Covered stent and preparation method thereof
By designing a multi-layered covered stent on the stent surface and utilizing the loading of active heparin and paclitaxel, the problems of stent restenosis and incomplete drug coating coverage were solved, achieving long-term stent patency and local therapeutic effect.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- THE FIRST AFFILIATED HOSPITAL OF TSINGHUA UNIV
- Filing Date
- 2024-11-21
- Publication Date
- 2026-05-22
AI Technical Summary
Existing stents are prone to restenosis and the drug coating cannot completely cover the stent, leading to in-stent thrombosis and intimal hyperplasia.
A membrane-coated scaffold is designed, comprising a metal scaffold body and a multilayer membrane loaded with active heparin and paclitaxel. The metal scaffold surface is coated with an ePTFE membrane by electrospinning-thermopressing, and the outer surfaces of the proximal and distal segments are impregnated with a drug premix to form a drug release layer that degrades rapidly and slowly, thereby preventing endothelial cell migration and smooth muscle cell proliferation.
It effectively prevents endothelial cells and smooth muscle cells from entering the stent mesh, slowly releases drugs to the lesion site, improves stent patency, reduces restenosis rate, and has mechanical expansion and local therapeutic effects.
Smart Images
Figure CN122070943A_ABST
Abstract
Description
Technical Field
[0001] This disclosure relates to the field of medical device technology, specifically to a covered stent and its preparation method. Background Technology
[0002] Atherosclerosis (AS) is a major cause of coronary heart disease, cerebral infarction, and peripheral vascular disease. With the aging of society, the incidence and harm of this disease are increasing daily. In recent years, endovascular stent implantation has become a preferred treatment for these conditions, but the main challenge lies in maintaining long-term patency. This is due to factors including stent thrombosis (ST) and in-stent restenosis (ISR). Stent damage to the endothelium, persistent fibrin deposition, and persistent vessel wall inflammation are risk factors for stent thrombosis. The pathological process of in-stent restenosis mainly involves intimal hyperplasia, proliferation of numerous smooth muscle cells, and increased extracellular matrix secretion.
[0003] With technological innovation, the use of new stents such as heparin-coated covered stents and drug-eluting stents has significantly improved patency rates in the short to medium term. Heparin-coated covered stents, in particular, have a heparin-based bioactive surface on their inner wall. The covering itself acts as a mechanical barrier to prevent smooth muscle cell migration, while the heparin coating prevents in-stent thrombosis. However, these covered stents still have the unavoidable drawback of endothelial migration and cell proliferation at the proximal and distal ends, leading to stent restenosis (12-month restenosis rate of 22-27%). Drug-eluting stents, primarily represented by nickel-titanium alloy paclitaxel-eluting stents, utilize a slow release of antithrombotic or antiproliferative drugs coated on the stent matrix. This provides sufficient therapeutic drug concentrations at the stent implantation site to reduce restenosis while avoiding systemic adverse reactions caused by excessively high blood drug concentrations. However, the drug coating is limited to the outer wall of the bare stent matrix, leaving a significant portion of the lesion uncovered and failing to completely inhibit intimal hyperplasia (12-month restenosis rate of 15-20%). Therefore, both types of new stents still have shortcomings that cannot be overcome. Summary of the Invention
[0004] The purpose of this disclosure is to address the shortcomings of existing stents, such as the tendency for stent restenosis and the inability of drug coatings to completely cover the stent, and to provide a new covered stent and its preparation method.
[0005] To achieve the above objectives, the first aspect of this disclosure provides a film-coated support, which includes a metal support body and a film fixed to the inner and outer surfaces of the metal support body. The metal stent body includes a proximal metal stent body, an intermediate metal stent body, and a distal metal stent body connected in sequence. The inner and outer surfaces of the intermediate metal stent body are covered with ePTFE membranes and loaded with active heparin. The inner and outer surfaces of the proximal and distal metal stent bodies are coated with ePTFE membranes and a double-layer drug-containing membrane; the double-layer drug-containing membrane includes a bottom layer membrane and a top layer membrane; the bottom layer membrane is a polybutyl methacrylate membrane, and the top layer membrane is a polyvinylidene fluoride-hexafluoropropylene copolymer membrane loaded with paclitaxel.
[0006] Optionally, the metal support body has a columnar structure with an inner diameter of 3.5-17.5 mm, preferably 4-14 mm, and an outer diameter of 4-18 mm, preferably 5-16 mm.
