Bionic self-locking microneedle structure, microneedle patch and preparation method

Abstract

The invention belongs to the technical field of medical equipment, and particularly relates to a bionic self-locking microneedle structure, a microneedle patch and a preparation method. The bionic self-locking microneedle structure comprises a needle body and a wing-shaped structure, the wing-shaped structures are evenly distributed in the circumferential direction of the needle body. The tip end of the wing-shaped structure and the tip end of the needle head are in the same direction, and the angle of the tip end is 25-45 degrees; the length of the wing-shaped structure is smaller than that of the needle body; the wing-shaped structure is located at the position 200-800 microns away from the bottom of the needle head. The number of the wing-shaped structures ranges from 2 to 10. The supporting wings, namely the wing-shaped structures, are integrally connected with the needle body, the contact area between the lower portions of the bionic wing-shaped structures and the skin is larger, and the adhesion capacity to the skin is better. Due to the wing-shaped structure, a reverse buckling effect can be formed between the micro-needle and surrounding tissues after the micro-needle is punctured into the skin, so that the pullout force caused by tissue rebound and body fluid lubrication is effectively resisted, and long-term stable retention of the micro-needle in the skin is realized.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medical devices, and particularly relates to a bionic self-locking microneedle structure, a microneedle patch and a preparation method. BACKGROUND

[0002] As a kind of high molecular material that can be dissolved in water and form stable solution or colloid, water-soluble polymer has excellent solubility, film-forming property and controllable viscoelasticity. The hydrophilic groups (such as hydroxyl, carboxyl, amino, etc.) on the molecular chain of the water-soluble polymer can be combined with water molecules through hydrogen bond or electrostatic interaction to form a hydration layer. Meanwhile, the water-soluble polymer can be controllably degraded or phase changed under specific conditions (such as pH, temperature, enzyme action), so it has good processing adaptability and environmental responsiveness. Therefore, the water-soluble polymer is widely used in daily chemical industry, biomedical, food industry and environmental engineering. On the one hand, the product (such as drug carrier, food packaging film, sewage treatment flocculant) with water-soluble polymer as functional substrate can realize the integrated effect of "functional response + material transformation" by swelling, dissolving or chain relaxation to achieve the controlled release of active ingredients, the in-situ formation of barrier layer or the adsorption and flocculation of pollutants after contacting with water phase medium, thereby avoiding the environmental burden of traditional non-water-soluble materials which are difficult to degrade or recycle. On the other hand, the biocompatibility and low toxicity of water-soluble polymer can reduce the negative impact on the ecological environment or living organisms, and meet the requirements of absorbable suture in medical field and skin-friendly formula in daily chemical industry. Therefore, the water-soluble polymer has irreplaceable application value in the industrial upgrading and product innovation under the guidance of sustainable development.

[0003] Microneedle is a kind of device arranged in array form on the backing layer by needle-shaped protrusions with a length of 50 μm to 5000 μm. As a new transdermal drug delivery technology, the core advantage of microneedle lies in its minimally invasive, painless, convenient operation and high delivery efficiency. The clinical application of microneedle as an efficient transdermal drug delivery tool is often limited by insufficient mechanical retention force between microneedle and skin tissue. The existing microneedle structure mainly takes the needle tip as the main part. After being applied to the skin, especially in the parts with frequent activities or more body fluid secretion, the microneedle is prone to come off, shift or even fall off from the puncture channel due to the elastic recoil of the subcutaneous tissue and the lubrication of the epidermal sweat and interstitial fluid, which leads to a significant reduction in drug delivery efficiency and cannot guarantee the accuracy of the drug dose and the treatment effect. In addition, the traditional microneedle structure mainly depends on the adhesive layer of the backing material to achieve adhesion, but the adhesion force will weaken with time and skin activity, and it is difficult to form a durable and effective anchoring support for the root of the microneedle. SUMMARY

[0004] In order to solve the above problems, the application provides a bionic self-locking microneedle structure and a preparation method thereof. The bionic self-locking microneedle structure is provided with a wing-shaped structure on the side wall of the microneedle, so that the wing-shaped structure can form a reverse buckle effect with the surrounding tissue after penetrating into the skin, thereby effectively resisting the ejection force caused by tissue rebound and body fluid lubrication, and realizing long-term stable retention of the microneedle in the skin.

[0005] In order to achieve the above-mentioned purpose, the technical scheme of the application is as follows.

