Spiny microneedle drug delivery carrier and preparation method and application thereof

Abstract

The invention relates to the technical field of drug delivery and discloses a spinous microneedle drug delivery carrier as well as a preparation method and application thereof. The spinous microneedle delivery carrier comprises a shell and a needle tip; the needle tip is conical and is arranged on the surface of the shell; the bottom of the needle tip and the shell form a communicated cavity. The mold for preparing the spinous microneedle drug delivery carrier is composed of a forming mold, a fixing piece and a fixing mold. According to the spinous microneedle drug delivery carrier, by means of natural wriggling of the intestinal tract, the needle tip can effectively penetrate through the intestinal tract wall, the drug is continuously delivered to the treatment position, and the limitation of a traditional drug delivery mode is avoided. The spinous microneedle drug delivery carrier can be used for preparing drugs acting on gastrointestinal tracts, and the application of the enteric capsule can prevent gastric acid from damaging the drug carrier and ensure the integrity of the drug carrier until the drug carrier is released into intestinal tracts.

Description

Technical Field

[0001] The present invention relates to the technical field of drug delivery, and more specifically, to a spiny microneedle drug delivery carrier and a preparation method and application thereof. Background Art

[0002] Oral administration has a low professional operation threshold and high patient compliance, but this approach encounters obvious obstacles when it comes to biologics (such as peptides, proteins, nucleic acids, and antibodies). These biological drugs are easily inactivated in the harsh chemical environment of the gastrointestinal tract, and are limited by the conservative absorption mechanism of the intestine, making it difficult to penetrate the mucus layer or cell barrier for transmission. Therefore, the oral utilization rate of biologics is usually very low (about 1%), and most need to be administered by injection. Injection administration may not only cause pain and skin infection, but also often cause nodules in the local muscles of patients, resulting in decreased patient compliance.

[0003] In terms of drug delivery and disease treatment, microneedles can deliver vaccines, small molecule drugs, biologics and other drugs for the treatment of hepatitis, diabetes, tumors, wound repair and other treatments. Microneedle patches prepared with microneedle arrays are a new type of superficial transdermal drug delivery method that can penetrate the stratum corneum of the skin in a directional manner and deliver drugs into the skin without pricking the pain nerves in the dermis. When delivering drugs with microneedles, the active ingredients are usually loaded into the microneedle array. After penetrating the surface layer of the skin, the microneedles gradually dissolve and slowly release the loaded drugs into the body. In addition to the advantages of transdermal delivery systems, microneedle drug delivery also has the following advantages: it has a sustained release effect on the release of drugs; by controlling the length of the microneedles, the needle tip can be prevented from touching the capillaries and nerve endings in the dermis, which can significantly reduce or eliminate the tingling sensation; the drug delivery method is convenient and the patient's compliance with the drug delivery is good. At present, the progress of microneedle drug delivery technology is mainly focused on the innovation of preparation materials and forms, such as from silicon, silicon oxide to metals, polymer materials, and then to hydrogel microneedles. On the other hand, microneedles can also be divided into solid, hollow, coated, soluble, hydrogel, etc., but this classification is more based on their physical properties and preparation methods rather than directly optimized designs for specific application requirements (such as gastrointestinal drug delivery).

[0004] Although there are new attempts in the form and application direction of microneedle technology, the research on microneedle drug delivery in the gastrointestinal tract still needs further attempts and optimization. Due to the particularity of the gastrointestinal environment (such as pH, the presence of enzymes, peristalsis, etc.), new requirements are put forward for the design and application of microneedles. Recently, in order to solve the problem of drug delivery in the gastrointestinal tract, some new research attempts have been made to apply microneedle technology to gastrointestinal drug delivery. By wrapping commercial enteric-coated capsules and swallowing them, the enteric-coated capsules are used to protect the microneedle drug carriers from being dissolved by gastric acid. When the capsule enters the small intestine, the enteric-coated capsules dissolve and release the microneedle carriers inside, and the microneedles penetrate the inner wall of the intestine to release the drugs.

[0005] Prior art CN218700634U provides a 3D printed laminated microneedle mold. The mold structure is relatively simple and can solve the problem of bubbles easily generated when injecting liquid into microneedle patches. However, the microneedle drug delivery carrier prepared by this patented mold is a microneedle patch with a sheet structure. Prior art CN219600125U provides a silk fibroin gel microneedle preparation mold. The mold has multiple holes for injecting liquid so that multiple microneedle patches can be formed at one time. During preparation, bubbles are discharged under negative pressure conditions. However, most of the preparation molds for microneedle drug delivery carriers are currently used for the preparation of microneedle patches. This type of planar structure microneedle patch cannot meet the application requirements of microneedle technology in gastrointestinal drug delivery. Summary of the invention

[0006] The present invention provides a spine-shaped microneedle drug delivery carrier to overcome the problem that the microneedle patch with a planar structure described in the prior art cannot meet the drug delivery requirements in the gastrointestinal tract.