[0007] Optionally, the length of the metal bracket body is 5-100mm, preferably 10-80mm.
[0008] Optionally, the length of the coating on the inner and outer surfaces of the proximal metal stent body and the distal metal stent body is 5-10 mm; the coating thickness is 0.05-0.3 mm, preferably 0.1-0.2 mm.
[0009] Optionally, the paclitaxel loading on the surface film is 0.5-1.5 μg / mm. 2 Preferably, it is 0.8-1.2 μg / mm 2 .
[0010] Optionally, the loading of active heparin on the coating of the inner surface of the intermediate metal scaffold body is 0.5-3 μg / mm. 2 Preferably, it is 1.0-2.0 μg / mm 2 .
[0011] Optionally, the metal support body includes a nickel-titanium alloy laser-engraved support.
[0012] On the other hand, this disclosure also provides a method for preparing the covered scaffold described in the first aspect, wherein the method includes the following steps: S1. Coat the inner and outer surfaces of the proximal and distal segments of the metal stent body with an ePTFE membrane to obtain the first membrane-coated stent. S2. Immerse the outer surfaces of the proximal and distal segments of the first coated stent in a first premixed solution containing poly(n-butyl methacrylate), remove them after complete immersion, and vacuum dry them to obtain the second coated stent. S3. Immerse the outer surfaces of the proximal and distal segments of the second covered stent into a second premixed solution containing paclitaxel and polyvinylidene fluoride-hexafluoropropylene copolymer. After complete immersion, remove the stent and vacuum dry it to obtain the third covered stent. S4. Coat the inner and outer surfaces of the middle section of the third covered stent with an ePTFE membrane, the ePTFE membrane being loaded with active heparin, to obtain the covered stent.
[0013] Optionally, the second premix also contains pharmaceutical excipients; Optionally, the pharmaceutical excipients include at least one of polyvinyl alcohol, polytetrafluoroethylene, polybutyl methacrylate, and polyvinylidene fluoride copolymer.
[0014] Optionally, in the second premix, the weight ratio of the paclitaxel drug, pharmaceutical excipients and polyvinylidene fluoride-hexafluoropropylene copolymer is 1:(1-3):(1-3).
[0015] Optionally, the vacuum drying conditions include: a temperature of 1-10℃, a time of 5-30h, and a vacuum degree of 1-1000Pa.
[0016] Through the above technical solution, this disclosure provides a covered stent and its preparation method. The outer layer of the covered stent is a rapidly degradable drug-loaded natural polymer layer. Through the rapid degradation of the material in the body, the drug is continuously released from the material, which plays a therapeutic role against surrounding tumors. The middle layer uses a slowly degradable drug-loaded polymer layer as support, which can prevent endothelial cells and smooth muscle cells from entering the stent mesh. It can be used to treat malignant vascular stenosis. It not only has a mechanical dilation effect, but also a local therapeutic effect. The provided drug-loaded covered stent slowly releases drugs to the lesion site, which can better solve the problem of benign and malignant vascular stenosis than ordinary bare stents or covered stents.
[0017] Other features and advantages of this disclosure will be described in detail in the following detailed description section. Attached Figure Description
[0018] The accompanying drawings are provided to further illustrate the present disclosure and form part of the specification. They are used together with the following detailed description to explain the present disclosure, but do not constitute a limitation thereof. In the drawings: Figure 1 This is a schematic diagram of the covered scaffold structure disclosed in this publication. Detailed Implementation
[0019] The specific embodiments of this disclosure will be described in detail below with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are for illustration and explanation only and are not intended to limit this disclosure.
[0020] The first aspect of this disclosure provides a film-coated support, which includes a metal support body and a film fixed to the inner and outer surfaces of the metal support body; The metal stent body includes a proximal metal stent body, an intermediate metal stent body, and a distal metal stent body connected in sequence. The inner and outer surfaces of the intermediate metal stent body are covered with ePTFE membranes, and the surface of the ePTFE membranes is loaded with active heparin. The inner and outer surfaces of the proximal and distal metal stent bodies are coated with ePTFE membranes and a double-layer drug-containing membrane; the double-layer drug-containing membrane includes a bottom layer membrane and a top layer membrane; the bottom layer membrane is a polybutyl methacrylate membrane, and the top layer membrane is a polyvinylidene fluoride-hexafluoropropylene copolymer membrane loaded with paclitaxel.
