CN116370811A - Self-orienting device for gastrointestinal tract administration - Google Patents

Abstract

The present application provides a self-orienting device for gastrointestinal administration. The device is formed by assembling a tumbler shell and a microneedle. The tumbler shell is designed to be a weighted shell with a hollow bottom and a hollow upper part, and a shell with a low mass center is created; the microneedles are disposed on the base of the tumbler housing. The tumbler housing is manufactured through a 3D printing strategy; after the microneedle device enters the intestinal tract, self-orientation is realized under the action of the gravity center, and a stable state is achieved, namely the microneedle faces the tissue wall of the intestinal tract; because of the action of intestinal peristalsis, the micro-needle can be easily pricked into the intestinal wall to promote the intestinal wall to generate a micro-channel, so that the medicine loaded on the micro-needle can be released into the tissue through the micro-channel, thereby avoiding the medicine from being degraded in the cavity. The self-oriented microneedle device developed by the invention is used for intestinal administration, and can be used for solving the clinical problems of avoiding rapid metabolism and degradation of drugs in vivo and low pharmacokinetics.

Description

A self-orienting device for gastrointestinal drug delivery

technical field

The invention belongs to the technical field of material science and relates to the technical field of medical treatment at the same time. It specifically involves the development of a self-orienting microneedle device for intestinal drug delivery, which can avoid the clinical problems of rapid metabolism and degradation of drugs in the body and low pharmacokinetics.

Background technique

Because proteases, endonucleases, bacteria, and pH in the gastrointestinal tract can affect biomacromolecules, the development of drug delivery only through the gastrointestinal tract is limited. To address this issue, approaches including nanoparticle encapsulation, co-administration of enzyme inhibitors, chemical modification of drugs, penetration enhancers, etc. have been developed before, but their pharmacokinetics and bioavailability is always at a low level. The ingestible robot is developed for drug delivery, which can protect the drug and prevent the drug from being released and degraded in the intestinal lumen, thereby increasing the bioavailability of the drug. Microneedles have the advantages of strong penetration ability, minimal invasiveness, simple operation, and adjustable drug release curve, etc., and have been widely used in the process of subcutaneous drug delivery. Research on gastrointestinal injection devices assembled with microneedles and robots has been gradually developed, but the current gastrointestinal injection devices are generally complex in structure, high in cost, lack of controllability, and may have potential risks such as gastrointestinal obstruction. Therefore, the development of effective gastrointestinal drug delivery systems is still highly anticipated.

Contents of the invention

The purpose of the present invention is to provide a self-orienting microneedle device that can be administered in the gastrointestinal tract to avoid the clinical problems of rapid metabolism and degradation of drugs in the body and low pharmacokinetics.

Technical scheme of the present invention is as follows:

A self-orienting device for gastrointestinal drug delivery, comprising a tumbler body and microneedles located on the outer surface of the bottom of the tumbler body.

Preferably, the height of the tumbler body is 8mm-12mm.

Preferably, the microneedles include a plurality of microneedles forming a microneedle array.

Preferably, the body of the tumbler is in the shape of a spherical segment, the end with a section is the bottom, and the microneedle array is located on the bottom of the spherical segment.

Preferably, the shape of the microneedles is conical or pyramidal.

Preferably, the microneedle aspect ratio (height/diameter) is 2:1-3:1.

Preferably, the diameter of the bottom end of the microneedle is 200 μm-450 μm; the height of the microneedle is 600 μm-900 μm; the diameter of the tip of the microneedle is <20 μm.

Preferably, a drug is also included.

Preferably, the drug is loaded on the surface of the microneedle. Or loaded inside the tumbler body.

Preferably, the tumbler body is made of biocompatible materials. Biocompatible materials such as: ABS-M30i material, PC-ISO material, semipermeable membrane resin, multicolor resin, etc.

In the present invention, the tumbler body is preferably designed with a hollow upper part and a solid lower part. The device is capable of self-orientation; the microneedles are loaded with drugs and delivered to the tissues of the gastrointestinal tract.

In a preferred embodiment of the present invention, the device is formed by 3D printing.

In a preferred embodiment of the present invention, the solid height of the bottom is in the range of 2 mm to 4 mm.

In a preferred embodiment of the present invention, the thickness of the hollow layer ranges from 0.5 mm to 1 mm.