[0007] Another object of the present invention is to provide a method for preparing a spine-shaped microneedle drug delivery carrier;

[0008] Another object of the present invention is to provide an application of a spine-shaped microneedle drug delivery carrier.

[0009] In order to solve the above technical problems, the technical solution of the present invention is as follows:

[0010] A spine-shaped microneedle drug delivery carrier comprises a shell and a needle tip; the needle tip is cone-shaped and arranged on the surface of the shell; the interior of the needle tip is a cavity, and the bottom of the needle tip forms a connected cavity with the shell.

[0011] Furthermore, the spine-shaped microneedle delivery carrier has a length of less than 15000 μm and a width of less than 8000 μm.

[0012] Preferably, the needle tip is 1000-1500 μm long, 500-800 μm in diameter, and the distance between the needle tip tops is 1.5-3.0 μm.

[0013] A spine-shaped microneedle drug delivery carrier mold is used to prepare the spine-shaped microneedle drug delivery carrier. The spine-shaped microneedle drug delivery carrier mold consists of the following structures: a molding mold, a fixing piece and a fixed mold; the fixed mold is provided with a groove that matches the molding mold, and the fixing piece is used to fix the molding mold to the fixed mold.

[0014] Preferably, the forming mold and the fixing mold are respectively composed of two identical components.

[0015] A method for preparing the spine-shaped microneedle drug delivery carrier mold comprises the following steps:

[0016] S1, pouring the material for preparing the molding mold into the mold, and heating and curing it, and obtaining a hard block with a built-in depression after the material hardens;

[0017] S2, preparing a needle tip model on the inner wall of the hard block with a built-in depression, and performing plasma treatment on the surface to obtain a molding mold;

[0018] S3, pouring the material for preparing the fixed mold into the mold whose shape is assembled with the forming mold, and after drying and curing, obtaining the fixed mold.

[0019] Preferably, the material for preparing the forming mold and / or the material for preparing the fixing mold comprises polydimethylsiloxane and a cross-linking agent.

[0020] Furthermore, a needle tip model was prepared by punching with a puncher, and the needle tip specifications were input through a microfluidic device, with a length of 1000-1500 μm, a diameter of 500-800 μm, and a needle tip top spacing of 1.5-3.0 μm.

[0021] Preferably, the needle tip has a length of 1200 μm, a diameter of 750 μm, and a distance between the needle tip tops of 1.5 μm.

[0022] Preferably, the molding mold 1 has a height of 1.4 cm, a width of 1.1 cm, and a thickness of 0.3 cm; the fixing mold 3 has a height of 1.7 cm, a width of 2.1 cm, and a thickness of 0.75 cm.

[0023] Conventional microneedle molds are mostly used to prepare planar microneedle patches. The mold of the present invention is mainly composed of four parts, including a forming mold and a fixed mold containing two identical components respectively. The components of the two fixed molds are combined into one and fixed by a fixing member, and the two components of the forming mold can be spliced ​​into one. The inside of the mold can be perfused with a photosensitive matrix and mixed with the drug, and a three-dimensional microneedle drug delivery carrier with a thorn-shaped structure is formed after photocuring. The mold for preparing the thorn-shaped structure microneedle drug delivery carrier adopts a decomposed structure and is composed of multiple molds. By assembling the modules, the precise preparation of the morphology of the thorn-shaped microneedle drug carrier can be achieved. At the same time, under the preferred specifications, the mold can be placed in a conventional centrifuge tube with a volume of 50mL, and the bubbles generated by the mold in the process of preparing the thorn-shaped microneedle drug delivery carrier are further removed by high-speed centrifugation to ensure the successful preparation of the sample.

[0024] A method for preparing the spine-shaped microneedle drug delivery carrier, using the spine-shaped microneedle drug delivery carrier mold, comprises the following steps:

[0025] S1, pouring the material solution for preparing the spine-shaped microneedle drug delivery carrier into a molding mold, treating it under negative pressure, and drying it;

[0026] S2, continue to add material solution into the molding die and continue drying;

[0027] S3, repeat S2 until the molding mold is filled;

[0028] S4, butting the two samples obtained in S3 in a molding die, and applying the material solution at the butt joint;

[0029] S5, placing the two butted molding dies in a fixed mold for assembly, fixing them with fixing parts, and then performing a drying process;

[0030] S6. Take out the sample obtained in S5 from the spine-shaped microneedle drug delivery carrier mold to obtain a spine-shaped microneedle drug delivery carrier.