[0021] The covered stent disclosed herein has a proximal and distal segment with an outer layer of natural polymer loaded with paclitaxel, which can rapidly degrade in vivo, allowing for the slow release of paclitaxel and providing a good therapeutic effect on surrounding tumors. The middle segment uses a slowly degradable polymer layer loaded with active heparin as support, which can prevent endothelial cells and smooth muscle cells from entering the stent mesh. This not only has a mechanical expansion effect but also a local therapeutic effect, and can slowly release drugs to the lesion site. Compared with ordinary bare stents or covered stents, it can better solve the problem of benign and malignant vascular stenosis.
[0022] Optionally, the metal support body has a columnar structure with an inner diameter of 3.5-17.5 mm, preferably 4-14 mm, and an outer diameter of 4-18 mm, preferably 5-16 mm.
[0023] Optionally, the length of the metal bracket body is 5-100mm, preferably 10-80mm.
[0024] Optionally, the length of the coating on the inner and outer surfaces of the proximal metal stent body and the distal metal stent body is 5-10 mm; the thickness of the coating is 0.05-0.3 mm, preferably 0.1-0.2 mm.
[0025] Optionally, the paclitaxel loading on the surface film is 0.5-1.5 μg / mm. 2 Preferably, it is 0.8-1.2 μg / mm 2 .
[0026] Optionally, the loading of active heparin on the coating of the inner surface of the intermediate metal scaffold body is 0.5-3.0 μg / mm. 2 Preferably, it is 1.0-2.0 μg / mm 2 .
[0027] Optionally, the metal support body includes a nickel-titanium alloy laser-engraved support.
[0028] The second aspect of this disclosure provides a method for preparing the covered scaffold described in the first aspect, the method comprising the following steps: S1. Coat the inner and outer surfaces of the proximal and distal segments of the metal stent body with an ePTFE membrane to obtain the first membrane-coated stent. S2. Immerse the outer surfaces of the proximal and distal segments of the first coated stent in a first premixed solution containing poly(n-butyl methacrylate), remove them after complete immersion, and vacuum dry them to obtain the second coated stent. S3. Immerse the outer surfaces of the proximal and distal segments of the second covered stent into a second premixed solution containing paclitaxel and polyvinylidene fluoride-hexafluoropropylene copolymer. After complete immersion, remove the stent and vacuum dry it to obtain the third covered stent. S4. Coat the inner and outer surfaces of the middle section of the third covered stent with an ePTFE membrane, and load active heparin onto the ePTFE membrane to obtain the covered stent.
[0029] The methods of coating the inner and outer surfaces of the metal stent body or the covered stent with an ePTFE membrane and the methods of loading active heparin onto the ePTFE membrane in this disclosure are not particularly limited and can be methods commonly used in the art.
[0030] Optionally, the method of coating the inner and outer surfaces of the metal stent body or the coated stent can be the electrospinning-hot pressing method conventional in the art.
[0031] Optionally, the second premix also contains pharmaceutical excipients; The pharmaceutical excipients include at least one of polyvinyl alcohol, polytetrafluoroethylene, polybutyl methacrylate, and polyvinylidene fluoride copolymer.
[0032] Optionally, in the second premix, the weight ratio of the paclitaxel drug, pharmaceutical excipients and polyvinylidene fluoride-hexafluoropropylene copolymer is 1:(1-3):(1-3).
[0033] Optionally, the vacuum drying conditions include: a temperature of 1-10℃, a time of 5-30h, and a vacuum degree of 1-1000Pa.
[0034] The present disclosure will be further illustrated by the following examples, but the present disclosure is not limited thereto.
[0035] Example 1 This embodiment uses a nickel-titanium alloy laser engraving bracket as the metal bracket body, and the metal bracket body has a columnar structure, such as... Figure 1As shown, the inner diameter is 4 mm, the outer diameter is 5 mm, the length of the proximal segment of the stent body is 5 mm, the length of the middle segment is 30 mm, and the length of the distal segment is 5 mm. The inner and outer surfaces of both the proximal and distal segments of the stent body have a coating length of 10 mm, consisting of an ePTFE membrane and a double-layer drug-eluting membrane, respectively. Both the ePTFE membrane and the double-layer drug-eluting membrane have a thickness of 0.5 mm. The double-layer drug-eluting membrane consists of a bottom layer membrane and a top layer membrane. The bottom layer membrane is made of poly(n-butyl methacrylate), and the top layer membrane is loaded with 1 μg / mm² of drug-eluting agent. 2 The paclitaxel-polyvinylidene fluoride-hexafluoropropylene copolymer membrane; the inner and outer surfaces of the intermediate metal scaffold body are coated with ePTFE membranes, and covalently grafted with 1μg / mm 2 The active heparin has a coating thickness of 0.5 mm.
