Barbed hollow drug delivery microneedle patch and preparation method thereof

Abstract

The invention discloses a barb hollow drug delivery microneedle patch and a preparation method thereof. The barb hollow microneedle patch comprises a substrate and microneedles, wherein a microneedle array is uniformly arranged on the substrate; the micro-needle body comprises a needle column, barbs, a needle tip and a hollow shaft, the hollow shaft extends to the tip, the tip pierces the skin to deliver medicine, the needle column is used for connecting the needle tip and the base, the needle column partially surrounds the barbs, and the barbs pierce the dressing without touching the skin to enhance the stability of the micro-needle patch. According to the hollow microneedle patch with the barbs, based on a plane projection micro three-dimensional photocuring molding technology in a 3D printing technology, the photosensitive resin with relatively good biocompatibility is used as a printing material, and hollow microneedle arrays with different barb angles are printed by using a Mosquare precision S140 photocuring printer; the barb shapes at different angles and traces left after the barb micro-needle pierces into a skin model can be observed under a microscopic device, and the mechanical performance of the barb micro-needle is obtained through actual measurement.

Description

Technical Field

[0001] The invention relates to a hollow drug delivery microneedle patch with barbs based on 3D printing and a preparation method thereof, belonging to the technical field of biomedical materials. Background Art

[0002] Traditional wound dressings (gauze and hydrogel) have been widely used to treat chronic wounds, but their disadvantages such as low drug release efficiency, adhesion to wound tissue and single function have hindered their further application in complete wound management. In order to solve these problems, people have made great efforts to explore multifunctional wound dressings. Among them, microneedle patches show great potential in constructing multifunctional dressings for smart wound management. Microneedles can penetrate the skin without reaching nerves and blood vessels, realizing minimally invasive drug delivery. Not only that, the manufacture of microneedle arrays with special structures and patterns can also give microneedle patches multiple functions in addition to treatment. Microneedle patches have been widely used in the fields of medical beauty and disease treatment as a painless drug delivery method in recent years. Microneedle patches are usually composed of multiple fine needle arrays of tens to hundreds of microns. Due to their short length, they do not touch nerves and blood vessels, so the whole process is almost painless and will not leave obvious wounds. The inserted microneedles can release drugs more efficiently under the skin, which is an ideal transdermal drug delivery method. Traditional microneedles are mostly made of metal. Although their mechanical properties are increased, their structure is single and they are prone to skin infection and metal poisoning. Biocompatible resins have low toxicity and irritation. In addition, biocompatible resins also have excellent physical properties, plasticity and processability, and are easy to manufacture microneedles of various shapes to meet different medical needs.

[0003] In general, traditional processes for manufacturing microneedles are usually complicated and heavily rely on manual operations. They face challenges such as limited material selection, poor biocompatibility, and lack of flexibility in customized design. Future microneedle manufacturing technology should emphasize high precision, personalization, good reproducibility, and green intelligence. Three-dimensional printing technology is an additive manufacturing technology. Due to its unique advantages such as programmability, batch production, and customizable production, it is also used in the manufacture of drug-loaded microneedles. Users can design microneedles with complex structures in drawing software such as CAD to adapt to the diversity of diseases. In addition, 3D printers work automatically in an environment without special requirements, and can more efficiently manufacture high-precision and reproducible target models, reducing the manpower and time required to develop new structures, promoting the customization of personalized designs, and providing a cost-effective solution.

[0004] The shapes of common 3D printed microneedles are generally pyramidal, cylindrical, conical, etc. Its structure is simple and easy to manufacture, and can be quickly produced in batches. However, to achieve long-term drug delivery, the structure of the microneedle needs to have higher stability. Therefore, based on some microstructures with high tissue adhesion in natural organisms (for example, microhooks of parasites, tail stings of bees, and needle hairs of porcupines), a hollow microneedle with barbs was developed. The barbs penetrate into the dressing without touching the skin, which has the effect of improving the adhesion of the microneedle patch. The needle tip is smooth and can easily penetrate into the skin to achieve drug delivery. A piezoelectric micropump is integrated above the microneedle base. This design is of great significance for the realization of long-term microneedle drug delivery. Summary of the invention

[0005] The technical problem to be solved by the present invention is to address the shortcomings of the above-mentioned existing drug delivery microneedles, and provide a microneedle for delivering medicine on a wound with a dressing and a preparation method thereof. The present invention uses 3D printing technology to manufacture hollow microneedles with barbs and integrates a piezoelectric micropump. The barbed part is inserted into the dressing to enhance the adhesion of the microneedle patch, and the needle tip part is inserted into the skin to achieve self-driven drug delivery.

