CN111588918A

CN111588918A - Method for coating film on surface of stent

Info

Publication number: CN111588918A
Application number: CN201911408813.3A
Authority: CN
Inventors: 董何彦; 胡义平; 张秀兰
Original assignee: Liaoning Yinyi Biotechnology Co ltd
Current assignee: Liaoning Yinyi Biotechnology Co ltd
Priority date: 2019-12-31
Filing date: 2019-12-31
Publication date: 2020-08-28

Abstract

The invention relates to a method for coating a stent surface, which is characterized in that an extensible tubular film is coated on the stent surface by adopting an adhesion mode, wherein the adhesion mode is an adhesive matrix, and the stent surface is the outer surface of a stent. The invention adopts the adhesive substrate to adhere the stent and the tubular membrane, realizes the stable combination of the tectorial membrane and the stent after being pressed and held, has the advantages of no displacement or falling off of the tectorial membrane, simple and controllable process and safe biological characteristic of the tectorial membrane stent, and solves the technical problem that the tectorial membrane stent based on a single membrane and a single frame can not be prepared by stably tectorial membrane on the surface of the stent by a non-sewing method. In addition, the technical scheme provided by the invention is based on the single-membrane single-frame covered stent, so that the puncture of the blood vessel and the covering of hemangioma can be effectively blocked, and the risk of inner leakage of the covered membrane or tearing of the blood vessel in the stent expansion process is reduced. The tubular membrane is of a microporous structure, and is beneficial to rapid endothelialization of blood vessels. The surface of the coating is coated with a drug coating, which can inhibit the adverse reaction of the lesion part and the lesion blood vessel and obtain long-term safety.

Description

Method for coating film on surface of stent

Technical Field

The invention relates to a manufacturing method of a medical apparatus, in particular to a method for coating a film on the surface of a stent, and belongs to the field of medical apparatuses.

Background

Coronary perforation is one of the rare but serious complications in percutaneous coronary intervention, and can cause acute pericardial tamponade, acute myocardial infarction, and may require pericardiocentesis or acute coronary artery bypass grafting. The incidence rate is 0.1-3.0%, and the incidence rate is mostly reported to be about 0.5%, which is related to the risk factors of patients, the use of instruments, the experience of operators and the like. Coronary aneurysm is also one of adverse symptoms seriously threatening the life of patients, and the incidence rate is 0.3% -4.5%. Coronary aneurysms often involve varying degrees of coronary stenosis, especially in cases of severe coronary stenosis, with high risk and difficult procedures. For coronary perforation and coronary aneurysms, patients can be life threatening if they are found out untimely or mishandled. The covered stent can conveniently and immediately block or cover a coronary artery perforation or coronary aneurysm part, and is the first choice mode for treating the coronary artery perforation or the coronary aneurysm. Emergency coronary artery bypass grafting or self-made covered stent is considered only when no covered stent is available or the covered stent cannot be successfully implanted.

Currently, the only coronary stent graft available on the market is GRAFTMASTER of yapei corporation, usa^®The coronary artery is preloaded with a membrane stent system (national instruments is imported 20153462417, U.S. patent No. 8496697B 2). The coronary artery covered stent is of a sandwich structure, a layer of expanded polytetrafluoroethylene film is embedded between two stents, and no drug coating is formed. The sandwich structure ensures that the covered stent has larger outer diameter, larger volume, poor flexibility and poor lesion passing capability, particularly for a far-end blood vessel and a tortuous blood vessel, the stent is difficult to completely cover lesions, and the implantation process is very difficult, consumes time and even fails or causes stent internal leakage, displacement and unloading; and when the stent graft is not smoothly operated repeatedly, the continuous bleeding of the coronary perforation may cause pericardial tamponade and hemodynamics instability. And the nominal pressure for releasing the stent needs 15 atm, the rated bursting pressure is close to 16 atm, which is higher than the pressure needed for releasing the common drug eluting stent; the balloon may be broken during the release process, and the stent is not fully expanded and cannot be effectively usedSealing lacerations or tumors, malapposition may also induce late thrombosis or restenosis [ Briguri C, et al. emery. electrotransfluoroethylene-converted transplantation to vascular coronary arteries. Circulation, 2000; 102: 3028-]. Furthermore, the "sandwich" structure of this covered stent results in a severe delay in early re-endothelialization, a high incidence of thrombosis, and a high incidence of restenosis in the long-term stent due to the absence of a drug coating [ Ly H, et al, antiviral and clinical sciences of a polytetrafluoroethylene-conjugated stent in design coronary arteries J Carbodiol, 2005; 95: 244-]。