The invention provides a self-orienting microneedle device for drug delivery in the gastrointestinal tract. The device is assembled from a tumbler shell and a microneedle. Self-orientation, reaching a stable state—the microneedle faces the intestinal tissue wall; due to the intestinal peristaltic force, the microneedle can easily penetrate into the intestinal wall, prompting the intestinal wall to produce fine channels, so the drug loaded on the microneedle It can be released into the tissue through microchannels, thus avoiding the degradation of the drug in the cavity.

Compared with prior art, the beneficial effect of the present invention is:

1. The preparation method of the self-orientable microneedle device of the present invention is quick and easy, the device is simple, easy to operate, and can be mass-produced.

2. The self-orientable microneedle device of the present invention can be positioned in the intestinal tract to realize the microneedle delivery of drugs in vivo.

3. The microneedle part of the self-orienting microneedle device of the present invention can also be prepared by template method, using different materials to achieve different degradation rates of drugs, which can meet various actual needs.

4. The self-orienting microneedle device of the present invention can realize the effective release of drugs in the gastrointestinal tract tissue without external stimulus response.

Description of drawings

Figure 1 is a schematic diagram of a self-orienting microneedle device.

Fig. 2 is a dimension diagram of a self-orienting microneedle device with different parameters and a corresponding physical diagram.

Fig. 3 is a graph showing the relationship between the drug loading amount of the microneedle and the drug concentration.

Fig. 4 is a fluorescence image of the depth of the microneedle device piercing into the intestinal tissue.

Figure 5 is the movement of the self-orienting microneedle device under the high-speed camera.

Figure 6 is the movement of the self-orienting microneedle device in the isolated intestine.

Detailed ways

In order to better understand the present invention, the content of the present invention will be further explained below in conjunction with the accompanying drawings and embodiments, but the content of the present invention is not limited to the following examples.

Example 1

1) Design and preparation of the microneedle device: design the shape of the device—the upper part is a hollow shell, and the bottom is a solid weighted layer (Fig. 1); the solid height of the bottom is set to 4 mm, and the thickness of the hollow shell is 0.5 mm (Fig. 2III). The shape of the microneedle is conical, the height is 600 μm, and the aspect ratio is 2:1 (Figure 1).

2) AutoCAD conducts 3D modeling of the microneedle device, and the built model is imported into STL format, imported into 3D printing software, and printed with biocompatible materials.

3) Manually remove the support material outside the formed microneedle device; weigh 10 g each of NaOH and Na ₂ SiO ₃ , add 500 ml of pure water to dissolve to prepare A solution. The device was placed in solution A and cleaned in an ultrasonic cleaner for 1 hour to remove the remaining support material on the outside and the support material in the hollow; use a 2ml syringe to clean the hollow under the pressure of the syringe. After all the support materials were removed, the device was ultrasonically cleaned in pure water and ethanol solution for 15 min, and finally dried in a vacuum oven at 40 °C for 2 h.

Example 2:

1) Design and preparation of the microneedle device: adjust the shape of the device (for example: spherical, ellipsoidal, spherical) (Figure 2I-III); set the bottom solid height to 4mm, and the thickness of the hollow shell to 0.5mm ( Figure 2(I-III)). The shape of the microneedle is set to be conical, the height is 600 μm, and the aspect ratio is 2:1.

2) AutoCAD conducts 3D modeling of the microneedle device, and the built model is imported into STL format, imported into 3D printing software, and printed with biocompatible materials.

3) Manually remove the support material outside the formed microneedle device; weigh 10 g each of NaOH and Na ₂ SiO ₃ , add 500 ml of pure water to dissolve to prepare A solution. The device was placed in solution A and cleaned in an ultrasonic cleaner for 1 hour to remove the remaining support material on the outside and the support material in the hollow; use a 2ml syringe to clean the hollow under the pressure of the syringe. After all the support materials were removed, the device was ultrasonically cleaned in pure water and ethanol solution for 15 min, and finally dried in a vacuum oven at 40 °C for 2 h.

Embodiment 3:

1) Design and preparation of the microneedle device: design the shape of the device as a spherical segment; adjust the solid height (for example: 2mm, 3mm, 4mm) (Fig. 2IV-VI); the thickness of the hollow shell is 1mm. The shape of the microneedle is set to be conical, the height is 600 μm, and the aspect ratio is 2:1.

2) AutoCAD conducts 3D modeling of the microneedle device, and the built model is imported into STL format, imported into 3D printing software, and printed with biocompatible materials.

