Curled microneedle capable of locally releasing hormone to prevent esophageal stenosis and preparation method of curled microneedle

Abstract

The invention discloses a curled microneedle capable of locally releasing hormone to prevent esophageal stenosis and a preparation method of the curled microneedle. The curled microneedle comprises a substrate and a needle tip, the substrate is a temperature-responsive shape memory polymer, when the temperature of the substrate is lower than the response temperature, the substrate is temporarily hardened and shaped, and when the temperature of the substrate is higher than the response temperature, the substrate is unfolded and attached to the inner cavity of the esophagus; the substrate comprises a bottom layer and a plurality of microneedle cores; the microneedle cores are fixed to the side, close to the esophagus, of the bottom layer at intervals. A mounting hole is formed in one end of the needle tip; the micro-needle core is tightly embedded into the mounting hole, and the needle tip is mounted on the substrate; the needle tip is made of a swelling degradable material, a therapeutic drug is loaded on the needle tip, and the therapeutic drug is gradually released on the inner wall of the esophagus through the needle tip; the initial form of the base is in a curled shape, the curled microneedle can be conveniently sent to a wound surface through a gastroscope, after a response temperature condition is given, the curled microneedle is unfolded to enable a needle tip to be fixedly planted on an esophageal wall, and triamcinolone acetonide carried on the curled microneedle is slowly released.

Description

Technical Field

[0001] The present invention belongs to the technical field of microneedles, and in particular relates to a curled microneedle for locally releasing hormones to prevent esophageal stenosis and a preparation method thereof. Background Art

[0002] With the continuous development of gastrointestinal endoscopic technology, its application in minimally invasive treatment of esophageal lesions has become more and more extensive. The accompanying problem of stenosis after esophageal endoscopic treatment has attracted widespread attention in the medical community. Among them, mucosal defects ≥3 / 4 of the esophageal circumference after esophageal ESD are high-risk factors for postoperative stenosis. Currently, glucocorticoids are still the main method for preventing postoperative stenosis in clinical practice, and the routes of administration include oral and local injection. However, the existing routes of administration still have obvious shortcomings. On the one hand, oral hormones for the prevention of stenosis have many systemic side effects such as obesity and immunosuppression, and the duration is long, resulting in low patient compliance; on the other hand, local injection of hormones into the wound requires higher surgical skills, which may cause adverse events such as bleeding, perforation, and mediastinal infection, and a single injection cannot produce a sustained drug effect. Multiple endoscopic injections at different times after surgery have many difficulties, such as increased risks, increased costs, low patient acceptance, and low clinical feasibility. Summary of the invention

[0003] To solve the above problems, the present invention proposes a curled microneedle for locally releasing hormones to prevent esophageal stenosis and a preparation method thereof. The base of the curled microneedle for locally releasing hormones to prevent esophageal stenosis is a bidirectional deformable material, and its initial shape is curled, which is convenient for delivering the curled microneedle to the wound surface through a gastroscope. After the response temperature condition is given, the curled base is deformed and opened at the corresponding position of the esophageal wound surface, and fits the esophageal cavity. The side carrying the needle tip faces the esophageal wall, so that the needle tip is implanted in the wound surface and slowly releases the triamcinolone acetonide carried thereon, producing a continuous drug effect, thereby preventing the occurrence of postoperative stenosis.

[0004] To achieve the above object, the present invention adopts the following technical solutions:

[0005] A curled microneedle for locally releasing hormones to prevent esophageal stenosis comprises a substrate and a needle tip; the substrate is a temperature-responsive shape memory polymer, when the temperature of the substrate is lower than the response temperature, the substrate is temporarily hardened and fixed, when the temperature of the substrate is higher than the response temperature, the substrate is unfolded and fits the inner cavity of the esophagus; the substrate comprises a bottom layer and a plurality of microneedle cores; the microneedle core (11) and the bottom layer (10) are integrally formed; a mounting hole is provided at one end of the needle tip; the microneedle core is tightly embedded in the mounting hole, and the needle tip (2) and the microneedle core (11) are mounted on the substrate by ultraviolet co-crosslinking; the needle tip is made of a swelling and degradable material, and is loaded with a therapeutic drug, which is gradually released on the inner wall of the esophagus through the needle tip.

[0006] Preferably, the material of the substrate is 6-caprolactone with different degrees of methacrylate, and 6-caprolactone with different degrees of methacrylate is represented by PCL. x -PGMA y .

[0007] Preferably, the ratios of x:y in the 6-caprolactone are 92:8 and 96:4 respectively.

[0008] Preferably, PCL 92 -PGMA 8 : PCL 96 -PGMA 4 =1.5:1.

[0009] Preferably, the response temperature of the substrate is 39°C.

[0010] Preferably, the material of the needle tip is methacryloyl dextran.

[0011] Preferably, the swelling ratio of the material of the needle tip is greater than 300%.

