WO2009082876A1 - A controlled degradation magnesium metal coating scaffold and its preparation method - Google Patents

A controlled degradation magnesium metal coating scaffold and its preparation method Download PDF

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Publication number
WO2009082876A1
WO2009082876A1 PCT/CN2008/001313 CN2008001313W WO2009082876A1 WO 2009082876 A1 WO2009082876 A1 WO 2009082876A1 CN 2008001313 W CN2008001313 W CN 2008001313W WO 2009082876 A1 WO2009082876 A1 WO 2009082876A1
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Prior art keywords
coating
stent
surface
magnesium
drug
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PCT/CN2008/001313
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French (fr)
Chinese (zh)
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Saying Dong
Zhengcai Zhang
Xiaogang Liu
Lixiao Zhao
Zhongjie Pu
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Lepu Medical Technology (Beijing) Co., Ltd.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28Materials for coating prostheses
    • A61L27/30Inorganic materials
    • A61L27/306Other specific inorganic materials not covered by A61L27/303 - A61L27/32
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28Materials for coating prostheses
    • A61L27/34Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08Materials for coatings
    • A61L31/10Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148Materials at least partially resorbable by the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606Coatings

Abstract

A controlled degradation magnesium metal coating scaffold includes a backbone made of medical high pure magnesium or Mg-alloy. The surface of the scaffold backbone has an anticorrosive coating. The surface of the anticorrosive coating has a degradable polymer film drug-loading coating which loads a curative drug. The preparation method of the scaffold includes: anticorrosive treating on the surface of the backbone to form anticorrosive coating, coating the degradable polymer film drug-loading coating on the surface of the anticorrosive coating, and coating the curative drug on the surface of the drug-loading coating and so on.

Description

Controllable Degradation of the magnesium metal and coated stents TECHNICAL FIELD

The present invention is in the field of medical devices, particularly relates to magnesium metal-coated stents and a preparation method of controlled degradation. Background technique

1976 German scholar Andreas' Gelongcige first proposed the idea of ​​mounting brackets inside the artery, coronary stents to the 1990s has been widely used in clinical treatment. Current technology has evolved to a coronary stent in stainless steel and cobalt chrome based drug eluting stent, but still fundamentally solve the stent thrombosis and restenosis fundamentally, the presence of high surgery restenosis, thrombosis strong endogenous permanently remain in the body and frame defects, long-term results unsatisfactory.

Magnesium material is one of Earth's most abundant reserves of elements, the human body is the fourth, the second most abundant intracellular cation in the human body is an important and indispensable nutrients in the body for about more than 20 grams of total. Magnesium in the course of life and promotes the formation of bone cells, or catalytic activation of the body 300 kinds of enzymes involved in energy metabolism, and delivery of energy, storage and use plays a key role. Magnesium three to affect metabolism in vivo protein synthesis by adjusting the structure of DNA and ribosomal RNA. Magnesium magnesium ion into the chemical reaction in an aqueous medium, magnesium ion is balanced by adjusting the kidney in vivo absorption and metabolism so that the magnesium alloy material is gradually degraded and absorbed in vivo. Magnesium alloys due to having good mechanical properties, corrosion resistance and controlled degradation products with minimal side effects, etc. selected become the material of the stent. Magnesium as biomedical materials with good medicine safety, especially for the treatment of cardiovascular disease. Although magnesium alloy stent having good magnetic resonance imaging (MRI) compatible, but can not be displayed in the "X ray", intravascular ultrasound guidance when placing must preclude; Another disadvantage magnesium alloy stents is too fast degradation rate , in about two months it had completely degraded.

Biodegradable polymer materials with non-toxic, non-irritating, easy processing, drug volume and other advantages. But as a scaffold, it is low in strength, hardness and rigidity can not meet the requirements; biodegradable polymer stent while there is poor control degradation, poor processing stability, poor storage stability, local accumulation of acidic degradation products, and a series of healing effect shortcomings.