3) Manually remove the support material outside the formed microneedle device; weigh 10 g each of NaOH and Na ₂ SiO ₃ , add 500 ml of pure water to dissolve to prepare A solution. The device was placed in solution A and cleaned in an ultrasonic cleaner for 1 hour to remove the remaining support material on the outside and the support material in the hollow; use a 2ml syringe to clean the hollow under the pressure of the syringe. After all the support materials were removed, the device was ultrasonically cleaned in pure water and ethanol solution for 15 min, and finally dried in a vacuum oven at 40 °C for 2 h.

Example 4:

1) Design and preparation of the microneedle device: the device is spherical, with a solid bottom height of 4mm; the thickness of the hollow shell is adjusted (for example: 0.5mm, 1mm) (Figure 2III, IV). The shape of the microneedle is set to be conical, the height is 600 μm, and the aspect ratio is 2:1.

2) AutoCAD conducts 3D modeling of the microneedle device, and the built model is imported into STL format, imported into 3D printing software, and printed with biocompatible materials.

3) Manually remove the support material outside the formed microneedle device; weigh 10 g each of NaOH and Na ₂ SiO ₃ , add 500 ml of pure water to dissolve to prepare A solution. The device was placed in solution A and cleaned in an ultrasonic cleaner for 1 hour to remove the remaining support material on the outside and the support material in the hollow; use a 2ml syringe to clean the hollow under the pressure of the syringe. After all the support materials were removed, the device was ultrasonically cleaned in pure water and ethanol solution for 15 min, and finally dried in a vacuum oven at 40 °C for 2 h.

Example 5:

1) Design and preparation of the microneedle device: the shape of the designed device is spherical, the solid shell height is 4 mm; the thickness of the hollow shell is 0.5 mm. Adjust the shape of the microneedles (for example, conical, pyramidal), the height is 600 μm, and the aspect ratio is 2:1.

2) AutoCAD conducts 3D modeling of the microneedle device, and the built model is imported into STL format, imported into 3D printing software, and printed with biocompatible materials.

3) Manually remove the support material outside the formed microneedle device; weigh 10 g each of NaOH and Na ₂ SiO ₃ , add 500 ml of pure water to dissolve to prepare A solution. The device was placed in solution A and cleaned in an ultrasonic cleaner for 1 hour to remove the remaining support material on the outside and the support material in the hollow; use a 2ml syringe to clean the hollow under the pressure of the syringe. After all the support materials were removed, the device was ultrasonically cleaned in pure water and ethanol solution for 15 min, and finally dried in a vacuum oven at 40 °C for 2 h.

Embodiment 6:

1) Design and preparation of the microneedle device: design the shape of the device as a spherical segment, set the solid height of the bottom to 4mm, and set the thickness of the hollow shell to 0.5mm. The shape of the microneedle is conical, the height of the microneedle can be adjusted (for example, 600 μm, 750 μm, 900 μm), and the aspect ratio is 2:1.

2) AutoCAD conducts 3D modeling of the microneedle device, and the built model is imported into STL format, imported into 3D printing software, and printed with biocompatible materials.

3) Manually remove the support material outside the formed microneedle device; weigh 10 g each of NaOH and Na ₂ SiO ₃ , add 500 ml of pure water to dissolve to prepare A solution. The device was placed in solution A and cleaned in an ultrasonic cleaner for 1 hour to remove the remaining support material on the outside and the support material in the hollow; use a 2ml syringe to clean the hollow under the pressure of the syringe. After all the support materials were removed, the device was ultrasonically cleaned in pure water and ethanol solution for 15 min, and finally dried in a vacuum oven at 40 °C for 2 h.

Example 7

1) Design and preparation of the microneedle device: design the shape of the device as a spherical segment, set the solid height of the bottom to 4mm, and set the thickness of the hollow shell to 0.5mm. The shape of the microneedle is set to be conical, the height is 600 μm, and the aspect ratio of the microneedle is adjusted (for example, 2:1, 3:1).

2) AutoCAD conducts 3D modeling of the microneedle device, and the built model is imported into STL format, imported into 3D printing software, and printed with biocompatible materials.

3) Manually remove the support material outside the formed microneedle device; weigh 10 g each of NaOH and Na ₂ SiO ₃ , add 500 ml of pure water to dissolve to prepare A solution. The device was placed in solution A and cleaned in an ultrasonic cleaner for 1 hour to remove the remaining support material on the outside and the support material in the hollow; use a 2ml syringe to clean the hollow under the pressure of the syringe. After all the support materials were removed, the device was ultrasonically cleaned in pure water and ethanol solution for 15 min, and finally dried in a vacuum oven at 40 °C for 2 h.