[0012] Preferably, the therapeutic drug loaded on the needle tip is triamcinolone acetonide.

[0013] A method for preparing a curled microneedle for locally releasing hormones to prevent esophageal stenosis comprises the following steps:

[0014] S1, pouring 6-caprolactone into a mold, curing it by ultraviolet light, and demolding to obtain a substrate; wherein the substrate includes a bottom layer and a plurality of microneedle cores;

[0015] S2, pouring methacryloyl dextran into a mold, and drying it in the sun to obtain a plurality of needle tips containing mounting holes;

[0016] S3, using the microneedle core of the substrate and the needle tip to UV co-crosslink, the needle tip is installed on the substrate, and after demolding, a solution containing a therapeutic drug is coated on the needle tip, and the solvent in the solution is evaporated at 60° C. to obtain a softened, uncurled microneedle;

[0017] S4. Curl the softened microneedle and place it into a cavity, perform curling programming at a temperature lower than the response temperature, and after the base is temporarily hardened and shaped, obtain a curled microneedle that locally releases hormones to prevent esophageal stenosis.

[0018] After adopting the above technical solution, the present invention has the following beneficial effects:

[0019] 1. The base of the present invention is a bidirectional deformable material, and its initial shape is curled, which is convenient for delivering the curled microneedle to the wound surface through a gastroscope. After the response temperature condition is given, the curled base is deformed and opened at the corresponding position of the esophageal wound surface, and fits the esophageal cavity. The side carrying the needle tip faces the esophageal wall, so that the needle tip is implanted in the wound surface and slowly releases the triamcinolone acetonide carried thereon, producing a continuous drug effect, thereby preventing the occurrence of postoperative stenosis.

[0020] 2. The present invention is a local application of glucocorticoids, which has the advantage of small systemic side effects. The curled microneedle is opened in the esophageal wound surface by temperature response, and the base is adapted to the esophageal lumen and fixed in the wound area. The needle tip containing triamcinolone acetonide solution is implanted in the wound surface to stably release hormones, which plays a role in continuous drug administration within a preset time and preventing postoperative stenosis. It has the advantages of simple operation, no need for multiple repetitions, and good patient compliance. After the drug is released, the base can deform again in response to the temperature and restore the initial curled state, so that it is discharged from the digestive tract, and the needle tip part can degrade by itself, which has no toxic effect on the body. Practice has proved that its clinical application is safe and reliable. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is a schematic diagram of the cross-section structure when the needle tip of the present invention is installed on an uncurled base;

[0022] Figure 2 It is a schematic diagram of the cross-section structure when the needle tip of the present invention is not installed on an uncurled base;

[0023] Figure 3 is a flow chart of the preparation of the uncurled microneedle of the present invention;

[0024] Figure 4 is a flow chart of the preparation of the curled microneedle of the present invention;

[0025] Figure 5 This is a temperature response test diagram of the substrate of the present invention.

[0026] The reference numerals in the figure are as follows:

[0027] 1. Base; 10. Bottom layer; 11. Microneedle core; 2. Needle tip; 20. Mounting hole. DETAILED DESCRIPTION

[0028] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0029] like Figures 1 to 5As shown, a curled microneedle for locally releasing hormones to prevent esophageal stenosis includes a substrate 1 and a needle tip 2; the substrate 1 is a temperature-responsive shape memory polymer (SMP), when the temperature of the substrate 1 is lower than the response temperature, the substrate 1 is temporarily hardened and fixed, when the temperature of the substrate 1 is higher than the response temperature, the substrate 1 is unfolded and fits the esophageal cavity; the substrate 1 includes a bottom layer 10 and a plurality of microneedle cores 11; the microneedle cores 11 and the bottom layer 10 are integrally formed; a mounting hole 20 is provided at one end of the needle tip 2; the microneedle core 11 is tightly embedded in the mounting hole 20, and the needle tip 2 and the microneedle core 11 are mounted on the substrate 1 by ultraviolet co-crosslinking; the material of the needle tip 2 is a swelling and degradable material, the needle tip 2 is loaded with therapeutic drugs, and the therapeutic drugs are gradually released on the inner wall of the esophagus through the needle tip 2.

[0030] The material of the substrate 1 is 6-caprolactone with different degrees of methacrylate, and 6-caprolactone with different degrees of methacrylate is represented by PCL. x -PGMA y .

[0031] The x:y ratio of the 6-caprolactone is 92:8 and 96:4 respectively.

[0032] PCL 92 -PGMA 8 : PCL 96 -PGMA 4 =1.5:1.

[0033] The response temperature of the substrate 1 is 39°C.

[0034] The needle tip 2 is made of methacryloyl dextran (DexMA).

[0035] The swelling rate of the material of the needle tip 2 is greater than 300%.

[0036] The therapeutic drug loaded on the needle tip 2 is triamcinolone acetonide.