[0036] The specific preparation process is as follows: S1. Using electrospinning-hot pressing, an ePTFE membrane is coated on the inner and outer surfaces of the proximal and distal sections of the metal scaffold body to obtain the first coated scaffold; (i.e., the ePTFE solution is stirred at 50°C for 5 hours to obtain a spinning solution, and then electrospinned at 25°C with an applied voltage of 18kV to obtain a spun fiber membrane. A pressure of 20MPa is applied at 120°C for 30 minutes, and the spun fiber membrane is hot-pressed onto the metal scaffold body). S2. Immerse the outer surfaces of the proximal and distal segments of the first coated stent in a first premixed solution containing poly(n-butyl methacrylate), remove them after complete immersion, and vacuum dry them to obtain the second coated stent. S3. The outer surfaces of the proximal and distal segments of the second covered stent are immersed in a second premixed solution containing paclitaxel and a polyvinylidene fluoride-hexafluoropropylene copolymer membrane. The weight ratio of the antiproliferative drug paclitaxel, the pharmaceutical excipient polyvinyl alcohol, and the polyvinylidene fluoride-hexafluoropropylene copolymer membrane in the second premixed solution is 0.5:1:1. After complete immersion, the stent is removed and vacuum dried at 4°C for 24 hours at a vacuum degree of 400 Pa to obtain the third covered stent. S4. Using the same method as in step S1, coat the inner and outer surfaces of the middle section of the third coated scaffold with ePTFE to form an ePTFE coating with a thickness of 0.1 mm. Immerse the scaffold in an active heparin solution for 1 hour, remove and clean it, and dry it at 4°C for 6 hours to form a 1.0 μg / mm² ePTFE coating. 2 The active heparin was used to obtain the coated scaffold.
[0037] Example 2 This embodiment uses a nickel-titanium alloy laser engraving bracket as the metal bracket body, and the metal bracket body has a columnar structure, such as... Figure 1As shown, the inner diameter is 7mm, the outer diameter is 8mm, the length of the proximal segment of the stent body is 10mm, the length of the middle segment is 80mm, and the length of the distal segment is 10mm. The inner and outer surfaces of both the proximal and distal segments of the stent body are coated with ePTFE membranes and double-layered drug-eluting membranes, each membrane being 10mm long and 0.1mm thick. The double-layered drug-eluting membranes are a bottom layer membrane and a top layer membrane; the bottom layer membrane is made of poly(n-butyl methacrylate), and the top layer membrane is loaded with 1μg / mm² of drug-eluting agent. 2 The paclitaxel-polyvinylidene fluoride-hexafluoropropylene copolymer membrane; the inner and outer surfaces of the intermediate metal scaffold body are coated with ePTFE membranes, and the membrane surface is loaded with 1 μg / mm 2 Active heparin.
[0038] The preparation method is the same as in Example 1.
[0039] Test Example 1 In vitro simulated implantation experiments were conducted to test the adhesion performance and controlled drug release performance of the drug-coated stent.
[0040] According to the standards in actual clinical work, the drug-coated stent system prepared in Example 1 above was implanted into an arterial model (diameter 1:1 matching) to observe the precise release performance and adhesion performance of the drug-coated stent. The stent can accurately position and slowly release drugs, and has better adhesion performance.
[0041] The residual drug concentration in the drug-coated stent was determined at different times to preliminarily determine the controlled release curve of the drug (paclitaxel, active heparin) in the drug coating. When the stent is used, the drug can be released slowly and uniformly.