Patent No. CN1857742A discloses the use of magnesium alloys in combination with a degradable polymer scaffold materials, magnesium alloy corrosion can delay and prolong the service life of the bracket, to improve the mechanical strength of the stent and the drug loading. However, since the surface corrosion treatment process without the magnesium alloy, in the blood, the polymer material may be a magnesium alloy and simultaneously the reaction begins to degrade, the presence or fast degradation rate of the magnesium alloy material drawbacks. SUMMARY

Object of the present invention to provide a magnesium metal-coated stents and a preparation method of controlled degradation, provided with a coating of a magnesium alloy and the coating material is biodegradable polymer on the stent, the stent may reduce the corrosion of the magnesium alloy and controlling the rate of release of drugs; anti-corrosion treatment of the surface of the magnesium alloy stents by this method, a magnesium alloy to degrade delay stent.

To achieve the above object, the present invention preclude the use of the following technical solutions:

Controllable Degradation of magnesium metal coated stent, which is a medical stent body made of high-purity magnesium or magnesium alloy, said stent body having a surface coating of anti-corrosion, anti-corrosion coating applied to the surface with a biodegradable polymer drug carrier film coating the drug carrier with a therapeutic drug coating.

Wherein said anti-corrosion coating may be a medically acceptable metal oxide coating, preferably a coating of magnesium oxide.

Wherein the degradable polymer film drug coating comprises one or more substances: polylactic acid, poly-L-lactic acid, polyglycolide, polyglycolic acid, poly cyanoacrylates, polycaprolactone , polyanhydrides, polylactic acid copolymer, poly-hydroxy valerate, poly-acetyl acid, polyorthoesters, polyethylene oxide, polybutylene copolymers, polyorthoesters, polycaprolactone, polyglycolic acid , polyethylene oxide, polybutylene terephthalate copolymers, methacrylate or acrylate, methacrylate or acrylate, polyurethane, silicone resin, polyvinyl alcohol, vinyl alcohol, polyglycolic acid, poly phosphatase, as well as between the polymers copolymers, collagen, gelatin, chitin.

Wherein said therapeutic agent comprises one or more of the following: antiproliferative agents, antibiotics, antimetabolites, hormone drugs, anticoagulant drugs, drugs suppressing the secretion and the like. Wherein said magnesium alloy may be a Mg-Al series alloy, a magnesium-manganese alloys, magnesium-zinc alloy series, the series magnesium alloy of zirconium, rare earth series magnesium alloy, magnesium-lithium alloy, magnesium-calcium alloy, or magnesium-silver alloy series or a combination of these kinds of systems made binary, ternary or multi-element alloy, magnesium content of any of the above magnesium alloy is greater than 50%.

Wherein said magnesium alloy is made into medical devices include, but are not limited to: vascular stents, bone sutures, bone screws, the bone connecting member, pushing the spine bone plate, suture anchors, hemostatic forceps, hemostatic screws, plates hemostasis, hemostasis folder and so on.

The present invention also provides a method for preparing controllably biodegradable magnesium metal coated stent, which is a medical stent body made of high-purity magnesium or magnesium alloy, the method comprising the steps of: said bracket body for corrosion protection, anti-corrosion treatment after the the anti-corrosion coating formed on the surface of the stent body; applying a coating on the surface of the preservative biodegradable polymer drug coating film; coating surface coated with the therapeutic agent in the pharmaceutical carrier.

In the former method, the stent body embalmed, by laser engraving or machining the bracket body is made.

Stent body should be clean, but also should be cleaned prior to the stent body surface corrosion treatment, including mechanical cleaning and chemical cleaning. Mechanical cleaning may be carried out according to the following steps: a stent body belt surface is polished, the surface for mechanically removing the oxide, adjusting the surface roughness; surface of the stent body using an ultrasonic wave cleaning, for removing the impurities of the body surface of the stent; chemical cleaning can be performed by the following steps: ethanol solvent cleaning of medical use; AR was washed with acetone after solvent cleaning of medical alcohol; deionized water solution of analytically pure acetone wash clean. Chemical cleaning may further comprise the steps of: stent body immersed into a sodium hydroxide solution, to remove grease and oxide; and then washed with deionized water, and dried in vacuo.