Furthermore, the invention patents CN103313734B, US8784477B2 and EP2661286B1 of yapeki usa relate to a stent graft having a double polytetrafluoroethylene layer system with high plasticity and high rigidity. The stent has a double-membrane double-stent structure, two layers of polytetrafluoroethylene membranes are arranged between an inner stent and an outer stent, one layer has higher plasticity, and the other layer has higher rigidity. It can be seen that the stent has a larger volume and outer diameter, requires a higher nominal pressure, and is more complex to manufacture.

The invention patent US7354449B2 relates to a covered stent with a double-layer polytetrafluoroethylene covered film structure, which can reduce the nominal pressure release stent, but the covered stent has a very complicated covered film process, double-layer covered films can be realized through nine procedures, more processes are not beneficial to the quality control of the production process, and the double-layer polytetrafluoroethylene film can influence the early endothelialization of the implanted stent.

The invention patent application CN104490502A relates to a bioabsorbable membrane covered stent for coronary artery perforation. The biological absorbable membrane covered stent consists of an inner stent and an outer stent which are coaxially carved in a tubular shape, and a covered membrane made of a biological absorbable material is arranged between the inner stent and the outer stent. It can be seen that the patent application of the invention adopts Yapei GRAFTMASTER^®The coronary artery covered stent is designed in a similar sandwich structure, and a middle polytetrafluoroethylene membrane is changed into a biological absorbable material covered membrane. But the bio-absorbable covering membrane has the defects of insufficient strength and fatigue performance, and the sandwiched double-layer bracket structure also ensures that the covered membrane bracket has large outer diameter, large volume and poor flexibilityThe problem of the existing Yapei covered stent can not be effectively solved through the poor capability of the pathological change.

The invention patent CN102961788B relates to a covered stent for treating aneurysm loaded by heparin, wherein the covered layer of the covered stent is composed of emulsion electrospun nano-fibers loaded by heparin, and the nano-fibers loaded by heparin have a multi-core layer structure. The fiber coating is formed on the surface of the stent by utilizing the electrostatic spinning technology to construct the coated stent, but the strength of the electrostatic spinning fiber membrane and the fatigue performance of the constructed stent system are insufficient, the coating is broken and damaged possibly in the processes of in vivo conveying, implanting and expanding, and potential safety hazards exist. In addition, the electrostatic spinning film covering process of the covered stent is complex and is not beneficial to production and quality control.

Utility model patent CN204600791U provides a biodegradable polymer film individual layer metal covered stent, including pipy individual layer metal stent main part, the weaving layer on support surface and the tectorial membrane that covers in the support main part outside. The main body of the stent is of a metal structure, the surface woven layer of the stent is an electrostatic spinning non-woven fabric, and the outer side film coating material is a degradable polymer. Although the stent covering membrane is degradable, the problem that the polytetrafluoroethylene membrane used at present is not degradable is solved, the material and biocompatibility of the electrostatic spinning fiber are unknown, the binding force between the braid and the stent main body and between the covering membrane and the braid are also unknown, the fatigue performance and the covering membrane strength of the covered stent system can be influenced by using the electrostatic spinning surface weaving and the degradable polymer covering membrane, and a great safety risk exists. In addition, the electrostatic spinning weaving and degradable polymer film covering process of the covered stent is complex and is not beneficial to production and quality control.