[0031] Furthermore, the material for preparing the spine-shaped microneedle drug delivery carrier includes a swellable material.

[0032] Preferably, the swellable material is gelatin methacrylate (GelMA).

[0033] Preferably, S3 fills the molding die with the material, and a cavity can be formed after drying.

[0034] Further preferably, in S1, the methacrylated gelatin aqueous solution and the photoinitiator 2959 ethanol solution are mixed and stirred evenly, poured into a molding mold, placed in a 37-40° C. water bath and vacuumed under negative pressure until the bubbles in the solution in the mold are removed; and dried at 37-40° C. for 10-20 minutes;

[0035] Still more preferably, the volume ratio of the methacrylated gelatin aqueous solution is 10 to 20% by weight.

[0036] Preferably, the volume ratio of the methacrylated gelatin aqueous solution is 15% by weight, and the volume ratio of the photoinitiator 2959 ethanol solution is 5% by weight.

[0037] Preferably, the volume ratio of the methacrylated gelatin aqueous solution to 100 μL of the photoinitiator 2959 ethanol solution is 100:1.

[0038] Further preferably, in S4, the amount of the material solution applied at the joint is 0.4% to 0.6% of the total amount of the material solution added in S1.

[0039] Preferably, the mold assembled in S5 can be subjected to high-speed centrifugation to remove air bubbles.

[0040] More preferably, in S5, drying is performed at 37 to 40°C for 4 to 12 hours.

[0041] Preferably, in S6, after the sample obtained in S5 is taken out from the spine-shaped microneedle drug delivery carrier mold, it is irradiated under ultraviolet light for 10 to 50 minutes.

[0042] An application of the spine-shaped microneedle drug delivery carrier is used to prepare drugs that act on the gastrointestinal tract.

[0043] Furthermore, the drug is stored in the cavity and / or shell and needle tip of the spine-shaped microneedle drug delivery carrier.

[0044] Preferably, the material solution for preparing the spine-shaped microneedle drug delivery carrier is mixed with the drug before preparing the spine-shaped microneedle drug delivery carrier, and the drug will be stored in the shell and the needle tip; during preparation, the drug is added to the cavity of the two samples and then the two molding molds are docked, and the drug will be stored in the cavity of the spine-shaped microneedle drug delivery carrier; or after the preparation of the spine-shaped microneedle drug delivery carrier is completed, the drug is injected into the cavity.

[0045] A drug acting on the gastrointestinal tract is prepared from the spine-shaped microneedle drug delivery carrier.

[0046] Preferably, after the drug is stored in the spine-shaped microneedle drug delivery carrier, it is packaged in an enteric-coated capsule to obtain a drug that acts on the gastrointestinal tract.

[0047] The spine-shaped microneedle drug delivery carrier prepared by the present invention can be wrapped with a commercial enteric-coated capsule, thereby protecting the spine-shaped microneedle drug delivery carrier from being smoothly orally taken into the stomach and not being digested and absorbed by gastric acid. When the capsule passes through the stomach and enters the intestine, the change in pH causes the enteric-coated capsule to dissolve and release the spine-shaped microneedle drug delivery carrier inside. Its unique needle tip structure enables the drug carrier to adhere well to the inner wall of the intestine, and the needle tip structure is pierced into the inner wall of the intestine with the help of the peristalsis and contraction of the intestine itself, thereby transporting the drug to the whole body through the lymphatic capillary network of the intestine.

[0048] Secondly, the spine-shaped microneedle drug delivery carrier prepared by the mold of the present invention adopts an innovative peristaltic drive method compared to conventional drug delivery capsules, which relies on natural physiological movement in the body to achieve power. This peristaltic drive mechanism does not require pre-reserved energy or external energy input during operation, so it can abandon non-biodegradable drive components such as metal springs, rubber elastomers and magnetic particles, ensuring higher biosafety. At the same time, the manufacturing materials used by the spine-shaped microneedle drug delivery carrier are both biocompatible and degradable, avoiding blockage of the intestine and having a high clinical transformation value.

[0049] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0050] 1. Effectively penetrate the intestinal wall. The spine-shaped microneedle drug delivery carrier of the present invention can smoothly pass through the mammalian intestine and successfully penetrate the small intestinal wall to achieve slow release of the drug. Under the action of intestinal peristalsis, the tip of the microneedle can effectively penetrate the intestinal wall, while the penetration effect on the intestinal wall is relatively light, and no obvious tissue damage will be caused, further ensuring its safety.