[0006] In order to achieve the above technical objectives, the technical solution adopted by the present invention is: a barbed hollow drug delivery microneedle patch, comprising a substrate 1, a needle column array 2, a barb array 3, and a needle tip 4; wherein the needle column array 2 is arranged on the upper surface of the substrate, the barb array 3 is arranged around the needle column body, and the needle tip 4 is connected to the top of the needle column; the needle tip 4 comprises a needle tip body 401 and a side opening 402, the bottom is connected to the needle column 2 as a whole, and the side opening 402 is opened at the top of the microneedle body 401;

[0007] A hollow shaft 5 is also provided, which passes through the base 1, the needle column 2 and the needle tip 4, and specifically includes a base hollow shaft 51, a needle column hollow shaft 52 and a needle tip hollow shaft 53; the hollow shaft 5 and the side opening 402 serve as a drug delivery channel.

[0008] The barb array 3 is a circular array of 6 barbs each, surrounding the outer side of the needle column body, with a total of 3 barb circular arrays.

[0009] The unit microneedle column of the needle column array 2 has a height of 0.5 to 2 mm, a diameter of 0.1 to 0.8 mm, a needle tip height of 0.3 to 1.0 mm, and a hollow shaft 5 height of 1.5 to 4.5 mm;

[0010] The unit barb of the barb array is 0.2-1.6 mm long, 0.2-0.8 mm wide at the top, 20-150 μm wide at the bottom, 10-100 μm high, 100-600 μm apart from the array, and has barb angles of 30°, 35°, 40°, 45°, 50°, 55°, and 60°.

[0011] The unit microneedle column of the needle column array 2 has a height of 1 to 1.5 mm, a diameter of 0.3 to 0.5 mm, a needle tip height of 0.45 to 0.8 mm, and a hollow shaft 5 height of 2.5 to 3.5 mm;

[0012] The unit barb of the barb array has a length of 0.4-0.8 mm, a top width of 0.3-0.6 mm, a bottom width of 40-100 μm, a height of 30-50 μm, and an array distance of 250-400 μm.

[0013] The substrate of the microneedle array is connected to an external piezoelectric micropump to form a self-driven drug delivery device, and the drug inlet catheter of the drug reservoir is connected to the external piezoelectric micropump.

[0014] The present invention also provides a method for preparing a barbed hollow drug delivery microneedle patch, the specific steps of which are as follows:

[0015] Step 1: Draw a 3D model of the hollow microneedle array patch with barbs to be printed, export the 3D model into a target file format and import it into the slicing software that comes with the 3D printer, set the position of the model on the printing platform and the slicing accuracy; the 3D model includes the substrate, barbs, needle tip structure parameters, and the number and layout of microneedles contained in the hollow microneedle array patch;

[0016] Step 2: After setting the parameters in the 3D printer, start the 3D printer to obtain a hollow microneedle array patch model with barbs, wherein the printing material used by the 3D printer is a photocurable biocompatible resin;

[0017] Step 3: Use 95% anhydrous ethanol to clean the uncured and residual printing material on the printed hollow microneedle array patch model with barbs, and place the naturally dried hollow microneedle array patch model with barbs in a light curing box, and use ultraviolet light for secondary curing at a set temperature to obtain the final hollow microneedle array patch.

[0018] The biocompatible material needs to be stored away from light before curing.

[0019] A piezoelectric micropump is bonded to the printed microneedle patch using toughened epoxy structural adhesive to form a self-driven drug delivery device; the piezoelectric micropump includes a piezoelectric vibrator and a micropump body, the piezoelectric vibrator is composed of a PZT layer and a metal substrate, and the pump chamber part is manufactured by a 3D printer.