At present, domestic covered stent products mainly focus on aorta, intracranial arteries and peripheral arteries, such as Shanghai minimally invasive WILLIS^®Intracranial covered stent system and Hercules^®Straight tube type stent graft and Aegis^®Bifurcated aortic stent graft, etc. The aorta covered stent consists of a single-layer metal stent and a covered membrane, and the covered membrane is mechanically sutured to the self-expansion type stent by adopting a medical non-absorbable suture. Due to the less tight connection, there is a risk of internal leakage. The outer diameter is larger after adopting a suture loading modeHowever, the coronary artery has a small diameter, and the coronary artery stent cannot be covered by using a suture mode.

Disclosure of Invention

The invention aims to provide a method for coating a film on the surface of a stent, which can solve the technical problem that the surface of the stent cannot be stably coated by a non-sewing method to prepare a single-film single-frame based covered stent.

In order to achieve the purpose, the invention adopts the following technical scheme:

a method for coating the surface of scaffold features that an extensible tubular film is adhered to the surface of scaffold by adhesive matrix and the surface of scaffold is the external surface of said scaffold.

The tubular membrane is made of synthetic polymer materials or natural polymer materials.

The tubular membrane is made of polytetrafluoroethylene, expanded polytetrafluoroethylene, polyfluortetraethylene, polyvinylidene fluoride, polychlorotrifluoroethylene, polystyrene, polyvinyl chloride, ultrahigh molecular weight polyethylene, low density polyethylene or high density polyethylene.

The tubular membrane is of a microporous structure.

The bonding mode is that the surface of the stent is coated with the bonding matrix, and then the tubular membrane is wrapped, and the stent and the tubular membrane are bonded through the bonding matrix.

The adhesive matrix is a sticky polymer, sugar or protein.

The bonding matrix is one or more of starch, protein, dextrin, animal glue, vegetable gum, shellac, hide glue, collagen, gelatin, polyamino acid and derivatives thereof, carageenan, zein, albumin, pectic acid, hyaluronic acid, chitosan and derivatives thereof, alitic acid, heparin, chondroitin sulfate, dextran, cyclodextrin, gum arabic, guar gum, rosin, phospholipid, polyethylene glycol and derivatives thereof, polyvinyl alcohol and derivatives thereof, polylactic acid and derivatives thereof, glycolide-lactide copolymer, polyglycolide and derivatives thereof, polycaprolactone and derivatives thereof, carboxymethyl cellulose, polyacrylate, polycarbonate and derivatives thereof, polyurethane and derivatives thereof, polyphosphate and derivatives thereof, polytetrafluoroethylene and cellulose and derivatives thereof.

The process for coating the bonding matrix on the surface of the stent is one or more of dip coating, smearing, spraying and quantitative coating by means of volumetric coating equipment.

The bracket is made of one or more of stainless steel, cobalt-based alloy, iron-based alloy, magnesium-based alloy, platinum-based alloy, titanium-based alloy, nickel-based alloy, zinc-based alloy and high polymer.

The tubular membrane is wrapped on the surface of the stent and then is pressed and held to the balloon catheter to form a covered stent system.

And a drug coating is coated on the surface of the covered stent system.

The drug coating process is one or more of dip coating, smearing, spraying and volume quantitative coating equipment.

The drug coating comprises an active drug.

The active drug is one or more of cytostatic agent, microtubule inhibitor, immunosuppressant, anti-inflammatory agent, anticoagulant, mitosis inhibitor, thrombosis inhibitor, lipid-lowering agent, and antioxidant.

The active drug is antibiotic, paclitaxel and its derivatives, taxane, taxol, docetaxel, epothilone, cabazitaxel, combretastatin, docetaxel trihydrate, rapamycin and its derivatives, everolimus, zotarolimus, tacrolimus, biolimus, novolimus, myolimus, temsirolimus, 5-fluorouracil, dexamethasone, probucol, colchicine, heparin, warfarin, vitamin K antagonists, aspirin, prostaglandins, vinblastine, vincristine, vinblastine, griseofulvin, penicillin, cephamycin, actinomycin D, daunorubicin, doxorubicin and its derivatives, camptothecin and its derivatives, anti-tumor antibody drugs, cyclophosphamide, cisplatin, acemetacin, resveratrol, argatroban, statins, triptycetin trioxide, antimycotic, biarsenized, aspirin, One or more of berberine, ginkgol, folium Ginkgo extract, hormone and plant alkaloid.