[0006] The first aspect of the application provides a bionic self-locking microneedle structure, comprising a needle body and a wing-shaped structure. The wing-shaped structures are uniformly distributed along the circumference of the needle body. The tip of the wing-shaped structure is in the same direction as the tip of the needle head, and the angle of the tip is 25°-45°. The length of the wing-shaped structure is less than the length of the needle body; the wing-shaped structure is located at a distance of 200-800 microns from the bottom of the needle head; preferably, the wing-shaped structure is located at a distance of 400 microns from the bottom of the needle head; the number of wing-shaped structures is not less than 2; each wing-shaped structure is a pyramid; the length of the wing-shaped structure is 100-300 microns, the width is 30-60 microns, and the thickness is 20-120 microns. The structure of the microneedle helps to hook at the epidermis which is the most tough skin, thereby increasing the fixing stability.

[0007] In another preferred embodiment, the number of wing-shaped structures is 2-10.

[0008] In another preferred embodiment, the needle body is a cone, the height of the needle body is 500-1000 microns, the bottom diameter is 100-400 microns, and the vertex angle is 25°-45°. The application uses a material with swelling properties to prepare the microneedle, which helps to puncture and fix on the basis of ensuring the structural strength.

[0009] The second aspect of the application provides a microneedle patch, wherein the bionic self-locking microneedle structures are arrayed on the microneedle patch. Specifically, the number of bionic self-locking microneedle structures is 100-1000, and the bionic self-locking microneedle structures are arrayed.

[0010] The third aspect of the application provides a preparation method of the microneedle patch, comprising the following steps: The hyaluronic acid and distilled water are mixed in a mass-volume ratio of 3-5 g:10-20 mL, centrifuged, and hyaluronic acid solution is obtained. The hyaluronic acid solution is coated in the mold with array-arranged self-locking bionic microneedle structure, deaerated, solidified, demolded, and the microneedle patch is obtained.

[0011] In another preferred embodiment, the purity of the hyaluronic acid is 97%, and the molecular weight is 30KDa-45KDa.

[0012] In another preferred embodiment, the centrifugal speed is 3000r / min-4000r / min, and the centrifugal time is 6min-8min.

[0013] In another preferred embodiment, the deaeration time is 6h-12h, and the pressure is-0.098MPa-0.0784MPa.

[0014] In another preferred embodiment, the solidification temperature is 15℃-27℃, and the time is 15h-30h.

[0015] Compared with the prior art, the present application has the following beneficial effects: The support wing, i.e., the wing-shaped structure, is integrally connected with the needle body, so that the wing-shaped structure is arranged at a distance of 200μm-800μm from the bottom of the needle head, and the wing-shaped structure with a length of 100μm-300μm, a width of 30μm-60μm, and a thickness of 20μm-120μm can make the microneedle have a larger contact area with the skin and better adhesion to the skin. The wing-shaped structure can form a reverse buckling effect with the surrounding tissue after penetrating the skin, thereby effectively resisting the expulsion force caused by tissue rebound and body fluid lubrication, and realizing long-term stable retention of the microneedle in the skin.

[0016] The hyaluronic acid with a molecular weight of 30KDa-45KDa used in the present application is a biological material, and after the microneedle penetrates the skin surface and mixes with the body fluid, it is dissolved, thereby releasing the carried exosome of stem cells and realizing the function of painless transdermal drug delivery.

[0017] The barb microneedle structure proposed in the present application can embed the skin in the bionic wing-shaped structure, thereby preventing the repulsive force caused by skin rebound from extruding the microneedle from the skin, so that the microneedle patch can be firmly attached to the skin surface, ensuring complete release of the drug. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 FIG. 1 is a schematic diagram of the bionic self-locking microneedle structure in the embodiment of the present application.

[0019] Figure 2A front view of the bionic self-locking microneedle structure in the embodiment of the present application.

[0020] Figure 3 A perspective view of the microneedle patch in the embodiment of the present application.

[0021] Figure 4 A top view of the microneedle patch in the embodiment of the present application.

[0022] Figure 5 A front view of the microneedle patch in the embodiment of the present application.

[0023] Legend: 1-needle body, 2-wing structure. DETAILED DESCRIPTION

[0024] In combination with the specific embodiments of the present application, the technical solutions in the present application are described clearly and completely, apparently, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by the person skilled in the art without making creative efforts, belong to the protection scope of the present application.

