Micro-needle patch imitating cocklebur barb structure and application of micro-needle patch in drug delivery

Abstract

The invention discloses a microneedle patch simulating a xanthium sibiricum barb structure and application of the microneedle patch in drug delivery. A preparation method of the microneedle patch comprises three steps. The method comprises the following steps: S1, obtaining a microneedle patch model simulating a xanthium sibiricum barb structure through 3D printing; s2, performing mold reversing on the microneedle patch model obtained in the step S1 to obtain a microneedle patch mold; and S3, preparing a material liquid for preparing the microneedle patch, pouring the material liquid into a microneedle patch mold, then placing the mold in a vacuum environment for 10-30 min to remove bubbles in the material liquid, then carrying out vacuum heating and drying on the mold until the material liquid is dried and formed, and then taking out the formed microneedle patch from the mold. The microneedle patch is used for transdermal drug delivery, the siberian cocklebur barbed structure of the microneedle patch can hook skin tissue after penetrating into the skin so as to increase the adhesive force of the microneedle patch on the skin, and possibility is provided for long-time drug controlled release of the microneedle.

Description

Technical Field

[0001] The present invention relates to the technical field of drug delivery, and in particular to a microneedle patch imitating the barbed structure of Xanthium sibiricum and its application in drug delivery. Background Art

[0002] Transdermal drug delivery technology is the third major drug delivery method after oral administration and injection. It has the advantages of improving patient compliance, achieving continuous drug delivery, avoiding gastrointestinal irritation and the first-pass effect of the liver. As the largest organ of the human body, the skin plays a key protective role in maintaining moisture and defending against external injuries. The outermost layer of the skin is the stratum corneum, with a thickness of about 10 - 15 μm, which constitutes the main obstacle to transdermal drug delivery technology, hindering the effective transmission of drugs and thus limiting the wide application of this technology. Microneedles are a minimally invasive or non-invasive transdermal drug delivery technology that enhances drug penetration by forming tiny channels on the skin surface, allowing drugs to directly enter the dermis or subcutaneous tissue, overcoming the skin barrier. This technology can be used in various applications such as drug delivery, vaccination, cosmetic treatment, and sampling of biomolecules. However, it remains challenging to achieve long-term attachment of microneedles to soft tissues for controlled drug delivery, mainly because the conventional microneedle body structure is flat and the adhesion force between the needle body and the tissue is insufficient.

[0003] Xanthium sibiricum is an annual herb of the genus Xanthium in the family Asteraceae. When the fruit of Xanthium sibiricum is mature, its surface has hooked spines, which are extremely thin and straight, with slightly thickened or almost unthickened bases. The barbs on the surface of the Xanthium sibiricum fruit can make it easily adhere to the fur of passing animals or the clothes of humans, and thus be carried to other places, enabling the seeds to spread in a wider area, expanding the distribution range of Xanthium sibiricum and being beneficial to the reproduction and spread of its population. Inspired by this technology, if the barbed structure of Xanthium sibiricum is combined with a microneedle patch, it is expected to solve the problem of insufficient adhesion of traditional microneedle patches. Summary of the Invention

[0004] Aiming at the problem of insufficient adhesion of traditional microneedle patches, the present invention innovatively combines the barbed structure of Xanthium sibiricum with a microneedle patch to provide a microneedle patch imitating the barbed structure of Xanthium sibiricum.

[0005] The preparation method steps of the microneedle patch imitating the barbed structure of Xanthium sibiricum provided by the present invention are as follows:

[0006] S1. Prepare a microneedle patch model imitating the barbed structure of Xanthium sibiricum by 3D printing.

[0007] S2. Perform a reverse mold on the microneedle patch model obtained in step S1 to obtain a microneedle patch mold.

