A novel drug-loaded airway stent and preparation method thereof

Abstract

The present invention belongs to the field of medical device technology, and specifically discloses a novel drug-loaded airway stent and a preparation method thereof. The novel drug-loaded airway stent comprises a support tube body, the surface of the support tube body is provided with holes, the inside of the holes is loaded with a drug / polymer complex, and the end face of the support tube body is designed with a buckle structure; the drug / polymer complex is composed of the following components by mass percentage: 2%-20% of drug, 75%-97.8% of polymer material, and 0.2%-5% of dispersant. The support tube body in this application can be designed and prepared according to the patient's airway characteristics, and after being implanted in the airway, it has better matching with the patient's airway to avoid displacement affecting the treatment effect; the drug loading inside the hole is less than the hole volume, which can provide a place for the cilia on the airway surface to move, and avoid problems such as airway discomfort or poor expectoration caused by the coated stent hindering the movement of cilia on the airway surface.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical devices, and particularly relates to a novel drug-loaded airway stent and a preparation method thereof. The stent has a "C"-shaped structure, has a drug-loaded function, and can be used to expand narrow airways and inhibit restenosis of airways. Background Art

[0002] Chronic obstructive pulmonary disease (COPD) is a chronic disease characterized by persistent respiratory symptoms and airflow limitation. Airway stenosis is the most obvious pathological change characteristic of the airway in COPD patients. Usually, obvious clinical symptoms may occur when the airway lumen is narrowed by more than 50%. When the lumen diameter is ≤10mm, severe exertional dyspnea will occur, and when the lumen diameter is ≤5mm, resting dyspnea may occur. After the occurrence of airway stenosis, obstructive emphysema, obstructive pneumonia or obstructive atelectasis at the distal end of the stenosis may occur, causing the patient to have obvious symptoms of dyspnea, such as irritable cough, weak sputum, and chest tightness. Severe stenosis can cause severe dyspnea, respiratory failure, and even death, seriously threatening the patient's life. In clinical practice, tracheotomy, intubation, or stent implantation are often used to relieve airway stenosis and save the patient's life.

[0003] Stent implantation is one of the quick and effective ways to relieve dyspnea in patients with airway stenosis. It is an emerging minimally invasive therapy and has gradually become the preferred method for treating benign airway stenosis in recent years. However, existing metal airway stents have great irritation to the airway, and have defects such as coagulation complications, flexure mismatch, permanent retention of metal foreign bodies in the body, and a high incidence of restenosis in the stent. A coated metal stent is a stent coated with a special membrane material (polytetrafluoroethylene, dacron, polyester, polyurethane, etc.) on a metal stent. It retains the function of the metal stent and has the characteristics of a membrane material. It can overcome the problem of restenosis caused by tumors and granulation tissue growing into the cavity of a bare metal stent. However, after the airway is covered, the ciliary movement of the mucosa is inhibited, which can easily lead to difficulty in expectoration.

[0004] Airway stents made of polymer materials such as polylactic acid and polycaprolactone have biodegradable properties, which can overcome the shortcomings of permanent retention of foreign matter in metal stents; silicone stents have the advantages of excellent biocompatibility and good elasticity. However, the shape and diameter of the above polymer-based airway stents prepared by existing extrusion and molding methods are basically fixed, which cannot meet the personalized needs of different patients with different airway shapes. Clinically, there is a problem of displacement, resulting in poor efficacy. Summary of the invention

[0005] The primary purpose of the present invention is to overcome the shortcomings and deficiencies in the prior art and to provide a novel drug-loaded airway stent having a "C"-shaped structure and a drug-loading function, which can be used to expand narrowed airways and inhibit restenosis of the airways.

[0006] Another object of the present invention is to provide a method for preparing the novel drug-eluting airway stent.