[0042] The outer layer of the covered stent disclosed herein is a rapidly degradable drug-loaded natural polymer layer. Through the rapid degradation of the material in the body, the drug is continuously released from the material, playing a therapeutic role against surrounding tumors. The middle layer uses a slowly degradable drug-loaded polymer layer as support, which can prevent endothelial cells and smooth muscle cells from entering the stent mesh. It can be used to treat malignant vascular stenosis. It not only has a mechanical dilating effect, but also a local therapeutic effect. The provided drug-loaded covered stent slowly releases drugs to the lesion site, which can better solve the problem of benign and malignant vascular stenosis than ordinary bare stents or covered stents.
[0043] The preferred embodiments of this disclosure have been described in detail above with reference to the accompanying drawings. However, this disclosure is not limited to the specific details of the above embodiments. Within the scope of the technical concept of this disclosure, various simple modifications can be made to the technical solutions of this disclosure, and these simple modifications all fall within the protection scope of this disclosure.
[0044] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, this disclosure will not describe the various possible combinations separately.
[0045] Furthermore, various different embodiments of this disclosure can be combined in any way, as long as they do not violate the spirit of this disclosure, they should also be regarded as the content disclosed in this disclosure.
Claims
1. A covered stent, characterized in that, The film-coated support includes a metal support body and a film fixed to the inner and outer surfaces of the metal support body; The metal stent body includes a proximal metal stent body, an intermediate metal stent body, and a distal metal stent body connected in sequence. The inner and outer surfaces of the intermediate metal stent body are covered with ePTFE membranes, and the surface of the ePTFE membranes is loaded with active heparin. The inner and outer surfaces of the proximal and distal metal stent bodies are coated with ePTFE membranes and a double-layer drug-containing membrane; the double-layer drug-containing membrane includes a bottom layer membrane and a top layer membrane; the bottom layer membrane is a polybutyl methacrylate membrane, and the top layer membrane is a polyvinylidene fluoride-hexafluoropropylene copolymer membrane loaded with paclitaxel.
2. The covered stent according to claim 1, wherein, The metal support body has a columnar structure with an inner diameter of 3.5-17.5 mm, preferably 4-14 mm, and an outer diameter of 4-18 mm, preferably 5-16 mm.
3. The covered stent according to claim 1, wherein, The length of the metal bracket body is 5-100mm, preferably 10-80mm.
4. The covered stent according to claim 3, wherein, The length of the coating on the inner and outer surfaces of the proximal and distal metal stent bodies is 5-10 mm; the coating thickness is 0.05-0.3 mm, preferably 0.1-0.2 mm.
5. The covered stent according to claim 1, wherein, The paclitaxel loading on the surface membrane is 0.5-1.5 μg / mm. 2 Preferably, it is 0.8-1.2 μg / mm 2 .
6. The covered stent according to claim 1, wherein, The loading of active heparin on the inner and outer surfaces of the intermediate metal scaffold body is 0.5-3 μg / mm. 2 Preferably, it is 1.0-2.0 μg / mm 2 .
7. The covered stent according to claim 1, wherein, The metal support body includes a nickel-titanium alloy laser-engraved support.
8. A method for preparing a covered scaffold according to any one of claims 1-7, wherein, The preparation method includes the following steps: S1. Coat the inner and outer surfaces of the proximal and distal segments of the metal stent body with an ePTFE membrane to obtain the first membrane-coated stent. S2. Immerse the outer surfaces of the proximal and distal segments of the first coated stent in a first premixed solution containing poly(n-butyl methacrylate), remove them after complete immersion, and vacuum dry them to obtain the second coated stent. S3. Immerse the outer surfaces of the proximal and distal segments of the second covered stent into a second premixed solution containing paclitaxel and polyvinylidene fluoride-hexafluoropropylene copolymer. After complete immersion, remove the stent and vacuum dry it to obtain the third covered stent. S4. Coat the inner and outer surfaces of the middle section of the third covered stent with an ePTFE membrane, and load active heparin onto the ePTFE membrane to obtain the covered stent.
9. The preparation method according to claim 8, wherein, The second premix also contains pharmaceutical excipients; the pharmaceutical excipients include at least one of polyvinyl alcohol, polytetrafluoroethylene, polybutyl methacrylate and polyvinylidene fluoride copolymer.
10. The preparation method according to claim 9, wherein, In the second premix, the weight ratio of the paclitaxel drug, pharmaceutical excipients, and polyvinylidene fluoride-hexafluoropropylene copolymer is 1:(1-3):(1-3). The vacuum drying conditions include: a temperature of 1-10℃, a time of 5-30h, and a vacuum degree of 1-1000Pa.