixture composed of a polymer-rich phase and a polymer-poor phase, ultimately forming pores. This microneedle fabrication process allows for the rapid preparation of microneedle patches of different sizes and arrays according to actual needs, thereby achieving personalized customization of porous microneedles.

[0049] The microneedle patch substrate has dimensions of 10mm x 10mm x 0.2mm (the dimensions of the microneedle substrate are adjustable). The microneedle array has a diameter of 300–500 micrometers, a height of 600–1000 micrometers, and a spacing of 600 or 1000 micrometers (the parameters of the microneedle array are also adjustable). The prepared porous polymer microneedle patch is inserted into ex vivo skin tissue. The microneedles can effectively penetrate the skin without breaking. The change in liquid absorption of the porous microneedle patch over time is measured using agarose hydrogel.

[0050] The styrene thermoplastic elastomer used in this invention is commercially available SEBS G1652, and 101 rapid qualitative filter paper is also commercially available.

[0051] Example 1

[0052] 1) Preparation of modified filter paper substrate: 101 rapid qualitative filter paper was used as the substrate raw material. To enhance the bonding strength between the filter paper and the slurry, a 20% (w / w) dimethyl sulfoxide solution of cellulose acetate was spin-coated onto the filter paper surface at 1500 rpm for 3 minutes. The filter paper was then immersed in water for 30 minutes, removed, and allowed to air dry to obtain the modified filter paper substrate for printing microneedles, as shown below. Figure 1 As shown.

[0053] 2) Preparation of microneedle slurry: Dissolve cellulose acetate in dimethyl sulfoxide and stir magnetically for six hours to form a homogeneous solution, wherein the mass fraction of cellulose acetate is 20%; add 28% fumed silica particles as rheology modifier to the above polymer solution and rotate at 1000 rpm for 10 minutes in a planetary mixer until the silica particles are uniformly dispersed to obtain the printing slurry.

[0054] 3) Printing microneedle structures: The prepared slurry is loaded into a syringe (10 mL), and a stainless steel dispensing needle with an inner diameter of 0.3 mm is installed. A piston is used to push the slurry to the bottom of the syringe. Finally, the syringe is mounted on an automatic dispensing machine. The array parameters are set to 10*10, the air pressure to 500 kPa, the printing speed to 10 mm / s, and the distance to 300 micrometers. Microneedle structures are then printed on the modified filter paper substrate, such as… Figure 2 As shown.

[0055] 4) Preparation of porous microneedle patches: Immerse the prepared microneedle structure in water for 2 hours, then remove and change the water. Repeat this step 3 times, and allow it to air dry overnight to finally form porous microneedles. Figure 3 As shown.

[0056] The porous microneedles have a height of 600 micrometers, a bottom diameter of 400 micrometers, and a spacing of 600 micrometers between adjacent microneedles. Due to light scattering from the micropores, the porous microneedles appear opaque white. The flexible nature of the porous microneedle patch is demonstrated as follows: Figure 4 As shown; Scanning electron microscope image of the cross-section of the porous microneedle. Figure 5 As shown.

[0057] Example 2

[0058] 1) Preparation of modified filter paper substrate: 101 rapid qualitative filter paper was used as the raw material for the substrate. In order to enhance the bonding strength between the filter paper and the slurry, a 20% (w / w) dimethyl sulfoxide solution of cellulose acetate was spin-coated on the surface of the filter paper at a speed of 1500 rpm for 3 minutes. The filter paper was then immersed in water for 30 minutes and removed and allowed to dry naturally to obtain the modified filter paper substrate for printing microneedles.

[0059] 2) Preparation of microneedle slurry: Dissolve cellulose acetate in dimethyl sulfoxide and stir magnetically for six hours to form a homogeneous solution, wherein the mass fraction of cellulose acetate is 20%; add 28% fumed silica particles as rheology modifier to the above polymer solution and rotate at 1000 rpm for 10 minutes in a planetary mixer until the silica particles are uniformly dispersed to obtain the printing slurry.