[0008] The specific method of making the mold is as follows: Place the microneedle patch model obtained in step S1 into a rectangular container with the needle tips facing upward, pour the pre-prepared mold-making liquid into the rectangular container so that the liquid level is 4 - 6 mm higher than the needle tips; then place the rectangular container in a vacuum environment for 2 - 3 hours to remove the air bubbles in the liquid. Next, place the rectangular container overnight or heat it in an oven until the liquid in it is completely solidified. Finally, remove the microneedle patch model from it to obtain the microneedle patch mold.

[0009] Preferably, the mold-making liquid described in step S2 is a mixed liquid of polydimethylsiloxane and a curing agent.

[0010] S3. Prepare the material liquid for preparing the microneedle patch, pour the material liquid into the microneedle patch mold, then place the mold in a vacuum environment for 10 - 30 min to remove the air bubbles in the material liquid, and then perform vacuum heating and drying on the mold until the material liquid is dried and formed, and then take out the formed microneedle patch from the mold.

[0011] Preferably, the specific method of step S3 is as follows:

[0012] S31. Prepare the material liquid for preparing the microneedle patch, and the material liquid contains drug components;

[0013] S32. Pour a part of the material liquid into the microneedle patch mold, then place the mold in a vacuum environment for 10 - 30 min to remove the air bubbles in the material liquid, take out the mold from the vacuum environment and scrape off the excess bubbly solution above the needle holes, and then perform vacuum heating and drying on the mold until the material liquid is dried and formed to form the needle tips; add the material liquid into the mold again, and place it in a vacuum environment for 10 - 30 min to remove the air bubbles in the material liquid, take out the mold from the vacuum environment and perform vacuum heating and drying until the material liquid is dried and formed to form the backboard of the microneedle patch, and finally take out the microneedle patch.

[0014] More preferably, the components of the material liquid further include polyvinyl alcohol and deionized water.

[0015] The present invention also provides the application of the microneedle patch imitating the burdock barb structure in transdermal drug delivery. The microneedle patch with the imitated burdock barb structure can hook the skin tissue after piercing the skin to increase the adhesion of the microneedle patch on the skin, realizing long-term controllable drug release of the microneedle. And the matrix material ratio and type of the microneedle patch can be adjusted according to the actual drug release time, and the drug type and content in the microneedle patch can be adjusted according to the actual treatment purpose.

[0016] Compared with the prior art, the advantages of the present invention are as follows:

[0017] (1) The microneedle patch with a structure mimicking the barbs of Xanthium sibiricum is a microneedle patch with a bionic structure that can achieve transdermal drug delivery. The structure mimicking the barbs of Xanthium sibiricum can hook the skin tissue after the microneedles penetrate the skin, increasing the adhesion of the microneedles in the tissue, solving the problem of insufficient adhesion of microneedles in the skin, and realizing controllable transdermal drug delivery for a longer time without highly skilled operation or significant pain.

[0018] (2) The matrix material ratio and type of the microneedle patch can be adjusted according to the actual drug release time, and the drug type and content in the microneedle patch can be adjusted according to the actual treatment purpose.

[0019] Other advantages, objectives and features of the present invention will be partially reflected by the following description, and partially will also be understood by those skilled in the art through the research and practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It is a scanning electron microscope image of the Xanthium sibiricum barb structure.

[0021] Figure 2 It is a 3D model image of the microneedle patch modeled by computer software in Example 1.

[0022] Figure 3 It is the reference plane 1 of the 3D model of the microneedle patch modeled by computer software in Example 1.

[0023] Figure 4 It is the microneedle patch model printed by 3D printing in Example 1.

[0024] Figure 5 It is the optical microscope photo of the microneedle patch prepared in Example 1.

[0025] Figure 6 It is the stress-strain curve and the fitted linear segment of the microneedle patch prepared in Example 1.

[0026] Figure 7 It is the adhesion-displacement curve of the microneedle patch prepared in Example 1. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0027] The following is a description of the preferred embodiments of the present invention with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are only for the purpose of illustrating and explaining the present invention, and are not used to limit the present invention.