[0051] 2. Overcome intestinal peristaltic resistance and stabilize drug delivery. The present invention uses the peristaltic force of the intestine to push the needle tip of the spine-shaped microneedle drug delivery carrier to penetrate the intestinal wall, ensuring that the drug can be slowly released from the microneedle carrier. When GelMA is used as the core material of the microneedle drug delivery carrier, its swellable properties enable the microneedle to expand rapidly after penetrating the intestine, enhancing adhesion to the intestinal wall. The average maximum adhesion of the spine-shaped microneedle drug delivery carrier to the intestinal wall is about 1.22N, and the needle tip enables the carrier to resist the driving force of 0.18 to 0.5N brought by intestinal peristalsis, thereby maintaining slow and continuous delivery of the drug.

[0052] 3. Improve drug retention and continuous delivery. The spine-shaped microneedle drug delivery carrier can firmly adhere to and continuously release drugs in the intestine due to its unique structure. Under the action of intestinal peristalsis, the microneedle enhances the adhesion to the intestinal wall through the swelling effect of its conical needle tip, improves the drug retention rate, and ensures that the drug is effectively released at the treatment site for a long time. This adhesion effect enhances the efficiency of drug delivery and significantly reduces the discomfort and risk during treatment.

[0053] 4. Break through the gastric acid barrier and protect the stable release of drugs. The application of enteric-coated capsules effectively protects the stability of the spine-shaped microneedle drug delivery carrier in the gastric acid environment, prevents gastric acid from destroying the drug carrier, and ensures the integrity of the drug carrier. When the enteric-coated capsule enters the intestine, the microneedle drug carrier is released, and the peristalsis of the intestine pushes the microneedle to penetrate the inner wall of the intestine and deliver the drug to the desired location, significantly improving the therapeutic effect of the drug.

[0054] 5. The spine-shaped microneedle structure improves penetration and efficiency. The spine-shaped microneedle drug delivery carrier has a larger surface area, which effectively increases the drug loading and release rate. The spine-shaped microneedle structure not only optimizes the drug delivery effect, but also enhances the interaction between the microneedle and intestinal tissue, promoting the rapid penetration and absorption of the drug.

[0055] 6. Size that meets clinical application requirements. The size of the spine-shaped microneedle drug delivery carrier meets the requirements of intestinal administration, can pass smoothly in the intestine and work effectively, and also ensures that the drug carrier can be completely placed in the enteric-coated capsule. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 This is a structural diagram of a spine-shaped microneedle drug delivery carrier mold;

[0057] Figure 2 This is a structural diagram of the body molding mold in the spine-shaped microneedle drug delivery carrier mold;

[0058] Figure 3 This is an exploded view of the mold of the spine-shaped microneedle drug delivery carrier;

[0059] The above, among which, 1. forming mold, 2. fixing part, 3. fixing mold.

[0060] Figure 4 This is the appearance of the mold of the spine-shaped microneedle drug delivery carrier;

[0061] Figure 5 This is a stereomicroscope image of the spine-shaped microneedle drug delivery carrier;

[0062] Figure 6 These are photos of the spiny microneedle drug delivery carrier in the rat intestine, A is the side view, B is the main view, and C is the top view;

[0063] Figure 7 These are photos of the spiny microneedle drug delivery carrier penetrating the intestinal wall. A is before the carrier puncture, B is intestinal peristalsis extrusion, and C is the removal of the carrier after puncture.

[0064] Figure 8 The adhesion effect of the spine-shaped microneedle drug delivery carrier on the intestinal wall;

[0065] Fig. 9 This is a graph showing the relationship between the pulling force and the displacement of the spiny microneedle drug delivery carrier;

[0066] Fig.10 This is a schematic diagram of the delivery process of the spine-shaped microneedle drug delivery carrier in the gastrointestinal tract. A is when it passes through the stomach, B is after reaching the intestine, and C is the release of the drug in the intestine. DETAILED DESCRIPTION

[0067] The present invention is further described below in conjunction with the accompanying drawings and specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0068] Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0069] Example 1

[0070] 1. Preparation of molds for spiny microneedle drug delivery carriers

[0071] Step 1: Pour a mixture of polydimethylsiloxane (liquid) and a crosslinking agent (for curing polydimethylsiloxane) into a metal mold and heat it at a high temperature. The metal mold can prepare a rectangular parallelepiped with a built-in semicircular depression. The semicircular depression of the obtained rectangular parallelepiped with a semicircular depression has a length of 8.54 mm and a width of 3 mm.

[0072] Step 2: After the polydimethylsiloxane is hardened, it is removed from the mold to obtain a rectangular polydimethylsiloxane block with a semicircular depression.

[0073] Step 3: Input the mold tip specifications through the microfluidic device. The tip shape is conical, the length is 1200μm, the diameter is 750μm, and the tip distance is 1.5mm. Punch the rectangular polydimethylsiloxane block with semicircular depressions obtained in the second step with a puncher, and then plasma treat the surface of the sample to obtain a molding mold.