[0060] 3) Printing microneedle structures: The prepared slurry is loaded into a syringe (10mL), and a stainless steel dispensing needle with an inner diameter of 0.3mm is installed. The slurry is pushed to the bottom of the syringe using a piston. Finally, the syringe is installed on an automatic dispensing machine. The array parameters are set to 6*6, the air pressure is set to 600kPa, the printing speed is 5mm / s, and the distance is 400 micrometers. The microneedle structures are printed on the modified filter paper substrate.

[0061] 4) Preparation of porous microneedle patch: Immerse the above-processed microneedle structure in water, keep it for 2 hours, take it out and change the water, repeat this step 3 times, and dry it at 80℃ for 30 minutes to finally form porous microneedles.

[0062] The porous microneedles have a height of 800 micrometers, a bottom diameter of 500 micrometers, and a spacing of 1000 micrometers between adjacent microneedles.

[0063] Example 3

[0064] 1) Preparation of modified SEBS substrate: Prepare a toluene solution of 18% (w / w) styrene thermoplastic elastomer (SEBS). Mix the prepared SEBS toluene solution with salicylic acid particles at a mass ratio of 1:3. Ball mill the mixture for 3 hours to ensure thorough mixing. Apply the mixed slurry to a film using a doctor blade coater. Allow it to dry naturally to form a film. Wash the film thoroughly with ethanol until all salicylic acid particles are removed, obtaining a porous SEBS membrane. Plasma-treat the porous SEBS membrane for 5 minutes to obtain a hydrophilic SEBS substrate.

[0065] A 20% (w / w) solution of cellulose acetate in dimethyl sulfoxide was coated onto the surface of a hydrophilic SEBS substrate. The SEBS substrate was then immersed in water for 30 minutes and allowed to air dry to obtain a modified SEBS substrate for printing microneedles.

[0066] 2) Preparation of microneedle slurry: Dissolve cellulose acetate in dimethyl sulfoxide and stir magnetically for six hours to form a homogeneous solution, wherein the mass fraction of cellulose acetate is 20%; add 28% fumed silica particles as rheology modifier to the above polymer solution and rotate at 1000 rpm for 10 minutes in a planetary mixer until the silica particles are uniformly dispersed to obtain the printing slurry.

[0067] 3) Printing microneedle structures: The prepared slurry is loaded into a syringe (10 mL), and a stainless steel dispensing needle with an inner diameter of 0.3 mm is installed. A piston is used to push the slurry to the bottom of the syringe. Finally, the syringe is mounted on an automatic dispensing machine. The array parameters are imported as 5*5, the air pressure is set to 600 kPa, the printing speed to 5 mm / s, and the distance to 400 micrometers. Microneedle structures are then printed on the modified SEBS substrate, such as… Figure 6 As shown.

[0068] 4) Preparation of porous microneedle patches: Immerse the printed microneedles in water for 2 hours, then remove and change the water. Repeat this step 3 times. Dry at 80℃ for 30 minutes to finally form porous microneedles. Figure 7 As shown.

[0069] The porous microneedles have a height of 800 micrometers, a bottom diameter of 500 micrometers, and a spacing of 1000 micrometers between adjacent microneedles. For example... Figure 8 As shown, the porous microneedle patch can withstand more than 100% tensile strain, and the microneedles will not fall off during the stretching process.

[0070] Example 4

[0071] Porous microneedle patches were prepared using the method in Example 2. The tips of the porous microneedles were pre-stained with Rhodamine B dye solution, that is, the porous microneedle patches were soaked in Rhodamine B (1 mg / mL) solution for 5 minutes. Then, the porous microneedle patches were inserted into the detached pig skin with thumb force and removed after 3 minutes.

[0072] like Figure 9 As shown, the Rhodamine B dye at the tip deposits in the pores formed on the pigskin, indicating that the microneedles can effectively penetrate the pigskin and the skin penetration efficiency can reach 100%.