[0020] The self-driven drug delivery device uses a signal generator to generate a sinusoidal signal which is amplified by a power amplifier and then acts on a piezoelectric micropump, and can be integrated with a microneedle array to achieve long-term stable drug delivery.

[0021] The above technical solution has the following advantages or beneficial effects:

[0022] (1) The present invention increases the stability of the microneedle patch by designing a barbed structure on the microneedle, and can be used in conjunction with a dressing to enhance its practical application value;

[0023] (2) The present invention uses a base, a needle column, a needle tip, barbs and a hollow shaft to form a 3D printing integrated structure, which is easy to integrate and has good application value;

[0024] (3) The microneedle of the present invention is combined with a piezoelectric micropump to achieve long-term drug delivery. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The embodiments of the present invention will be described more fully with reference to the attached drawings, which are provided for illustration and description only and are not intended to limit the scope of the present invention.

[0026] Figure 1 A schematic diagram of a microneedle patch with barbs for delivering medicine to a wound with a dressing according to the present invention;

[0027] Figure 2 It is a design cross-sectional view of the present invention;

[0028] Figure 3 It is a cross-sectional view of the needle tip portion left after the needle is inserted into the gelatin of the present invention;

[0029] Figure 4 It is a schematic diagram of the present invention after piercing the gelatin with the dressing;

[0030] Figure 5 The morphological pictures of 30°, 45° and 60° barbs under an optical microscope;

[0031] Figure 6 Stress and displacement curves of 30°, 35°, 40°, 45°, 50°, 55° and 60° barbs inserted and pulled out of the skin model.

[0032] The above-mentioned figure marks represent: 1. base; 2. needle column; 3. barb; 4. needle tip; 5. hollow shaft; 301. barb body; 302. barb support; 401. needle tip body; 402. needle tip side opening; 51. base hollow shaft; 52. needle column hollow shaft; 53. needle tip hollow shaft. DETAILED DESCRIPTION

[0033] In order to enable those skilled in the art to better understand the technical solution of the present invention, the embodiments of the present invention are further described in detail below with reference to the accompanying drawings.

[0034] The experimental methods used in the following examples are conventional methods unless otherwise specified, and the reagents, methods and equipment used are conventional reagents, methods and equipment in the art unless otherwise specified.

[0035] Example 1

[0036] like Figure 1 As shown in FIG. 1 , a schematic diagram of a 3D printed hollow microneedle with barbs provided in this embodiment is shown in FIG. Figure 2 As shown, it comprises: a base 1, a needle column array 2 is arranged on the base 1, a barb array 3 is arranged around the needle column body, a needle tip 4 is connected to the top of the needle column, and a hollow shaft 5 passes through the base 1, the needle column 2 and the needle tip 4; the needle tip 4 is used for drug delivery, such as Figure 2 As shown, the hollow shaft includes a base hollow shaft 51, a needle column hollow shaft 52 and a needle tip hollow shaft 53; wherein the needle tip 4 also includes: a needle tip body 401, which is connected to the needle column 2 at the bottom, and a side opening 402, which is opened at the top of the microneedle body 401; in order to achieve the integrated integration of the hollow microneedles, the base part in the present invention is also hollow, and can be integrated with the piezoelectric micropump device as a part of the microchannel.

[0037] Example 2

[0038] This embodiment provides a method for preparing a barbed hollow drug delivery microneedle patch, and the specific steps are as follows:

[0039] Step 1: Draw a 3D model of the hollow microneedle array patch with barbs to be printed, export the 3D model into a target file format and import it into the slicing software that comes with the 3D printer, set the position of the model on the printing platform and the slicing accuracy; the 3D model includes the substrate, barbs, needle tip structure parameters, and the number and layout of microneedles contained in the hollow microneedle array patch;

[0040] Step 2: After setting the parameters in the 3D printer, start the 3D printer to obtain a hollow microneedle array patch model with barbs, wherein the printing material used by the 3D printer is a photocurable biocompatible resin; specifically, the height of the unit microneedle column is 0.5-2mm, the ideal height is 1-1.5mm, the diameter is 0.1-0.8mm, the ideal diameter is 0.3-0.5mm, the needle tip height is 0.3-1.0mm, the ideal height is 0.45-0.8mm, the hollow shaft 5 height is 1.5-4.5mm, and the ideal height is 2.5-3.5mm. The height parameter of the needle column can be changed according to different dressing thicknesses.