[0007] The purpose of the present invention is achieved through the following technical solutions:

[0008] A novel drug-loaded airway stent comprises a support tube body, the surface of the support tube body is provided with holes, the interior of the holes is loaded with a drug / polymer complex, and the end face of the support tube body is designed with a snap structure; the drug / polymer complex is composed of the following components in mass percentage: 2%-20% of drug, 75%-97.8% of polymer material, and 0.2%-5% of dispersant.

[0009] In one embodiment, the support tube body is a "C"-shaped, unclosed tubular object with a thickness of 1-3 mm.

[0010] In one embodiment, a non-through hole is disposed on the surface of the support tube body, and the depth of the hole is 60%-80% of the thickness of the support tube body.

[0011] In one embodiment, the support tube body is made of biodegradable polymer material and / or non-degradable polymer material.

[0012] In one embodiment, the biodegradable polymer material is a thermoplastic, biodegradable polymer material, preferably one or a mixture of at least two of polylactic acid (PLA), polycaprolactone (PCL) and polylactic-co-glycolic acid (PLGA).

[0013] In one embodiment, the non-degradable polymer material is a thermoplastic, non-degradable polymer material, preferably one of polyurethane (TPU), ethylene vinyl acetate copolymer (EVA), ethylene-acrylate copolymer (EMA) and ethylene-α-olefin copolymer (POE).

[0014] In one embodiment, a positioning hole is provided at one end of the support tube body, and a positioning pin is provided at the other end of the support tube body, and the positioning pin is inserted into the positioning hole to form the buckle structure. For example, after the novel drug-eluting airway stent is implanted into the patient's airway, the positioning pin is inserted into the positioning hole through the support device to form a closed tubular object, which expands the airway and plays a supporting role.

[0015] In one embodiment, the loading amount of the drug / polymer complex is 70%-80% of the volume of the hole. The drug loaded inside the hole releases the drug through the migration effect. The drug loading amount is less than the hole volume, which can provide a place for the cilia on the airway surface to move, avoiding the problem of the stent-covered stent hindering the movement of the cilia on the airway surface, causing airway discomfort or poor sputum discharge.

[0016] In one embodiment, the polymer material has a melting temperature or softening temperature of ≤70°C and a melt flow index of ≥20g / 10min (test temperature: 190°C, load 2.16kg), and is preferably ethylene vinyl acetate copolymer (EVA) or polycaprolactone (PCL).

[0017] In one embodiment, the drug is one or a mixture of at least two of anti-tumor platinum drugs, drugs that interfere with transcription and prevent RNA synthesis, antibiotics, anti-signal transduction drugs, anti-tumor adjuvant drugs and anti-tumor antibody drugs.

[0018] In one embodiment, the anti-tumor platinum is preferably oxaliplatin, carboplatin or nedaplatin.

[0019] In one embodiment, the drug that interferes with the transcription process and prevents RNA synthesis is preferably aclarubicin, doxorubicin or mitoxantrone.

[0020] In one embodiment, the antibiotic is preferably bleomycin, bleomycin or mitomycin.

[0021] In one embodiment, the anti-signal transduction drug is preferably erlotinib, gefitinib, imatinib or dasatinib.

[0022] In one embodiment, the anti-tumor adjuvant drug is preferably alizapride, azasetron, ondansetron, clodronate or mesna.

[0023] In one embodiment, the anti-tumor antibody drug is preferably rituximab, ibritumomab tiuxetan, cetuximab or bevacizumab. In one embodiment, the dispersant is preferably polyethylene glycol (PEG-1000) or / and poloxamer (such as 188, 407).

[0024] In one embodiment, the drug / polymer complex is prepared by the following method: 2%-20% of the drug, 75%-97.8% of the polymer material and 0.2%-5% of the dispersant are evenly mixed, melt-blended at 60-80°C, and then hot-pressed into a cylinder at 60-85°C; the percentages are mass percentages.