The drug coating comprises a drug-loaded matrix.

The drug-carrying matrix is one or more of starch, protein, dextrin, animal glue, plant gum, shellac, hide glue, collagen, gelatin, polyamino acid and derivatives thereof, carrageenin, zein, albumin, pectic acid, hyaluronic acid, chitosan and derivatives thereof, alitanic acid, heparin, chondroitin sulfate, dextran, cyclodextrin, acacia, guar gum, rosin, phospholipid, polyethylene glycol and derivatives thereof, polyvinyl alcohol and derivatives thereof, polylactic acid and derivatives thereof, glycolide-lactide copolymer, polyglycolide and derivatives thereof, polycaprolactone and derivatives thereof, carboxymethyl cellulose, polyacrylate, polycarbonate and derivatives thereof, polyurethane and derivatives thereof, polyphosphate and derivatives thereof, polytetrafluoroethylene and cellulose and derivatives thereof.

Compared with the prior art, the invention has the beneficial effects that: the invention provides a method for coating a membrane on the surface of a stent, which adopts an adhesive substrate to adhere the stent and a tubular membrane, realizes the stable combination of the membrane and the stent after being pressed and held, has the advantages of no displacement or falling of the membrane, simple and controllable process and safe biological characteristics of the membrane-coated stent, and solves the technical problem that the membrane-coated stent based on a single membrane and a single frame can not be prepared by stably coating the surface of the stent by a non-sewing method. Moreover, the single-membrane single-frame-based covered stent provided by the invention can effectively block the perforation of the blood vessel and cover hemangioma, and reduce the risk of inner leakage of the covered membrane or tearing of the blood vessel in the stent expansion process. The tubular membrane is of a microporous structure, and is beneficial to rapid endothelialization of blood vessels. The surface of the coating is coated with a drug coating, which can inhibit the adverse reaction of the lesion part and the lesion blood vessel and obtain long-term safety.

Drawings

FIG. 1 is a schematic structural view of a stent graft of the present invention;

in the figure: 1. adhesive matrix, 2, balloon, 3, membrane, 4, scaffold.

Detailed Description

In the embodiment of the invention, the tubular membrane is a microporous structure, which is beneficial to the rapid endothelialization of blood vessels.

In an embodiment of the invention, the tubular membrane is elastic and stretchable.

In the embodiment of the invention, the surface of the covered stent system is coated with the drug coating, so that adverse reactions of a lesion part and a lesion blood vessel can be inhibited, and long-term safety is obtained.

For a further understanding of the present invention, preferred embodiments of the present invention will be described below with reference to examples. The description is intended to be illustrative of the features and advantages of the invention, and should not be taken to limit the scope of the invention.

Example 1

Taking a stainless steel bracket, spraying shellac on the surface, and drying for 1 h. The spraying parameters are as follows: the flow rate of the injection pump is 0.06ml/min, the ultrasonic power is 0.8W, the pressure of the nitrogen is 7psi, the rotating speed is 350rpm, and the advancing speed is 0.1 mm/s. The shellac layer thickness was 2 μm. Cutting the expanded polytetrafluoroethylene tubular membrane, pre-sleeving the membrane on the stent, bonding, and pressing and holding the membrane to the front end balloon of the balloon catheter.

Example 2

The stent graft crimped to the balloon in example 1 was taken, and the surface was sprayed with paclitaxel and glycolide-lactide copolymer, wherein the thickness of the drug coating was 2 μm.

Example 3

Taking a stainless steel bracket, spraying shellac on the surface, and drying for 1 h. The spraying parameters are as follows: the flow rate of the injection pump is 0.06ml/min, the ultrasonic power is 0.8W, the pressure of the nitrogen is 7psi, the rotating speed is 350rpm, and the advancing speed is 0.1 mm/s. The shellac layer thickness was 2 μm. Cutting high-density polyethylene tubular film, pre-sheathing on the stent, bonding, and pressing to the front end balloon of the balloon catheter. And spraying copolymer of paclitaxel and glycolide and lactide on the surface of the coating, wherein the thickness of the coating is 2 μm.