[0041] The length of the unit barb is 0.2-1.6mm, the ideal length is 0.4-0.8mm, the upper width is 0.2-0.8mm, the ideal upper width is 0.3-0.6mm, the lower width is 20-150μm, the ideal lower width is 40-100μm, the height is 10-100μm, and the ideal height is 30-50μm. The barbs are arranged in a circular array of 6 each, and 3 linear arrays are designed on the needle column. The array distance is 100-600μm, and the ideal distance is 250-400μm. The parameters of the barbs can also be set according to different dressing thicknesses. In order to select the best barb angle, microneedle patches without barbs and with barb angles of 30°, 35°, 40°, 45°, 50°, 55°, and 60° were printed respectively;

[0042] Step 3: Use 95% anhydrous ethanol to clean the uncured and residual printing material on the printed hollow microneedle array patch model with barbs, and place the naturally dried hollow microneedle array patch model with barbs in a light curing box, and use ultraviolet light for secondary curing at a set temperature to obtain the final hollow microneedle array patch.

[0043] Step 2: Use 5% gelatin as a skin model, attach a layer of wound dressing on the surface, pass the microneedle through the dressing, insert the needle tip into the skin model, and leave the barb part inside the dressing. Then pull out the needle tip, cut the skin model to get the cross-section model after the microneedle is inserted, and observe its structure under a microscope. Figure 4 shown.

[0044] Step 3: Use AB glue (toughened epoxy structural glue) to bond the piezoelectric micropump device to the printed microneedle patch. The piezoelectric micropump device mainly includes a piezoelectric vibrator and a micropump body. The piezoelectric vibrator is composed of a PZT layer and a metal substrate. The pump chamber part is made by a 3D printer. The overall device uses a signal generator to generate a sinusoidal signal, which is amplified by a power amplifier and acts on the piezoelectric micropump. It can be integrated with the microneedle array to achieve long-term and stable drug delivery.

[0045] The microneedle array model designed using 3D drawing software is shown in Figure 2. Figure 1 As shown in the figure, the microneedle array patch prepared by 3D printing has a complete appearance, including needle columns, needle tips and hollow shafts of different shapes and barbs of different angles. The schematic diagram of barbs of different angles under an optical microscope is shown in Figure 5 The diameter of the microneedle tip is about 20-30um, and the difference between the set angle and the actual angle is about 10μm, with high precision.

[0046] Schematic diagram of microneedle patch applied to gelatin skin model Figure 3After the microneedle patch was pressed on the gelatin skin model with a dressing by fingers, the punctured skin model was cut and observed under an optical microscope. The penetration depth of the microneedle was about 700 to 800 μm. In addition, the insertion force and extraction force of the microneedles without barbs and with barbs at different angles were tested. Figure 6 As shown, it can be found that as the barb angle increases, the insertion force and the withdrawal force also increase, which proves that when the microneedle has a barb structure, its stability can be enhanced. When the barb angle is 60°, the withdrawal force can reach about 2.8N / needle.

[0047] When the 3D printed hollow drug delivery microneedle with barbs is working, the base 1, needle column 2, barbs 3, needle tip 4 and hollow shaft 5 are a 3D printed integrated structure, which facilitates the drug to be transmitted from the base hollow shaft 51 to the needle tip hollow shaft 53 through the needle column hollow shaft 52, and then delivered from the needle tip side opening 402. The barbs 3 surround the needle column 2, and when the dressing is inserted, the barb structure can be well inserted into the dressing, and the dressing is close to the skin, so that the microneedle can achieve long-term and stable drug delivery, and enhance the practical application value.