[0025] The preparation method of the novel drug-loaded airway stent comprises the following steps: first, scanning the patient's airway to obtain an airway image, converting the airway image into a 3D digital graphic through 3D-MAX software, and designing a 3D printing model of the novel drug-loaded airway stent according to the 3D digital graphic; then, drying and heating and melting the polylactic acid to prepare a 3D printing wire; then, using a 3D melt-blown (FDM) printer to print the 3D printing wire to obtain a support tube body; finally, loading the drug / polymer complex into the interior of the hole of the support tube body to obtain a novel drug-loaded airway stent.

[0026] Compared with the airway stent prepared by the existing extrusion and molding methods, the present invention has the following advantages and effects over the prior art:

[0027] (1) The support tube body in the present application can be designed and prepared according to the patient's airway characteristics, and after being implanted in the airway, it can better match the patient's airway to avoid displacement that affects the treatment effect;

[0028] (2) The holes reserved on the surface of the support tube body in the present application are loaded with drugs, and a better airway stenosis treatment effect is achieved through the synergistic effect of the drugs and the support of the stent;

[0029] (3) The drug loaded inside the pores is released through the migration effect. The drug loading amount is less than the pore size, which can provide a place for the cilia on the airway surface to move, thus avoiding the covered stent hindering the movement of cilia on the airway surface, causing airway discomfort or difficulty in expectoration. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 A schematic diagram of the structure of a novel drug-eluting airway stent provided by the present invention;

[0031] Figure 2 for Figure 1 Schematic diagram of the buckle structure of the new drug-eluting airway stent;

[0032] Figure 3 for Figure 1 Schematic diagram of the process for preparing a novel drug-eluting airway stent. DETAILED DESCRIPTION

[0033] The present invention is further described in detail below in conjunction with examples and drawings, but the embodiments of the present invention are not limited thereto.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in the technical field of this application. The terms used in this specification are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0035] like Figure 1As shown, a novel drug-loaded airway stent includes a support tube body 1 (3D printed polymer base), the surface of the support tube body 1 is provided with holes 2, the interior of the holes 2 is loaded with drug-loaded gel, and the end face of the support tube body 1 is designed with a snap structure 3.

[0036] The support tube body 1 is a "C"-shaped, unclosed tubular object with a thickness of 1-3 mm, and in this embodiment, the thickness is 2 mm.

[0037] The surface of the support tube body 1 is provided with non-through holes, and the depth of the holes 2 is 60%-80% of the thickness of the support tube body 1. In this embodiment, the depth of the holes is 1.5 mm.

[0038] like Figure 2 As shown, one end of the support tube body 1 is provided with a positioning hole 31, and the other end of the support tube body 1 is provided with a positioning pin 32, and the positioning pin 32 is inserted into the positioning hole 31 to form the buckle structure 3. When the novel drug-loaded airway stent is implanted into the patient's airway, the positioning pin is inserted into the positioning hole through the support device to form a closed tubular object, which expands the airway and plays a supporting role.

[0039] It should be noted that the loading amount of the drug / polymer complex is smaller than the volume of the hole. The drug loaded inside the hole releases the drug through the migration effect. The drug loading amount is less than the hole size, which can provide a place for the cilia on the airway surface to move, avoiding the covered stent hindering the movement of cilia on the airway surface, causing airway discomfort or poor sputum discharge.

[0040] The preparation method of the novel drug-eluting airway stent includes the following steps: first, use CT to scan the patient's airway to obtain an airway image, convert the airway image into a 3D digital graphic through 3D-MAX software, and design a 3D printing model of the novel drug-eluting airway stent based on the 3D digital graphic; then, dry and heat the polylactic acid to prepare a 3D printing wire; then, use a 3D melt-blown (FDM) printer to print the 3D printing wire to obtain a support tube body; finally, load the drug / polymer complex into the interior of the holes of the support tube body to obtain a novel drug-eluting airway stent. The schematic flow chart of the preparation method is as follows: Figure 3 shown.