Example 4

Spraying dextran on the surface of the stainless steel bracket, and drying for 1 h. The spraying parameters are as follows: the flow rate of the injection pump is 0.06ml/min, the ultrasonic power is 0.8W, the pressure of the nitrogen is 7psi, the rotating speed is 350rpm, and the advancing speed is 0.1 mm/s. The thickness of the dextran layer was 3 μm. Cutting the expanded polytetrafluoroethylene tubular membrane, pre-sleeving the membrane on the stent, bonding, and pressing and holding the membrane to the front end balloon of the balloon catheter. And spraying copolymer of paclitaxel and glycolide and lactide on the surface of the coating, wherein the thickness of the coating is 2 μm.

Example 5

Soaking stainless steel bracket in dextran solution for 10min, naturally drying for 10min, and repeating for 6 times. The thickness of the dextran layer was 4 μm. Cutting the expanded polytetrafluoroethylene tubular membrane, pre-sleeving the membrane on the stent, bonding, and pressing and holding the membrane to the front end balloon of the balloon catheter.

Example 6

The stent graft crimped to the balloon in example 5 was taken, and the surface was sprayed with paclitaxel and glycolide-lactide copolymer, wherein the thickness of the drug coating was 2 μm.

Example 7

And (3) spraying albumin on the surface of the cobalt-chromium alloy bracket, and drying for 0.5 h. The spraying parameters are as follows: the flow rate of the injection pump is 0.05ml/min, the ultrasonic power is 0.8W, the pressure of the nitrogen is 7psi, the rotating speed is 350rpm, and the advancing speed is 0.1 mm/s. The thickness of the albumin layer was 3 μm. Cutting the expanded polytetrafluoroethylene tubular membrane, pre-sleeving the membrane on the stent, bonding, and pressing and holding the membrane to the front end balloon of the balloon catheter. And spraying copolymer of paclitaxel and glycolide and lactide on the surface of the coating, wherein the thickness of the coating is 2 μm.

Example 8

And (3) taking the cobalt-chromium alloy bracket, spraying shellac on the surface of the cobalt-chromium alloy bracket, and drying for 1 hour. The spraying parameters are as follows: the flow rate of the injection pump is 0.05ml/min, the ultrasonic power is 0.8W, the pressure of the nitrogen is 7psi, the rotating speed is 350rpm, and the advancing speed is 0.1 mm/s. The shellac layer thickness was 2 μm. Cutting the expanded polytetrafluoroethylene tubular membrane, pre-sleeving the membrane on the stent, bonding, and pressing and holding the membrane to the front end balloon of the balloon catheter. Rapamycin and polylactic acid are sprayed on the surface of the coating, and the thickness of the medicine coating is 3 mu m.

Example 9

And (3) taking the cobalt-chromium alloy bracket, spraying shellac on the surface of the cobalt-chromium alloy bracket, and drying for 1 hour. The spraying parameters are as follows: the flow rate of the injection pump is 0.05ml/min, the ultrasonic power is 0.8W, the pressure of the nitrogen is 7psi, the rotating speed is 350rpm, and the advancing speed is 0.1 mm/s. The shellac layer thickness was 2 μm. Cutting the expanded polytetrafluoroethylene tubular membrane, pre-sleeving the membrane on the stent, bonding, and pressing and holding the membrane to the front end balloon of the balloon catheter. Immersing the covered stent in heparin sodium and polyethylene glycol solution for 5min, naturally drying for 10min, and repeating for 6 times. The drug coating thickness was 4 μm.

Comparative example 1

Cutting the expanded polytetrafluoroethylene tubular membrane, sleeving the membrane on a stainless steel bracket, pre-tightening, compressing and extruding, and pressing and holding the membrane to the front end balloon of the balloon catheter.