[0073] Example 5

[0074] A layer of plastic wrap was placed on the agarose hydrogel (1.5 wt%). The microneedle patches prepared in Examples 1-3 were inserted into the hydrogel by applying thumb force. The initial mass of the patch and the mass at time points of 1, 3, 5, 10, 20 and 40 minutes were recorded to calculate the liquid absorption mass at each time point.

[0075] The results are as follows: Figure 10 As shown, the three porous microneedle patches exhibit similar liquid absorption trends, with the amount of liquid absorbed by the patches increasing sharply in the first 5 minutes and reaching near saturation after about 10 minutes.

[0076] Comparative Example 1

[0077] PLA, PLA@PDA@PEG polymer, PVDF, and PSF solutions were cast into a PDMS mold. The negative mold containing the polymer solution was then immersed in water to induce phase separation between the polymer and the solvent. Finally, the cured polymer microneedles were peeled off the PDMS mold and the final porous polymer microneedles were obtained through a freeze-drying process.

[0078] The volume of fluid aspirated at 10 minutes is as follows Figure 11 As shown.

[0079] Comparative Example 2

[0080] The difference between Comparative Example 2 and Comparative Example 1 is that the polymer solution used is PVA, while the other conditions are the same.

[0081] The amount of liquid absorbed over time, such as Figure 12 As shown.

[0082] Comparative Examples 1 and 2 illustrate existing methods for the integrated preparation of microneedle patches, with liquid absorption volumes of 0.2 mg to 1.2 mg and 3.8 ± 0.2 mg per 10 minutes, respectively. This demonstrates that the microneedle patch provided by our invention exhibits superior liquid absorption capacity compared to existing porous microneedle patches.

[0083] Comparative Example 3

[0084] The difference between Comparative Example 3 and Example 3 is that the mass fraction of styrene thermoplastic elastomer in the toluene solution is 12%, 15%, 18%, and 20%, respectively, while other preparation conditions are the same.

[0085] The volume of liquid aspirated in 10 minutes is shown in the table below:

[0086]

[0087] Increasing the mass fraction of styrene thermoplastic elastomer will increase the final liquid absorption of the product, but further increases in concentration will increase the thickness of the styrene thermoplastic elastomer matrix, which will significantly affect the performance.

[0088] Comparative Example 4

[0089] The difference between Comparative Example 4 and Example 3 is that the mass ratio of SEBS toluene solution to salicylic acid particles is 1:2.5, 1:3, 1:4, and 1:5, while other preparation conditions are the same.

[0090] The volume of liquid aspirated in 10 minutes is shown in the table below:

[0091]

[0092] The larger the proportion of salicylic acid particles, the greater the porosity and the more liquid it can hold. However, improving the quality of salicylic acid can also make the substrate softer, resulting in poorer puncture results and making it unusable.

[0093] Comparative Example 5

[0094] The difference between Comparative Example 5 and Example 3 is that a dimethyl sulfoxide solution of cellulose acetate with a mass fraction of 10%, 15%, 25%, and 30% was coated onto the surface of a hydrophilic SEBS substrate, while the other preparation conditions were the same.

[0095] At a mass fraction of 10%, it is impossible to coat the surface of the hydrophilic SEBS substrate due to the low bonding strength, making it unusable.

[0096] At a mass fraction of 15%, a film was successfully coated on the surface of the hydrophilic SEBS substrate, but the needles fell off during use and the bonding strength was not high.

[0097] At a mass fraction of 25%, a film was successfully coated on the surface of the hydrophilic SEBS substrate, but this affected some of the substrate micropores, resulting in a decrease in liquid absorption.

[0098] At a mass fraction of 30%, a film was successfully coated on the surface of the hydrophilic SEBS substrate, but it blocked the micropores of the substrate, resulting in a sharp decrease in liquid absorption and a lack of practicality.

[0099] Comparative Example 6

[0100] The difference between Comparative Example 6 and Example 3 is that the mass fractions of cellulose acetate and silica particles in the microneedle slurry are different, while the other preparation conditions are the same.