[0074] Step 4: After completing the preparation of the two molding molds, start preparing the fixed mold. Also use polydimethylsiloxane, pour it into the mold, and wait for it to dry and demold.

[0075] Step 5: Assemble the two forming molds and the fixed mold. When there is no gap between the molds, the size is appropriate.

[0076] Step 6: Punch holes in the fixed mold for fixing with fixing parts (screws, nuts) to prevent the mold from falling apart due to high-speed centrifugation during the microneedle preparation process.

[0077] 2. Preparation of spine-shaped microneedle drug delivery carrier

[0078] Step 1: Mix 10 mL of methacrylated gelatin aqueous solution (15% by weight in volume) with 100 μL of photoinitiator 2959 (5% by weight in volume) dissolved in anhydrous ethanol, stir at a stirring rate of 300 r / min for 8 min, pour the mixture into a molding mold, place the mixture in a 37°C water bath and evacuate under negative pressure for 10 min, remove the bubbles in the solution in the mold, and continue evacuating under negative pressure for 10 min.

[0079] Step 2: Place the above solution and the mold in a 37°C oven for 15 minutes, then continue to add the sample solution in the first step into the mold and continue drying for 15 minutes. Repeat the above steps until the sample solution dries and fills the entire mold.

[0080] Step 3: dock the two dried samples obtained in the second step in a molding mold, apply 50 μL of the sample solution described in the first step at the docking point of the samples, and then place the two docked samples into a fixed mold.

[0081] Step 4: Fix the mold with fixings (screws, nuts).

[0082] Step 5: After the mold fixed with the nut in step 4 is fast centrifuged to remove bubbles, it is placed in a 37°C oven for drying for 8 hours and then taken out of the oven. The fixing screws of the mold are then loosened and the screws are removed, and the sample in the mold is taken out.

[0083] Step 6: The sample taken out in step 5 is irradiated with a UV curing lamp (power 15W) for 15 minutes to obtain a spine-shaped microneedle drug delivery carrier with a cavity structure. After the spine-shaped microneedle drug delivery carrier is prepared, the drug is injected into the cavity.

[0084] Example 2

[0085] 1. Preparation of molds for spiny microneedle drug delivery carriers

[0086] The preparation scheme is consistent with that of Example 1.

[0087] 2. Preparation of spine-shaped microneedle drug delivery carrier

[0088] Step 1: Mix 10 mL of methacrylated gelatin aqueous solution (20% by weight in volume) with 100 μL of photoinitiator 2959 (5% by weight in volume) dissolved in anhydrous ethanol, stir at a stirring rate of 300 rpm for 10 min, pour the mixture into a molding mold, place the mixture in a 40°C water bath and evacuate the mixture under negative pressure for 10 min, remove the bubbles in the solution in the mold, and continue evacuating the mixture under negative pressure for 10 min.

[0089] Step 2: Place the above solution and the mold in a 40°C oven for heating and drying for 20 minutes, then continue to add the sample solution in the first step into the mold and continue drying for 20 minutes. Repeat the above steps until the sample solution dries and fills the entire mold.

[0090] Step 3: dock the two dried samples obtained in step 2 in the molding mold, apply 50 μL of the sample solution in step 1 at the docking point of the samples, and then place the two docked samples into the fixed mold. Step 4: fix the mold with fixing parts (screws, nuts).

[0091] Step 5: After the mold fixed with the nut in step 4 is fast centrifuged to remove bubbles, it is placed in a 37°C oven for drying for 12 hours, and then the mold is taken out of the oven. Subsequently, the fixing screws of the mold are loosened and the screws are removed, and then the sample in the mold is taken out.

[0092] Step 6: The sample taken out in step 5 is irradiated with a UV curing lamp (power 15W) for 30 minutes to obtain a spine-shaped microneedle drug delivery carrier with a cavity structure. After the spine-shaped microneedle drug delivery carrier is prepared, the drug is injected into the cavity.

[0093] Example 3

[0094] 1. Preparation of molds for spiny microneedle drug delivery carriers

[0095] The preparation scheme is consistent with that of Example 1.

[0096] 2. Preparation of spine-shaped microneedle drug delivery carrier

[0097] Step 1: Mix 10 mL of methacrylated gelatin aqueous solution (10% by weight to volume), 100 μL of photoinitiator 2959 (5% by weight to volume) dissolved in anhydrous ethanol and the drug, stir continuously for 5 min at a stirring rate of 300 rpm, pour it into a molding mold, place it in a 37°C water bath and vacuum it under negative pressure for 10 min, remove the bubbles in the solution in the mold, and continue vacuuming under negative pressure for 10 min.