Example 8

1) Design and preparation of the microneedle device: the designed device is in the shape of a spherical segment, the height of the solid bottom is 4 mm, and the thickness of the hollow shell is 0.5 mm. The microneedles are conical, with a height of 600 μm and a ratio of height to diameter of the microneedles of 2:1.

2) AutoCAD conducts 3D modeling of the microneedle device, and the built model is imported into STL format, imported into 3D printing software, and printed with biocompatible materials.

3) Manually remove the support material outside the formed microneedle device; weigh 10 g each of NaOH and Na ₂ SiO ₃ , add 500 ml of pure water to dissolve to prepare A solution. The device was placed in solution A and cleaned in an ultrasonic cleaner for 1 hour to remove the remaining support material on the outside and the support material in the hollow; use a 2ml syringe to clean the hollow under the pressure of the syringe. After all the support materials were removed, the device was ultrasonically cleaned in pure water and ethanol solution for 15 min, and finally dried in a vacuum oven at 40 °C for 2 h.

4) Drug loading of the microneedle: print a small container that matches the size of the microneedle; configure methylene blue solutions of different concentrations as the drug solution; use a pipette gun to draw 10 μl of the drug solution to fill the small container, and then cover the container with the microneedle , the tip of the microneedle is in contact with the drug solution, taken out after 30 seconds, and finally dried; repeat this step 5-7 times to load as much drug as possible on the surface of the microneedle. Put the microneedles into PBS solution to dissolve, and it can be found that within a certain range, the drug loading of the microneedles is proportional to the drug concentration (Figure 3).

Example 9

1) Design and preparation of the microneedle device: the designed device is in the shape of a spherical segment, the height of the solid bottom is 4 mm, and the thickness of the hollow shell is 0.5 mm. The microneedles are conical, with a height of 600 μm and a ratio of height to diameter of the microneedles of 2:1.

2) AutoCAD conducts 3D modeling of the microneedle device, and the built model is imported into STL format, imported into 3D printing software, and printed with biocompatible materials.

3) Manually remove the support material outside the formed microneedle device; weigh 10 g each of NaOH and Na ₂ SiO ₃ , add 500 ml of pure water to dissolve to prepare A solution. The device was placed in solution A and cleaned in an ultrasonic cleaner for 1 hour to remove the remaining support material on the outside and the support material in the hollow; use a 2ml syringe to clean the hollow under the pressure of the syringe. After all the support materials were removed, the device was ultrasonically cleaned in pure water and ethanol solution for 15 min, and finally dried in a vacuum oven at 40 °C for 2 h.

4) The microneedle penetrates the intestinal tract: soak the microneedle part in the fluorescent solution cy 5.5, and protect it from light; cut the large intestine tissue into a cube of 2cm*2cm, insert the microneedle containing cy 5.5 into the tissue, and press It was taken off after 5 minutes; the fluorescence intensity inside the tissue was taken by laser confocal; it can be seen that there is still weak fluorescence at a depth of 280 μm (Figure 4), which indicates that the microneedle has successfully penetrated into the intestinal tissue and released the drug.

Example 10

1) Design and preparation of the microneedle device: the designed device is in the shape of a spherical segment, the height of the solid bottom is 4 mm, and the thickness of the hollow shell is 0.5 mm. The microneedles are conical, with a height of 600 μm and a ratio of height to diameter of the microneedles of 2:1.

2) AutoCAD conducts 3D modeling of the microneedle device, and the built model is imported into STL format, imported into 3D printing software, and printed with biocompatible materials.

3) Manually remove the support material outside the formed microneedle device; weigh 10 g each of NaOH and Na ₂ SiO ₃ , add 500 ml of pure water to dissolve to prepare A solution. The device was placed in solution A and cleaned in an ultrasonic cleaner for 1 hour to remove the remaining support material on the outside and the support material in the hollow; use a 2ml syringe to clean the hollow under the pressure of the syringe. After all the support materials were removed, the device was ultrasonically cleaned in pure water and ethanol solution for 15 min, and finally dried in a vacuum oven at 40 °C for 2 h.