Cytotoxicity test

The covered stents prepared in the example 1, the example 5 and the comparative example 1 are taken, and the test solution is prepared at 37 ℃ and 72h by taking a culture medium as a leaching medium. Human vascular smooth muscle cells growing in logarithmic phase were co-cultured with the test solution, and the relative proliferation rate of each group of cells was determined by MTT colorimetry, and the results are shown in table 1:

TABLE 1 relative cell proliferation Rate

Numbering	Relative cell proliferation Rate (%)
		Example 1	102
Example 5	103
		Comparative example 1	101

As can be seen, human vascular smooth muscle cells grew normally after coculture with the leach solutions of the covered stents prepared in examples 1, 5 and 1. According to standard GB/T14233.2 test method for medical infusion, blood transfusion and injection apparatus part 2: the biological test method is classified, the cytotoxicity reaction of the leaching liquor is 0 grade, and the leaching liquor has no cytotoxicity. It can be seen that the stent grafts prepared in example 1, example 5 and comparative example 1 have no cytotoxicity. Indicating that the introduction of the adhesive matrix does not create a biosafety risk.

Drug release test

After the stent graft prepared in example 2 is released, the stent graft is immersed in a certain volume of slow release solution (phosphate buffer solution), and is oscillated at 37 ℃ and 60 rpm. And respectively taking out the stent at a preset time point, immersing the stent in fresh slow-release solution, and continuously slowly releasing. And taking a sample to be detected, and adding equal volume of acetonitrile for dilution. The diluted solution was filtered through a 0.45 μm filter, and the subsequent filtrate was injected into a high performance liquid chromatography system for detection, and the drug release rate was determined as shown in table 2:

TABLE 2 drug Release Rate

Time of release	Cumulative release rate
		1 day	29%
7 days	48%
		14 days	57%
28 days	75%
		60 days	94%

As can be seen, the stent graft prepared in example 2 can release the drug paclitaxel continuously within two months. The covered stent can continuously release paclitaxel to inhibit intimal hyperplasia while playing a role of blocking vascular perforation or covering hemangioma, thereby obtaining long-term safety.

The methods and references of the present invention have been described in terms of preferred embodiments, which are set forth only to aid in the understanding of the principles of the invention, and it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as appropriate variations and combinations, may be made to implement and apply the techniques of the present invention without departing from the spirit and scope of the invention. It is specifically intended that such modifications or suitable variations and combinations be within the scope of the invention as claimed. Those skilled in the art can implement and use the techniques of this invention by making modifications, or appropriate alterations and combinations, of the methods and applications described herein without departing from the spirit, scope, and content of the invention.

Claims

1. A method for coating a stent surface is characterized by comprising the following steps: the expandable tubular film is coated on the surface of the stent by adopting a bonding mode, the bonding mode adopts bonding matrix for bonding, and the surface of the stent is the outer surface of the stent.

2. The method according to claim 1, wherein the tubular membrane is made of a synthetic polymer material or a natural polymer material.

3. The method for coating the surface of a stent according to claim 1, wherein the tubular membrane has a microporous structure.

4. The method of claim 1, wherein the adhering is performed by coating the adhesive matrix on the surface of the stent and then coating the tubular membrane, and the stent and the tubular membrane are adhered to each other via the adhesive matrix.

5. The method for coating the surface of a stent according to claim 1 or 4, wherein the adhesive matrix is an adhesive polymer, sugar or protein.

6. The method for coating the surface of the stent according to claim 1, wherein the tubular membrane is pressed and held to a balloon catheter after being coated on the surface of the stent to form a stent-graft system.

7. The method for coating the surface of a stent according to claim 6, wherein the stent graft system is coated with a drug coating.

8. The method of claim 7, wherein the drug coating comprises an active drug.

9. The method of claim 8, wherein the active agent is one or more of a cytostatic agent, a microtubule inhibitor, an immunosuppressive agent, an anti-inflammatory agent, an anticoagulant, a mitotic inhibitor, a thrombosis inhibitor, a lipid-lowering agent, an antioxidant.

10. The method of claim 7, wherein the drug coating comprises a drug-loaded matrix.