[0098] Step 2: Place the above solution and the mold in a 37°C oven for heating and drying for 10 minutes, then continue to add the sample solution in the first step into the mold and continue drying for 10 minutes. Repeat the above steps until the sample solution dries and fills the entire mold.

[0099] Step 3: Place the drug in the concave part of the dried sample obtained in step 2, then dock the two sample molding molds, apply 50 μL of the sample solution described in step 1 at the docking point, and then place the docked two samples into the fixed mold. Step 4: Fix the mold with fixing parts (screws, nuts).

[0100] Step 5: After the mold fixed with the nut in step 4 is fast centrifuged to remove bubbles, it is placed in a 37°C oven to dry for 4 hours, and then the mold is taken out of the oven. Subsequently, the fixing screws of the mold are loosened and the screws are removed, and then the sample in the mold is taken out.

[0101] Step 6: Irradiate the sample taken out in step 5 with a UV curing lamp (power 15W) for 10 minutes to obtain the spiny microneedle drug delivery carrier.

[0102] Step 7: Place the obtained spine-shaped microneedle drug delivery carrier into an enteric-coated capsule.

[0103] Test Method

[0104] 1. Observation of spiny microneedle drug delivery carrier

[0105] The morphology of the spiny microneedle drug delivery carrier was observed under a stereo microscope, and various structural parameters were measured.

[0106] 2. Observation of the spiny microneedle drug delivery carrier in the rat intestine

[0107] After the spine-shaped microneedle drug delivery carrier was placed in the rat intestine, a camera was used to take photos and observe.

[0108] 3. Effect of spiny microneedle drug delivery carrier on intestinal puncture

[0109] A section of rat small intestine with a length of about 4.5 cm was cut and a 1×0.5 cm opening was made. The prepared spine-shaped microneedle drug delivery carrier was then placed in the intestine and the incision was closed. After lightly pressing for 1 minute to simulate intestinal peristalsis, the spine-shaped microneedle drug delivery carrier was removed for photographic observation.

[0110] 4. Adhesion effect of spiny microneedle drug delivery carrier in the intestine

[0111] Three identical samples of spiny microneedle drug delivery carriers were prepared for testing and observation to ensure the reliability of the experimental results. One end of the spiny microneedle drug delivery carrier was tied to a 10.0N tensile gauge hook using a thin wire, and then the spiny microneedle drug delivery carrier was pressed into the rat intestine, and the tensile gauge was pulled to measure the adhesion of the spiny microneedle drug delivery carrier to the intestinal wall.

[0112] Results Analysis

[0113] 1. Structure of the spiny microneedle drug delivery carrier and mold

[0114] like Figure 1 As shown, the spine-shaped microneedle drug delivery carrier mold includes two molding molds 1, two fixing molds 3 and a plurality of fixing parts 2; Figure 2 As shown, the concave portion of each molding die 1 is the same semi-spine shape (a hemispherical or semi-spherical shape with a needle tip); Figure 3 As shown, when in use, the two molding dies 1 are fixed in the fixed die 3 through the fixing parts 2 .

[0115] like Figure 4 As shown, in the spine-shaped microneedle drug delivery carrier mold prepared in Example 1, each molding mold 1 has a height of 1.4 cm, a width of 1.1 cm, and a thickness of 0.3 cm; each fixed mold 3 has a height of 1.7 cm, a width of 2.1 cm, and a thickness of 0.75 cm.

[0116] like Figure 5 As shown, the total length (L4) of the spine-shaped microneedle drug delivery carrier prepared in Example 1 under a stereo microscope reaches 8233.560 μm, and the width (L5) is 3302.214 μm. The needle tip length (L1) of the spine-shaped microneedle drug delivery carrier is 1013.46 μm, the diameter (L3) is 531.133 μm, the distance between the tops of the two needle tips (L2) is 1654.543 μm, and the distance between the bottoms of the needle tips (L6) is 909.514 μm. The length of the spine-shaped microneedle drug delivery carrier prepared in Example 2 is about 0.9 cm, and the maximum width is about 0.6 cm. The length of the spine-shaped microneedle drug delivery carrier prepared in Example 3 is about 0.7 cm, and the maximum width is about 0.4 cm.

[0117] 2. Observation of the spiny microneedle drug delivery carrier in the rat intestine

[0118] The anatomical and physiological characteristics of rats are similar to those of humans and other mammals. The principle of action of the spine-shaped microneedle drug delivery carrier is mainly based on its ability to penetrate the skin or intestinal mucosal barrier to form microchannels to achieve drug delivery or biological sample collection. The application of this principle is universal to a certain extent, that is, the action and effect of the spine-shaped microneedle drug delivery carrier are similar in the intestinal environment of different organisms.