4) The self-orientation process of the microneedle device on a common plane: put the microneedle device upside down (close to 180°), place it on a common wooden plane, and use a high-speed camera to photograph the microneedle device from inversion (180°) to stable (0 °) For each frame, observe the state of the microneedle device at different time points. The photos show that the microneedle device will eventually reach a stable state after being shaken, and the entire self-orientation time is about 0.6s (Fig. 5).

Example 11

1) Design and preparation of the microneedle device: the designed device is in the shape of a spherical segment, the height of the solid bottom is 4 mm, and the thickness of the hollow shell is 0.5 mm. The microneedles are conical, with a height of 600 μm and a ratio of height to diameter of the microneedles of 2:1.

2) AutoCAD conducts 3D modeling of the microneedle device, and the built model is imported into STL format, imported into 3D printing software, and printed with biocompatible materials.

3) Manually remove the support material outside the formed microneedle device; weigh 10 g each of NaOH and Na ₂ SiO ₃ , add 500 ml of pure water to dissolve to prepare A solution. The device was placed in solution A and cleaned in an ultrasonic cleaner for 1 hour to remove the remaining support material on the outside and the support material in the hollow; use a 2ml syringe to clean the hollow under the pressure of the syringe. After all the support materials were removed, the device was ultrasonically cleaned in pure water and ethanol solution for 15 min, and finally dried in a vacuum oven at 40 °C for 2 h.

4) The self-orientation process of the microneedle device on the isolated intestinal tract: the microneedle device was placed upside down (close to 180°), placed on a section of large intestine mucosa, and a high-speed camera was used to shoot the microneedle device from inversion (180°) to stable (0 °) For each frame, observe the state of the microneedle device at different time points. The photos show that the microneedle device does not shake, but reaches a stable state directly, and the entire self-orientation time is about 1.2s (Fig. 6).

Fig. 2 is a dimension diagram of a self-orienting microneedle device with different parameters and a corresponding physical diagram. (I) is a spherical device, (II) is an ellipsoidal device, and (III) is an ellipsoidal device. (IV) is a solid height of 4mm, (V) is a solid height of 3mm, and (VI) is a solid height of 2mm. Figure 2 shows that the 3D printed device conforms to the designed shape and size with little deviation.

Fig. 3 is a graph showing the relationship between the drug loading amount of the microneedle and the drug concentration. Figure 3 shows that within a certain range, the drug loading on the microneedles will increase with the increase of drug concentration.

Figure 4 shows that microneedles can penetrate into intestinal tissue and release fluorescent drugs.

Each small picture in Figure 5 represents the state of the microneedle device at different time points during the self-orientation process. These figures illustrate that the microneedle device can achieve self-orientation and finally reach a stable state.

Figure 6 represents the self-orientation process of the device on the isolated intestinal tract with optimal parameters. These figures demonstrate that the microneedle device can self-orientate on the intestinal tract.

Claims (10)

1. A self-orienting device for gastrointestinal administration, characterized in that: it includes a tumbler body and a microneedle positioned on the outer surface of the bottom of the tumbler body. 2. A self-orienting device for gastrointestinal drug delivery according to claim 1, characterized in that: the height of the tumbler body is 8mm-12mm. 3. A self-orienting device for gastrointestinal drug delivery according to claim 1, characterized in that: said microneedles comprise a plurality of microneedles forming a microneedle array. 4. A self-orienting device for gastrointestinal drug delivery according to claim 3, characterized in that: the tumbler body is in the shape of a spherical segment, and the microneedle array is located on the bottom surface of the segmental segment. 5 . A self-orienting device for gastrointestinal drug delivery according to claim 1 , wherein the microneedles are conical or pyramidal in shape. 6 . The self-orienting device for gastrointestinal drug delivery according to claim 5 , wherein the aspect ratio of the microneedles is 2:1-3:1. 7. A self-orienting device for gastrointestinal drug delivery according to claim 5, characterized in that: the diameter of the bottom end of the microneedle is 200 μm-450 μm; the height of the microneedle is 600 μm-900 μm; the diameter of the tip of the microneedle is < 20 μm. 8. A self-orienting device for gastrointestinal drug delivery according to any one of claims 1-7, characterized in that it further comprises drugs loaded on the tumbler body and/or the microneedles. 9. A self-orienting device for gastrointestinal drug delivery according to claim 8, wherein the drug is loaded on the surface of the microneedle, or loaded inside the tumbler body. 10. A self-orienting device for gastrointestinal drug delivery according to any one of claims 1-7, characterized in that: the tumbler body is made of biocompatible materials.

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