[0048] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A barbed hollow drug delivery microneedle patch, characterized in that: The invention comprises a base (1), a needle column array (2), a barb array (3), and a needle tip (4); wherein the needle column array (2) is arranged on the upper surface of the base, the barb array (3) is arranged around the needle column body, and the needle tip (4) is connected to the upper part of the needle column; the needle tip (4) comprises a needle tip body (401) and a side opening (402), the lower part is connected to the needle column as a whole, and the side opening (402) is opened at the top of the needle tip body 401; A hollow shaft (5) is also provided, and the hollow shaft (5) passes through the base (1), the needle column 2 and the needle tip (4), and specifically includes a base hollow shaft (51), a needle column hollow shaft (52) and a needle tip hollow shaft (53); the hollow shaft (5) and the side opening (402) serve as a drug delivery channel.

2. The barbed hollow drug delivery microneedle patch according to claim 1, characterized in that: The barb arrays (3) are arranged in a circular array with 6 barbs each, surrounding the outer side of the needle column body, with a total of 3 barb circular arrays.

3. The barbed hollow drug delivery microneedle patch according to claim 1, characterized in that: The microneedle column height of the needle column array (2) is 0.5-2 mm, the diameter is 0.1-0.8 mm, the needle tip height is 0.3-1.0 mm, and the hollow shaft 5 height is 1.5-4.5 mm; The unit barb of the barb array is 0.2-1.6 mm long, 0.2-0.8 mm wide at the top, 20-150 μm wide at the bottom, 10-100 μm high, 100-600 μm apart from the array, and has barb angles of 30°, 35°, 40°, 45°, 50°, 55°, and 60°.

4. The barbed hollow drug delivery microneedle patch according to claim 1, characterized in that: The microneedle column height of the needle column array (2) is 1 to 1.5 mm, the diameter is 0.3 to 0.5 mm, the needle tip height is 0.45 to 0.8 mm, and the hollow shaft 5 height is 2.5 to 3.5 mm; The unit barb of the barb array has a length of 0.4-0.8 mm, a top width of 0.3-0.6 mm, a bottom width of 40-100 μm, a height of 30-50 μm, and an array distance of 250-400 μm.

5. The barbed hollow drug delivery microneedle patch according to claim 1, characterized in that: The substrate of the microneedle array is connected to an external piezoelectric micropump to form a self-driven drug delivery device, and the drug inlet conduit of the drug storage device is connected to the external piezoelectric micropump.

6. A method for preparing a barbed hollow drug delivery microneedle patch according to any one of claims 1 to 5, characterized in that: The specific steps are as follows: Step 1: Draw a 3D model of the hollow microneedle array patch with barbs to be printed, export the 3D model into a target file format and import it into the slicing software that comes with the 3D printer, set the position of the model on the printing platform and the slicing accuracy; the 3D model includes the substrate, barbs, needle tip structure parameters, and the number and layout of microneedles contained in the hollow microneedle array patch; Step 2: After setting the parameters in the 3D printer, start the 3D printer to obtain a hollow microneedle array patch model with barbs, wherein the printing material used by the 3D printer is a photocurable biocompatible resin; Step 3: Use 95% anhydrous ethanol to clean the uncured and residual printing material on the printed hollow microneedle array patch model with barbs, and place the naturally dried hollow microneedle array patch model with barbs in a light curing box, and use ultraviolet light for secondary curing at a set temperature to obtain the final hollow microneedle array patch.

7. The method for preparing a barbed hollow drug delivery microneedle patch according to claim 6, characterized in that: The biocompatible material needs to be stored away from light before curing.

8. The method for preparing a barbed hollow drug delivery microneedle patch according to claim 6, characterized in that: A piezoelectric micropump is bonded to the printed microneedle patch using toughened epoxy structural adhesive to form a self-driven drug delivery device; the piezoelectric micropump includes a piezoelectric vibrator and a micropump body, the piezoelectric vibrator is composed of a PZT layer and a metal substrate, and the pump chamber part is manufactured by a 3D printer.

9. The method for preparing a barbed hollow drug delivery microneedle patch according to claim 8, characterized in that: The self-driven drug delivery device uses a signal generator to generate a sinusoidal signal which is amplified by a power amplifier and then acts on a piezoelectric micropump, and can be integrated with a microneedle array to achieve long-term stable drug delivery.

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