[0119] In order to verify whether the size of the spine-shaped microneedle drug delivery carrier is suitable for the small intestine of mammals and to evaluate its penetration ability, the spine-shaped microneedle drug delivery carrier prepared in Example 2 was placed in the intestine of rats and photographed using a camera to observe the effect of the spine-shaped microneedle drug delivery carrier in the intestine of rats. Figure 6 As shown in the figure, the spine-shaped microneedle drug delivery carrier of this size can pass through the rat intestine smoothly, and no obvious tissue damage to the intestinal lining is observed. Under the state of simulated intestinal peristalsis, the tip of the spine-shaped microneedle drug delivery carrier can penetrate the inner layer of the small intestine wall, achieve slow release of the drug, and thus improve the retention rate of the drug to provide continuous drug delivery.

[0120] 3. Test of the effect of spiny microneedle drug delivery carrier on intestinal puncture

[0121] During the digestion process of the gastrointestinal tract, the peristalsis of the stomach and intestines is not activated by the input of external energy, but by its inherent continuous contraction force. Intestinal peristalsis is an unconscious and coordinated process in the digestive process. It will autonomously alternate between contraction and relaxation to promote food mixing and propulsion. This continuous force can push the microneedle tip to penetrate the inner wall of the intestine for drug delivery. The intestinal peristalsis of the human body can contract nearly 10 times in the radial direction per minute. The magnitude of these contraction forces is usually between 0.18 and 0.5N / cm, which just matches the force required for the microneedle tip to penetrate the inner wall of the intestine. The contraction force generated during these peristalsis processes can provide sufficient driving force for the microneedle to overcome the resistance encountered when piercing the lumen wall.

[0122] according to Figure 7 The results showed that the spine-shaped microneedle drug delivery carrier left slight penetration marks on the intestinal wall after slight pressure, indicating that intestinal peristaltic contraction can push the needle tip of the spine-shaped microneedle drug delivery carrier into and penetrate the intestinal wall. At the same time, the penetration marks of the needle tip on the intestinal wall were light and would not cause obvious damage to the intestine.

[0123] 4. Adhesion effect of spiny microneedle drug delivery carrier in the intestine

[0124] In Example 1, the needle tip of the thorn-shaped microneedle drug delivery carrier is composed of a swellable GelMA material. When these microneedles penetrate the intestinal mucosa, their hydrophilic tips can absorb water and swell, thereby producing an interlocking effect with the tissue, greatly enhancing the adhesion strength. In addition, the conical needle tip of the thorn-shaped microneedle drug delivery carrier not only helps to reduce the resistance and depth of the microneedle when penetrating the tissue, reducing damage to the intestinal mucosa, but also enables the microneedle to fit the tissue surface more closely after swelling, thereby improving the adhesion effect of the thorn-shaped microneedle drug delivery carrier. This design not only optimizes the efficiency of drug delivery, but also reduces the risk and discomfort during treatment.

[0125] according to Figure 8 and Fig. 9 When the pulling force of sample one was 0.25N, the displacement of the spiny microneedle drug delivery carrier did not change. When the pulling force continued to increase to 1.15N, the spiny microneedle drug delivery carrier began to move 0.4cm to the right. When the pulling force of sample two was 0.6N, the displacement of the spiny microneedle drug delivery carrier did not change. When the pulling force reached 1.3N, the spiny microneedle drug delivery carrier moved 0.5cm to the right. When the pulling force of sample three was 0.5N, the displacement of the spiny microneedle drug delivery carrier did not change. When the pulling force was 1.2N, the spiny microneedle drug delivery carrier moved 0.45cm to the right. The above experimental results show that the average maximum adhesion force of the spine-shaped microneedle drug delivery carrier on the intestinal wall is about 1.22N, and the intestinal peristalsis can generate a driving force of 0.18N to 0.5N on the spine-shaped microneedle drug delivery carrier, indicating that the spine-shaped microneedle drug delivery carrier can resist a certain degree of driving force of intestinal peristalsis, thereby staying in the treatment position and achieving continuous delivery of drugs.

[0126] 5. Use enteric-coated capsules to encapsulate spiny microneedle drug delivery carriers for gastrointestinal drug delivery

[0127] The shell material of enteric-coated capsules is usually a high molecular polymer, such as acrylic resin or cellulose acetate phthalate, which has significant pH sensitivity. When the enteric-coated capsule passes through the stomach, in the acidic environment of gastric acid (pH about 1.5 to 3.5), the molecular chains of these materials can remain stable, preventing water penetration and capsule disintegration, thereby effectively isolating the external acidic environment from eroding the spine-shaped microneedle drug delivery carrier loaded inside. This characteristic ensures that the active ingredients and structure of the spine-shaped microneedle drug delivery carrier will not be destroyed before reaching the intestine.