[0041] The novel drug-loaded airway stent described in the present invention is a "C"-shaped unsealed composite tubular device, which is curled into a tubular object with a smaller diameter and implanted into the patient's airway stenosis through a pusher. After implantation, the buckle structure is clamped, the support tube body plays a supporting role, and the surface holes play a role in loading drugs. The present invention can expand the airway cross-section through the mechanical expansion effect, prevent tumor tissue from growing into the cavity, and provide a certain space for the movement of cilia on the airway surface. It has broad application prospects in the field of benign airway stenosis.

[0042] Example 1

[0043] First, a CT scan of the patient's airway structure is used to obtain an airway image, and the airway image is converted into a 3D digital graphic through 3D-MAX software. A 3D printing model of a new drug-loaded airway stent is designed according to the 3D digital graphic; then, EVA (VA content of 18%, melt flow index of 20g / 10min) is heated and melted to prepare a 3D printing wire; then, a 3D melt-blown (FDM) printer is used to print the 3D printing wire to obtain a support tube body;

[0044] 2 g of paclitaxel, 0.5 g of PEG-1000, and 97.5 g of EVA were accurately weighed and blended in a torque rheometer at a temperature of 70° C. to prepare a drug / polymer material composite; the composite was hot-pressed into a cylindrical shape in a hot press at a temperature of 80° C.

[0045] The drug / polymer complex is loaded into the reserved holes of the support tube body to obtain a new drug-loaded airway stent.

[0046] Example 2

[0047] First, a CT scan of the patient's airway structure is used to obtain an airway image, which is converted into a 3D digital graphic using 3D-MAX software, and a 3D printing model of a new drug-loaded airway stent is designed based on the 3D digital graphic; then, EVA (VA content of 22%, melt flow index of 30g / 10min) is heated and melted to prepare a 3D printing wire; then, a 3D melt-blown (FDM) printer is used to print the 3D printing wire to obtain a support tube body;

[0048] 10 g of mitomycin, 3 g of poloxamer 188, 60 g of EMA, and 27 g of EVA were accurately weighed and blended in a torque rheometer at a temperature of 80° C. to prepare a drug / polymer material composite; the composite was hot-pressed into a cylindrical shape in a hot press at a temperature of 90° C.

[0049] The drug / polymer complex is loaded into the reserved holes of the support tube body to obtain a new drug-loaded airway stent.

[0050] Example 3

[0051] First, a CT scan of the patient's airway structure is used to obtain an airway image, which is then converted into a 3D digital graphic using 3D-MAX software, and a 3D printing model of a novel drug-loaded airway stent is designed based on the 3D digital graphic; then, POE (melt flow index is 20g / 10min) is heated and melted to prepare a 3D printing wire; then, a 3D melt-blown (FDM) printer is used to print the 3D printing wire to obtain a support tube body;

[0052] 10 g of aclarubicin, 10 g of mitomycin, 5 g of poloxamer 407, and 75 g of POE were accurately weighed and blended in a torque rheometer at a temperature of 65° C. to prepare a drug / polymer material composite; the composite was hot-pressed into a cylindrical shape in a hot press at a temperature of 70° C.

[0053] The drug / polymer complex is loaded into the reserved holes of the support tube body to obtain a new drug-loaded airway stent.

[0054] Example 4

[0055] First, a CT scan of the patient's airway structure is used to obtain an airway image, which is then converted into a 3D digital graphic using 3D-MAX software, and a 3D printing model of a novel drug-loaded airway stent is designed based on the 3D digital graphic; then, TPU (melt flow index is 25g / 10min) is heated and melted to prepare a 3D printing filament; then, a 3D melt-blown (FDM) printer is used to print the 3D printing filament to obtain a support tube body;

[0056] 2 g of oxaliplatin, 1 g of ibritumomab tiuxetan, 1 g of PEG-1000, and 96 g of EVA were accurately weighed and blended in a torque rheometer at a temperature of 65° C. to prepare a drug / polymer material composite; the composite was hot-pressed into a cylindrical shape in a hot press at a temperature of 70° C.