[0025] The method described in each embodiment of the present application is a conventional method, unless otherwise specified. The materials, reagents, etc. used, unless otherwise specified, can be obtained from commercial channels.

[0026] Microneedle is a kind of device arranged in array form by needle-like protrusions with a length of 50-5000 μm on a backing layer, as an emerging transdermal drug delivery technology. The advantages of microneedle technology are embodied in the following three aspects: firstly, the micropore channel constructed by microneedle can directly shorten the drug permeation path, greatly improve the transdermal absorption rate of drug, reduce the metabolic loss of drug after entering the systemic circulation, and improve the local concentration of drug in the target tissue of skin, thereby enhancing the drug efficacy; secondly, the size of the needle-like protrusions of microneedle is small, and the depth of penetration is usually only to the stratum corneum to the epidermis, without touching the pain nerve endings in the dermis, so that the microneedle can realize minimally invasive and painless drug delivery experience, and significantly reduce the discomfort and use threshold of the user; thirdly, the length, array density and backing layer morphology of the needle-like protrusions of microneedle can be customized according to the drug delivery site, drug type and delivery requirement, and microneedle has both convenience and accuracy of delivery; according to the differences in action principle and structural characteristics, microneedle can be divided into five categories: solid microneedle, hollow microneedle, coated microneedle, hydrogel microneedle and water-soluble microneedle. Among them, the water-soluble microneedle is made of water-soluble polymer matrix, and its action mechanism is special. Due to the water-solubility of the matrix, the water-soluble microneedle will gradually dissolve under the action of skin tissue fluid after penetrating into the skin, and the drug loaded in the microneedle can be directly released into the surrounding tissue with the dissolution of the matrix. The water-soluble microneedle has good biocompatibility, and by designing the type, molecular weight and ratio of water-soluble polymer, the water-soluble microneedle can be endowed with different dissolution rates and drug release properties.

[0027] The existing microneedle structure is prone to come off, shift or even fall off from the penetration channel after being applied to the skin, especially in the parts with frequent activities or more body fluid secretion, due to the elastic recoil of the subcutaneous tissue and the lubrication of the epidermal sweat and tissue fluid, which leads to a significant reduction in drug delivery efficiency and cannot guarantee the accuracy of the drug dose and the treatment effect. In addition, the traditional microneedle structure relies on the adhesive layer of the backing material to achieve adhesion, but the adhesion force will weaken with time and epidermal activity, and it is difficult to provide long-lasting and effective anchoring support for the root of the microneedle. In order to overcome this technical bottleneck, an innovative structure that can form mechanical interlocking with the skin tissue and enhance the anchoring ability of the microneedle is needed, so as to improve the retention stability of the microneedle in the body and the reliability of drug release. Therefore, the present application proposes a microneedle design with a self-locking structure, which adds a fin-shaped structure to the side wall of the microneedle, so that it can form a reverse buckling effect with the surrounding tissue after penetrating into the skin, thereby effectively resisting the ejection force caused by tissue rebound and body fluid lubrication, and realizing the long-term stable retention of the microneedle in the skin.

[0028] The following will specifically describe a bionic self-locking microneedle structure and its preparation method.

[0029] A bionic self-locking microneedle structure, as shown in Figure 1 , comprises a needle body 1 and a fin-shaped structure 2. The needle body 1 is a cone with a height of 500μm~1000μm, a bottom diameter of 100μm~400μm, and a apex angle of 25°~45°.

[0030] The wing-like structures 2 are evenly distributed along the circumference of the needle body 1; the tip of the wing-like structures 2 is in the same direction as the tip of the needle 1, and the angle of the tip is 25°~45°; the length of the wing-like structures 2 is less than the length of the needle body 1.

[0031] Specifically, the wing-like structure 2 is located 200μm to 800μm from the bottom of the needle tip 1, preferably 800μm from the bottom of the needle tip 1; the number of wing-like structures 2 is 2 to 10. The wing-like structure 2 is pyramidal in shape; the length of the wing-like structure 2 is 100μm to 300μm, the width is 30μm to 60μm, and the thickness is 20μm to 120μm.