[0128] like Fig.10 As shown, after the thorn-shaped microneedle drug delivery carrier of the loaded drug wrapped in the enteric-coated capsule prepared in Example 3 enters the human intestine, the capsule dissolves in the alkaline intestinal environment (pH about 6-8), gradually begins to disintegrate, thereby releasing the thorn-shaped microneedle drug delivery carrier in the intestine, and by means of a unique shape structure, the thorn-shaped microneedle drug delivery carrier can adhere to the intestine after release. Under the peristaltic action of the intestine, the thorn-shaped microneedle drug delivery carrier is gradually contracted and squeezed, so that its needle tip penetrates the intestinal wall and the drug loaded by the needle tip is achieved. The therapeutic effect of painless administration. At the same time, the thorn-shaped microneedle drug delivery carrier can also improve the retention rate of the drug and realize the continuous delivery of the drug. Therefore, it is ensured that the thorn-shaped microneedle drug delivery carrier can be completely put into the enteric-coated capsule, and it is also necessary to penetrate the inner layer of the intestinal wall during the peristalsis of the intestine, and it can pass through the intestine smoothly. The total length of the thorn-shaped microneedle drug delivery carrier is generally less than 15000um and the width is less than 8000um.

[0129] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the embodiments here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A spiny microneedle drug delivery carrier, characterized in that: The spine-shaped microneedle delivery carrier comprises a shell and a needle tip; the needle tip is cone-shaped and is placed on the surface of the shell; the interior of the needle tip is a cavity, and the bottom of the needle tip forms a connected cavity with the shell.

2. The spiny microneedle drug delivery carrier according to claim 1, characterized in that: The spine-shaped microneedle delivery carrier has a length of less than 15000 μm and a width of less than 8000 μm.

3. A mold for preparing a spiny microneedle drug delivery carrier, characterized in that: A method for preparing the spine-shaped microneedle drug delivery carrier according to any one of claims 1 to 2, wherein the mold for preparing the spine-shaped microneedle drug delivery carrier comprises the following structural components: a molding mold (1), a fixing member (2) and a fixing mold (3); the fixing mold (3) is provided with a groove matching the molding mold (1), and the fixing member (2) is used to fix the molding mold (1) and the fixing mold (3) together.

4. A method for preparing a mold for preparing a spine-shaped microneedle drug delivery carrier according to claim 3, characterized in that: The following steps are involved: S1, pouring the material for preparing the molding mold (1) into the mold, heating and melting, and solidifying, and after the material hardens, a hard block with a built-in depression is obtained; S2, preparing a needle tip model on the inner wall of the hard block with a built-in depression, and performing plasma treatment on the surface to obtain a molding mold (1); S3, pouring the material for preparing the fixed mold (3) into a mold whose shape is matched with the forming mold (1), and after drying and curing, obtaining the fixed mold.

5. The method for preparing the spine-shaped microneedle drug delivery carrier mold according to claim 4, characterized in that: Preparation of needle tip model: Punch with a puncher and input needle tip specifications through a microfluidic device, with a length of 1000-1500 μm, a diameter of 500-800 μm, and a needle tip top spacing of 1.5-3.0 μm.

6. A method for preparing the spine-shaped microneedle drug delivery carrier according to any one of claims 1 to 2, characterized in that: Using the mold for preparing the spine-shaped microneedle drug delivery carrier according to claim 3 comprises the following steps: S1, pouring the material solution for preparing the spine-shaped microneedle drug delivery carrier into a molding mold, treating it under negative pressure, and drying it; S2, continue to add material solution into the molding die and continue drying; S3, repeat S2 until the molding mold is filled; S4, butting the two samples obtained in S3 in a molding die, and applying the material solution at the butt joint; S5, placing the butted forming mold (1) in a fixed mold (3) for assembly, fixing it with a fixing member (2), and then performing a drying process; S6. Take out the sample obtained in S5 from the spine-shaped microneedle drug delivery carrier mold to obtain a spine-shaped microneedle drug delivery carrier.

7. The method for preparing the spine-shaped microneedle drug delivery carrier according to claim 6, characterized in that: The material for preparing the spine-shaped microneedle drug delivery carrier includes a swellable material.

8. An application of the spiny microneedle drug delivery carrier according to any one of claims 1 to 2, characterized in that: Used to prepare drugs that act on the gastrointestinal tract.

9. The use of the spine-shaped microneedle drug delivery carrier according to claim 8, characterized in that: The drug is stored in the cavity and / or shell and needle tip of the spine-shaped microneedle drug delivery carrier.

10. A drug acting on the gastrointestinal tract, characterized in that: The drug delivery carrier is prepared from the spiny microneedle drug delivery carrier according to any one of claims 1 to 2.

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