[0028] Example 1

[0029] A preparation method of a microneedle patch with a structure mimicking the barbs of Xanthium sibiricum is as follows:

[0030] (1) First, according to the scanning electron microscope image of the Xanthium sibiricum barb structure ( Figure 1), a 3D model of a burdock burr-like structure is designed using computer modeling software. The size of the microneedle patch is 20*20 mm; the needle array is 33*33; the needle pitch is 600 μm; the bottom diameter of the needle is 340 μm; the height of the needle is 650 μm. From Figure 2 the reference plane 1 of Figure 3 observation, the curvature of the hook construction line 1 (inside) is 2.15, the radius of curvature is 0.46, and the curvature of the construction line 2 (outside) is 2.34, the radius of curvature is 0.43. Then, a microneedle patch model of a burdock burr-like structure as shown in Figure 4 is printed using a 3D printer. Figure 4 In

[0031] , figure (b) is a partial enlarged view of figure (a). In this step, since the tip of the microneedle is extremely thin, the tip of the printed model may be subjected to a certain amount of stress during the demolding process in the subsequent steps. Therefore, when selecting the 3D printing material, it is required that the printing material has a certain mechanical strength to prevent the tip of the model from breaking during the demolding process. For example, in this embodiment, the main material used for 3D printing is HTL (High Temperature Resistant Liquid), also known as standard resin, which is a high-temperature resistant photosensitive resin suitable for the 405 nm curing band and can meet the usage requirements.

[0032] (2) Perform a reverse mold on the 3D-printed microneedle patch model. The specific steps are as follows: Use Dow Corning DC184 to mix the main agent polydimethylsiloxane and the curing agent in a weight ratio of 10:1 to obtain a reverse mold liquid. Place the 3D-printed microneedle patch model in a square container with the needle tip facing up, pour the reverse mold liquid into the square container so that the liquid level is 5 mm higher than the needle tip; then place the square container in a vacuum environment and place it in an environment with a vacuum degree of about 0.7 MPa for 2 hours to completely eliminate the bubbles in the liquid. Place the square container with the bubbles eliminated in a 37-degree Celsius electrothermal blast drying oven overnight to ensure that the reverse mold liquid is completely cured. When the reverse mold liquid is completely cured, carefully remove the microneedle patch model from it to finally obtain a microneedle patch mold.(3) Gradually add 3 g of polyvinyl alcohol (type 1788) into 20 mL of deionized water in portions, and use a magnetic stirrer to slowly stir during the addition process to reduce the aggregation of polyvinyl alcohol particles; after stirring overnight, a 15% polyvinyl alcohol solution is obtained. Add the required drug components according to the treatment purpose during the preparation of the polyvinyl alcohol solution. Add an appropriate amount of the polyvinyl alcohol solution into the microneedle patch mold, and then place it in a vacuum environment. Place it in an environment with a vacuum degree of about 0.8 MPa for 15 minutes. Then take it out of the vacuum environment and scrape off the excess solution with bubbles above the needle holes. Add an appropriate amount of the polyvinyl alcohol solution again, and repeat the above steps 3 times. Finally, scrape off the excess solution and place the mold in a vacuum drying oven at 37 °C and let it stand for 4 hours to dry the liquid and form the needle tips. Add the solution again, place it in an environment with a vacuum degree of about 0.8 MPa for 15 minutes, take out the mold and put it back into the vacuum drying oven at 37 °C and let it stand overnight until the liquid dries and forms the microneedle backplane. Finally, slowly remove the microneedle patch. The optical microscope photo of the needle tips of the prepared microneedle patch is as Figure 5 shown. It can be clearly seen that the microneedle patch has a barbed structure imitating Xanthium sibiricum.

[0033] Test the mechanical properties of the microneedle patch during compression by a texture analyzer to obtain Figure 6 the stress-strain curve shown. Find the linear segment on the curve, and linearly fit to calculate that the Young's modulus of the material is about 111.65 MPa, which is much higher than the Young's modulus of the skin, 0.13 MPa. This shows that the microneedle patch has the potential to pierce the skin.