[0032] A type of microneedle patch, such as Figure 2 As shown, the aforementioned biomimetic self-locking microneedle structure is arrayed on the microneedle patch. The biomimetic self-locking microneedle structure was designed using SolidWorks modeling software, and a resin microneedle anode template was prepared by photopolymerization 3D printing. The microneedle body is a cone with a height of 800 μm, a bottom diameter of 400 μm, and an inclination angle of 75°. Each microneedle body 1 has a wing-like structure 2, distributed circumferentially along the needle body 2 in a pyramidal shape, extending outward from the needle body surface at a 60° inclination angle. There are 6 wings, evenly distributed on the needle body and integrally formed with it. The wings are 213 μm long, 20 μm wide, and 47 μm thick, with a distance of 280 μm from the bottom of the needle body.

[0033] The specific preparation process of the above microneedle patch is as follows: The polydimethylsiloxane PDMS precursor (Base Elastomer) and G-328 epoxy curing agent (CuringAgent) were mixed evenly at a mass ratio of 10:1 and injected into a container containing a resin microneedle positive template. The microneedles were 800µm in length and placed in a vacuum desiccator. They were then treated with a vacuum pump at -0.098MPa for 30 minutes until the air bubbles were eliminated. After that, the container was placed at 25°C for 24 hours to allow it to cure completely. After curing, the microneedle positive template was separated from the PDMS to obtain the PDMS microneedle negative template.

[0034] The hyaluronic acid microneedle material with a mass percentage of 97% and a molecular weight of 30KDa-45KDa is dissolved in distilled water, the mass of the hyaluronic acid microneedle material is 4.5g, the volume of the distilled water is 15mL, the target rotation speed is 3000rpm, the lifting speed is 9gears, the descending speed is 9gears, the centrifugal temperature is 4℃, the centrifugal time for maintaining the target rotation speed is 6min, the bubbles are removed and the uniformity of the hyaluronic acid is ensured, the hyaluronic acid microneedle solution is obtained, the hyaluronic acid microneedle solution is added into the PDMS microneedle negative mold, a glass rod is pressed for 25 times, it is placed in a vacuum dryer, a vacuum pump is used for low pressure treatment for 8h, after supplementing the solution, it is dried at 25℃ for 24h to form, and the microneedle patch is obtained.

[0035] Although preferred embodiments of the application have been described herein, changes and modifications can be suggested to one skilled in the art, and it is intended that the application encompass such changes and modifications as fall within the scope of the appended claims.

[0036] Obviously, numerous modifications and variations of the present application are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the application can be practiced otherwise than as specifically described herein.

Claims

1. A biomimetic self-locking microneedle structure, characterized in that, The needle body (1) and the fin structure (2) are included. The fin structure (2) is evenly distributed along the circumference of the needle body (1). The tip of the fin structure (2) is in the same direction as the tip of the needle (1), and the angle of the tip is 25°-45°. The length of the fin structure (2) is less than the length of the needle body (1); the fin structure (2) is located at a distance of 200-800 μm from the bottom of the needle (1); the number of fin structures (2) is not less than 2. Each of the fin structures (2) is a pyramid; the length of the fin structure (2) is 100-300 μm, the width is 30-60 μm, and the thickness is 20-120 μm.

2. The bionic self-locking microneedle structure of claim 1, wherein, The number of fin structures (2) is 2-10.

3. The bionic self-locking microneedle structure of claim 1, wherein, The needle body (1) is a cone; the height of the needle body (1) is 500-1000 μm, the bottom diameter is 100-400 μm, and the vertex angle is 25°-45°.

4. A microneedle patch, characterized by, The microneedle patch has an array of the bionic self-locking microneedle structure of claim 1.

5. A method of making the microneedle patch of claim 4, wherein, The steps include: BHA and distilled water are mixed in a mass-volume ratio of 3-5 g:10-20 mL, centrifuged, and a BHA solution is obtained. The BHA solution is coated in a mold with an array of the bionic self-locking microneedle structure, degassed, left to solidify, demolded, and a microneedle patch is obtained.

6. The production method according to claim 5, wherein The molecular weight of the BHA is 30-45 KDa.

7. The preparation method according to claim 5, characterized in that, The centrifugation speed is 3000-4000 r / min, and the centrifugation time is 6-8 min.

8. The preparation method according to claim 5, characterized in that, The degassing time is 6-12 h, and the pressure is -0.098-0.0784 MPa.

9. The preparation method according to claim 5, characterized in that, The solidification temperature is 15-27 °C, and the time is 15-30 h.

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