[0037] A method for preparing a curled microneedle for locally releasing hormones to prevent esophageal stenosis comprises the following steps:

[0038] S1. PCL x -PGMA y Pour into a mold, cure by ultraviolet irradiation, and demould to obtain a substrate 1; wherein the substrate 1 includes a bottom layer 10 and a plurality of microneedle cores 11;

[0039] S2, pouring methacryloyl dextran (DexMA) containing triamcinolone acetonide into a mold, and drying it in the sun to obtain a plurality of needle tips 2 containing mounting holes 20;

[0040] S3, using the microneedle core 11 of the substrate 1 to co-crosslink with the needle tip 2, the needle tip 2 is installed on the substrate 1, and after demolding, a solution containing a therapeutic drug is coated on the needle tip 2 again, and the solvent in the SMP is volatilized at 60° C. to obtain a softened, uncurled microneedle;

[0041] S4, curling the softened microneedle and placing it in the cavity, performing curling programming under the condition of less than the response temperature, and after the substrate 1 is temporarily hardened and fixed, a curled microneedle that locally releases hormones to prevent esophageal stenosis is obtained

[0042] The temperature of the curling programming in step S4 is -20°C.

[0043] The above is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A curled microneedle for local release of hormones to prevent esophageal stenosis, characterized in that: The invention comprises a substrate (1) and a needle tip (2); the substrate (1) is a temperature-responsive shape memory polymer; when the temperature of the substrate (1) is lower than the response temperature, the substrate (1) is temporarily hardened and fixed; when the temperature of the substrate (1) is higher than the response temperature, the substrate (1) is unfolded and fits the inner cavity of the esophagus; the substrate (1) comprises a bottom layer (10) and a plurality of microneedle cores (11); the microneedle cores (11) and the bottom layer (10) are integrally formed; a mounting hole (20) is provided at one end of the needle tip (2); the microneedle core (11) is tightly embedded in the mounting hole (20), and the needle tip (2) and the microneedle core (11) are mounted on the substrate (1) by ultraviolet co-crosslinking; the material of the needle tip (2) is a swelling and degradable material; the needle tip (2) is loaded with a therapeutic drug, and the therapeutic drug is gradually released on the inner wall of the esophagus through the needle tip (2).

2. The curled microneedle for local release of hormones to prevent esophageal stenosis according to claim 1, characterized in that: The material of the substrate (1) is 6-caprolactone with different degrees of methacrylate, and 6-caprolactone with different degrees of methacrylate is represented by PCL. x -PGMA y .

3. The curled microneedle for local release of hormones to prevent esophageal stenosis as claimed in claim 2, characterized in that: The x:y ratio of the 6-caprolactone is 92:8 and 96:4 respectively.

4. The curled microneedle for local release of hormones to prevent esophageal stenosis as claimed in claim 3, characterized in that: PCL 92 -PGMA8:PCL 96 -PGMA4=1.5:1。 5. The curled microneedle for local release of hormones to prevent esophageal stenosis according to claim 1, characterized in that: The response temperature of the substrate (1) is 39°C.

6. The curled microneedle for local release of hormones to prevent esophageal stenosis according to claim 1, characterized in that: The material of the needle tip (2) is methacryloyl dextran.

7. The curled microneedle for local release of hormones to prevent esophageal stenosis as claimed in claim 1, characterized in that: The swelling rate of the material of the needle tip (2) is greater than 300%.

8. The curled microneedle for local release of hormones to prevent esophageal stenosis as claimed in claim 1, characterized in that: The therapeutic drug loaded on the needle tip (2) is triamcinolone acetonide.

9. A method for preparing the curled microneedles for locally releasing hormones to prevent esophageal stenosis as claimed in any one of claims 1 to 8, characterized in that: The following steps are involved: S1, pouring 6-caprolactone into a mold, curing it by ultraviolet light irradiation, and obtaining a substrate (1) after demoulding; wherein the substrate (1) includes a bottom layer (10) and a plurality of microneedle cores (11); S2, pouring methacryloyl dextran into a mold, and drying it in the sun to obtain a plurality of needle tips (2) containing mounting holes (20); S3, using the microneedle core (11) of the substrate (1) and the needle tip (2) to crosslink by ultraviolet light, installing the needle tip (2) on the substrate (1), coating the needle tip (2) with a solution containing a therapeutic drug after demoulding, and volatilizing the solvent in the solution at 60° C. to obtain a softened, uncurled microneedle; S4. Curl the softened microneedle and place it in a cavity, and perform curling programming at a temperature lower than the response temperature. After the base (1) is temporarily hardened and fixed, a curled microneedle that locally releases hormones to prevent esophageal stenosis is obtained.

10. The method for preparing a curled microneedle for locally releasing hormones to prevent esophageal stenosis according to claim 9, characterized in that: The temperature of the curling programming in step S4 is -20°C.

Images