[0034] Similarly, use a texture analyzer to test the adhesion of the microneedle patch. Use 8 layers of M sealing film stacked and combined as the punctured object. This sealing film has certain mechanical strength and toughness and will not be torn during the stretching process, and can simulate the skin resistance and elasticity. The test results are as Figure 7 shown. Through analysis, it is found that compared with the adhesion of the purchased ordinary straight needle patch, the adhesion of the microneedle patch with the barbed structure imitating Xanthium sibiricum of the present invention is significantly improved, which proves that the barbed structure imitating Xanthium sibiricum of the microneedle patch of the present invention has the function of increasing adhesion.

[0035] The above are only the preferred embodiments of the present invention, and do not impose any form of limitation on the present invention. Although the present invention has been disclosed above with the preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some changes or modifications to the above-disclosed technical content to be equivalent embodiments within the scope of the technical solution of the present invention. However, as long as it does not depart from the content of the technical solution of the present invention, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A microneedle patch imitating the barbed structure of Xanthium sibiricum, characterized in that The preparation method comprises the following three steps; S1. Obtain a microneedle patch model with a cocklebur thorn-like structure through 3D printing; S2. Perform a reverse mold on the microneedle patch model obtained in step S1 to obtain a microneedle patch mold; S3. Prepare a material solution for preparing the microneedle patch, pour the material solution into the microneedle patch mold, then place the mold in a vacuum environment for 10 - 30 min to remove the air bubbles in the material solution, then perform vacuum heating and drying on the mold until the material solution is dried and formed, and then separate the mold from the microneedle patch to obtain the microneedle patch.

2. The microneedle patch with a burdock burr structure imitation as claimed in claim 1, wherein, The specific method of reverse mold in step S2 is as follows: Place the microneedle patch model obtained in step S1 into a rectangular container with the needle tips facing upward, pour the pre-prepared reverse mold solution into the rectangular container so that the liquid level is 4 - 6 mm higher than the needle tips; then place the rectangular container in a vacuum environment for 2 - 3 hours to remove the air bubbles in the liquid, next place the rectangular container overnight or heat it in an oven until the liquid in it is completely cured, and finally remove the microneedle patch model from it to obtain the bionic microneedle model.

3. The microneedle patch with a cocklebur barbs structure as claimed in claim 2, wherein The reverse mold solution is a mixed solution of polydimethylsiloxane and a curing agent.

4. The microneedle patch with a structure imitating the barbs of Xanthium, as described in claim 1, is characterized in that The specific steps of step S3 are as follows: S31. Prepare a material solution for preparing the microneedle patch, and the material solution contains a drug component; S32. Pour a part of the material solution into the microneedle patch mold, then place the mold in a vacuum environment for 10 - 30 min to remove the air bubbles in the material solution, take out the mold from the vacuum environment and scrape off the excess solution with air bubbles above the needle holes, then perform vacuum heating and drying on the mold until the material solution is dried and formed to form the needle tips; add the material solution into the mold again, and place it in a vacuum environment for 10 - 30 min to remove the air bubbles in the material solution, take out the mold from the vacuum environment and perform vacuum heating and drying until the material solution is dried and formed to form the back plate of the microneedle patch, and then separate the mold from the microneedle patch to obtain the microneedle patch.

5. The microneedle patch with a burdock burr-like structure according to claim 4, wherein The components of the material solution also include polyvinyl alcohol and deionized water.

6. Use of a microneedle patch having a cocklebur thorn-like structure according to any one of claims 1-5, characterized in that, For transdermal drug delivery.

7. The application of the microneedle patch with the structure imitating the barbs of Xanthium, as claimed in claim 6, wherein, The microneedle patch with a cocklebur thorn-like structure can hook the skin tissue after piercing the skin to increase the adhesion of the microneedle patch to the skin.

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