[0057] The drug / polymer complex is loaded into the reserved holes of the support tube body to obtain a new drug-loaded airway stent.

[0058] Example 5

[0059] First, a CT scan of the patient's airway structure is used to obtain an airway image, which is then converted into a 3D digital graphic using 3D-MAX software, and a 3D printing model of a novel drug-loaded airway stent is designed based on the 3D digital graphic; then, PCL (melt flow index is 20 g / 10 min) is heated and melted to prepare a 3D printing filament; then, a 3D melt-blown (FDM) printer is used to print the 3D printing filament to obtain a support tube body;

[0060] 20 g of paclitaxel, 1 g of PEG-1000, and 79 g of PCL were accurately weighed and blended in a torque rheometer at a temperature of 70° C. to prepare a drug / polymer material complex; the complex was hot-pressed into a cylindrical shape in a hot press at a temperature of 80° C.

[0061] The drug / polymer complex is loaded into the reserved holes of the support tube body to obtain a new drug-loaded airway stent.

[0062] Example 6

[0063] First, a CT scan of the patient's airway structure is used to obtain an airway image, which is then converted into a 3D digital graphic using 3D-MAX software, and a 3D printing model of a novel drug-loaded airway stent is designed based on the 3D digital graphic; then, PCL (melt flow index is 20 g / 10 min) is melted to prepare a 3D printing filament; then, a 3D melt-blown (FDM) printer is used to print the 3D printing filament to obtain a support tube body;

[0064] 5 g of paclitaxel, 1 g of poloxamer 407, and 94 g of PCL were accurately weighed and blended in a torque rheometer at a temperature of 70° C. to prepare a drug / polymer material composite; the composite was hot-pressed into a cylindrical shape in a hot press at a temperature of 80° C.

[0065] The drug / polymer complex is loaded into the reserved holes of the support tube body to obtain a new drug-loaded airway stent.

[0066] Example 7

[0067] First, a CT scan of the patient's airway structure was used to obtain an airway image, which was converted into a 3D digital graphic using 3D-MAX software, and a 3D printing model of a new drug-loaded airway stent was designed based on the 3D digital graphic; then, PLGA (melt flow index of 20 g / 10 min) and PLA (melt flow index of 5 g / 10 min) were mixed in a ratio of 8:2 and melt-blended to prepare a 3D printing filament; then, a 3D melt-blown (FDM) printer was used to print the 3D printing filament to obtain a support tube body;

[0068] 10 g of aclarubicin, 2 g of alizapride, 1 g of PEG-1000, 0.5 g of poloxamer 188, and 86.5 g of PCL were accurately weighed and blended in a torque rheometer at a temperature of 70° C. to prepare a drug / polymer complex; the complex was hot-pressed into a cylindrical shape in a hot press at a temperature of 70° C.

[0069] The drug / polymer complex is loaded into the reserved holes of the support tube body to obtain a new drug-loaded airway stent.

[0070] Example 8

[0071] First, a CT scan of the patient's airway structure was used to obtain an airway image, which was converted into a 3D digital graphic using 3D-MAX software, and a 3D printing model of a new drug-loaded airway stent was designed based on the 3D digital graphic; then, PLGA (melt flow index of 20 g / 10 min) and PLA (melt flow index of 5 g / 10 min) were mixed in a ratio of 8:2 and melt-blended to prepare a 3D printing filament; then, a 3D melt-blown (FDM) printer was used to print the 3D printing filament to obtain a support tube body;

[0072] 10 g of aclarubicin, 2 g of alizapride, 1 g of PEG-1000, 0.5 g of poloxamer 188, and 86.5 g of PCL were accurately weighed and blended in a torque rheometer at a temperature of 70° C. to prepare a drug / polymer material complex; the above-mentioned complex was hot-pressed into a cylindrical shape in a hot press at a temperature of 80° C.