[0101] When the mass fraction of cellulose acetate is 10%, the mass fraction of silica particles is set to 20% and 40%. When the mass fraction of silica particles is 40%, the porosity of the porous microneedles decreases, affecting the liquid absorption of the final product. When the mass fraction of silica particles is 20%, the solution viscosity is insufficient, and the microneedles cannot be shaped.

[0102] When the mass fraction of cellulose acetate is 30%, the mass fraction of silica particles is set to 10%, 20%, and 40%. When the mass fraction of silica particles is 40%, the viscosity is too high, there are almost no pores, and the liquid absorption decreases significantly. When the mass fraction of silica particles is 20%, the viscosity is moderate, and the microneedles can be shaped, but the porosity is still low. When the mass fraction of silica particles is 10%, the viscosity is too low, and the microneedles cannot be shaped.

[0103] Therefore, our invention selects 20% cellulose acetate and 28% fumed silica particles by mass in the microneedle slurry. Under these conditions, the optimal ratio of microneedle strength and microneedle porosity can be achieved, while ensuring the microneedle's shape.

[0104] In Examples 1 and 2, the same flexible paper substrate was used, but the size of the microneedles was changed. When the size of the microneedles increased, the liquid absorption rate in the first five minutes was significantly improved. However, due to the large-area porous structure of the substrate, the substrate determined the final saturated liquid absorption volume, and the saturated liquid absorption volumes of the two were similar.

[0105] In Examples 2 and 3, the microneedle structures are the same, and the liquid absorption rate is roughly the same in the first five minutes, then increases rapidly, with about 9 mg of liquid being extracted within 5 minutes. However, the substrates are different, namely a paper substrate and a SEBS porous substrate. Due to the strong affinity of paper fibers for water and the highly porous structure, the paper substrate can store more liquid. However, the SEBS porous membrane has better elasticity and toughness. Therefore, although the saturated liquid absorption capacity of the SEBS porous membrane is relatively slightly lower when used as a substrate, its application range is wider.

[0106] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method of making a flexible substrate-hard porous microneedle patch, characterized by: The preparation method comprises the following steps: Preparation of microneedle paste: cellulose acetate is dissolved in dimethyl sulfoxide to obtain a polymer solution, and fumed silica particles are added into the polymer solution and stirred until the fumed silica particles are uniformly dispersed to obtain a microneedle paste; The mass fraction of cellulose acetate in the microneedle paste is 20%, and the mass fraction of fumed silica particles is 28%; Printing of microneedle structure: the prepared microneedle paste is printed on a flexible substrate by an automatic dispensing machine to form a microneedle structure; Preparation of porous microneedle patch: the prepared microneedle structure is soaked in water, and after drying, a porous microneedle patch is obtained; The flexible substrate is a hydrophilic styrene thermoplastic elastomer; The preparation method of the hydrophilic styrene thermoplastic elastomer comprises the following steps: Preparation of toluene solution of styrene thermoplastic elastomer with a mass fraction of 15-18%; The prepared toluene solution of styrene thermoplastic elastomer is mixed with salicylic acid particles at a mass ratio of 1:3, and the two are fully mixed by ball milling for 3 hours to obtain a slurry; After the mixed slurry is coated by a doctor blade, it is naturally dried into a film, and the salicylic acid particles in the film are washed away with ethanol to obtain a styrene thermoplastic elastomer porous film; The styrene thermoplastic elastomer porous film is subjected to plasma treatment for 5 minutes to obtain a hydrophilic styrene thermoplastic elastomer.

2. The production method according to claim 1, characterized by: The printing of the microneedle structure, wherein the volume of the needle tube on the automatic dispensing machine is 10 mL, and the inner diameter of the needle head is 0.3 mm.

3. The production method according to claim 1, wherein: The printing of the microneedle structure, wherein the air pressure is set to 400-600 kPa, the printing speed is 5-10 mm / s, and the distance is 200-400 microns.

4. The flexible substrate-hard porous microneedle patch prepared by the preparation method of any one of claims 1-3.

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