[0073] The drug / polymer complex is loaded into the reserved holes of the support tube body to obtain a new drug-loaded airway stent.

[0074] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A novel drug-eluting airway stent, characterized in that: It comprises a support tube body, the surface of which is provided with holes, the inside of which is loaded with a drug / polymer complex, and the end surface of which is designed with a buckle structure; the drug / polymer complex is composed of the following components by mass percentage: 2%-20% of drug, 75%-97.8% of polymer material, and 0.2%-5% of dispersant; The support tube body is a "C"-shaped, unclosed tubular object with a thickness of 1-3 mm; The surface of the support tube body is provided with non-through holes, and the depth of the holes is 60%-80% of the thickness of the support tube body; The support tube body is made of biodegradable polymer material and / or non-degradable polymer material; the biodegradable polymer material is a thermoplastic, biodegradable polymer material; the non-degradable polymer material is a thermoplastic, non-degradable polymer material; The preparation method of the novel drug-loaded airway stent comprises the following steps: first, scanning the patient's airway to obtain an airway image, converting the airway image into a 3D digital graphic through 3D-MAX software, and designing a 3D printing model of the novel drug-loaded airway stent according to the 3D digital graphic; then, drying and heating and melting the polylactic acid to prepare a 3D printing wire; then, using a 3D melt-blown printer to print the 3D printing wire to obtain a support tube body; finally, loading the drug / polymer complex into the inside of the hole of the support tube body to obtain a novel drug-loaded airway stent; A positioning hole is provided at one end of the support tube body, and a positioning pin is provided at the other end of the support tube body, and the positioning pin is inserted into the positioning hole to form the buckle structure; The loading amount of the drug / polymer complex is 70%-80% of the volume of the pore; The drug is one or a mixture of at least two of anti-tumor platinum, drugs that interfere with transcription and prevent RNA synthesis, antibiotics, anti-signal transduction drugs, anti-tumor adjuvant drugs and anti-tumor antibody drugs; the dispersant is polyethylene glycol and / or poloxamer.

2. The novel drug-eluting airway stent according to claim 1, characterized in that: The biodegradable polymer material is one of polylactic acid, polycaprolactone and polylactic acid-glycolic acid copolymer or a mixture of at least two thereof; the non-degradable polymer material is one of polyurethane, ethylene vinyl acetate copolymer, ethylene-acrylate copolymer and ethylene-α-olefin copolymer.

3. The novel drug-eluting airway stent according to claim 1, characterized in that: The melting temperature or softening temperature of the polymer material is ≤70°C, and the melt flow index is ≥20g / 10min. The test temperature of the polymer material is 190°C and the load is 2.16kg.

4. The novel drug-eluting airway stent according to claim 1, characterized in that: The polymer material is ethylene vinyl acetate copolymer or polycaprolactone; the anti-tumor platinum is oxaliplatin, carboplatin or nedaplatin; the drug that interferes with the transcription process and prevents RNA synthesis is aclarubicin, doxorubicin or mitoxantrone; the antibiotic is bleomycin, bleomycin or mitomycin; the anti-signal transduction drug is erlotinib, gefitinib, imatinib or dasatinib; the anti-tumor adjuvant drug is alizarin, azasetron, ondansetron, clodronate or mesna; the anti-tumor antibody drug is rituximab, ibritumomab tiuxetan, cetuximab or bevacizumab.

5. The novel drug-eluting airway stent according to claim 1, characterized in that: The drug / polymer complex is prepared by the following method: 2%-20% of the drug, 75%-97.8% of the polymer material and 0.2%-5% of the dispersant are uniformly mixed, melt-blended at 60-80° C., and then hot-pressed into a cylinder at 60-85° C.; the percentages are mass percentages.

Images