In this method, anticorrosion treatment can be applied to anodic oxidation or chemical oxidation methods. Chemical oxidation processing, a method can be implemented: immersing the stent body in chemical oxidation bath temperature of 343 ~ 353K, the oxidation time is 0.5 to 2.0 minutes, the bath contains: potassium dichromate 15 ~ 20g / L nitric acid 15 ~ 25g / L, sodium chloride 0.75 ~ 1.25 g / L. Anodic oxidation treatment, oxidation can preclude the use of alternating current, the specific method is mounted on the same two electrodes stent body, the stent is immersed in the bath, the temperature is 293 333K, oxidation time is 10 to 50 minutes, a current density of 0.1 ~ 10A / dm 2, the AC voltage employed is 50 ~ 90 V, the bath contains: potassium permanganate 15 ~ 20g / L, trisodium phosphate 15 ~ 55 gL, potassium fluoride 25 ~ 55g / L, potassium hydroxide 65 ~ 165g / L, aluminum hydroxide, 15 ~ 65 g / L; this process may preclude the use of dipping, spraying, thermal spraying, electrostatic coating, sol-gel, a coating method such as supercritical liquid, in the preservative surface coating is applied biodegradable polymer drug coating film. For example, the anti-corrosion treatment after the stent was immersed in a solution of a polymer degradable material, after an appropriate soaking, and dried in vacuo. Concentration of the biodegradable polymer material solution is typically about 1.0mg / mL, soaking time is usually 5~20 minutes. Of course, the stent at different solutions soaking time may be adjusted, for example, when using immersion 5~15 minutes a solution of polylactic acid, and polyglycolic acid solution, preclude the use or 20 minutes, mainly with degradable high polymer type and the desired film thickness was about. May preclude the removal of excess surface solution with a low speed centrifugal manner, for example, centrifuged at lOOOrpm 3 minutes. Vacuum drying temperature may be provided in the 30 ~ 40 ° C, 30 ~ 60min to drying.

In this method, a therapeutic drug may be employed a dip coating method or spray coating of drug coating on the surface. Rapamycin, for example, spray coating may be: methanol as solvent, at a concentration of l ~ 15 g / ml solution of rapamycin on the stent surface orienting body ultrasonic spray coating, uniform rotation bracket body, the bracket according to the drug content coating surface of the body claims 1 to 15 times; dip coating method may be: an organic solvent as tetrahydrofuran, to a concentration of 1 ~ 15 g / ml solution of rapamycin, the stent body was immersed in the above solution 5 10 minutes, four times repeated dipping.

In this method, coating a coating process degradable polymer coating or film coated drug therapeutic medicine, the selection of any one or a combination of the following: dipping, spraying, thermal spraying, electrostatic coating , sol-gel, supercritical liquid coating.

In this method, it may preclude the use of anti-corrosion treatment method for preserving according to any one of the following or more of: ion implantation, laser surface treatment, thermal diffusion, metal plating, vapor deposition, the organic coating. The present invention has positive beneficial effects include:

1, excellent mechanical properties and drug: through controlled degradation of pure magnesium and magnesium alloy stents coated surface-treated metal material remained provided excellent mechanical properties, improve the mechanical strength of the stent, the implant material magnesium during the service device can effectively maintain good mechanical properties; while the surface layer of the biodegradable polymer used, greatly improves the stent carrying the desired type and quantity of drugs, to improve the stability of the drug constant; such magnesium alloy coating with the coating composition of the degradable polymeric material, may be fixed by adjusting the thickness of the polymer layer, molecular weight and different drugs and doses, may carry a variety of therapeutic drugs, drug loading greater than 30%;

2, to reduce the rate of material degradation magnesium, elongate support life: due to the dense polymer material, regardless of its thickness, the polymer material is difficult to prevent water molecules reaching the surface of the magnesium alloy, magnesium alloy and therefore will begin simultaneously with the polymeric material degradation; preparation of surface corrosion of the coating alloy, a magnesium alloy retard corrosion and prolong the service life of the stent, which greatly reduces the rate of degradation of the magnesium alloy and controlling the drug release, the stent avoids degradation caused by using the function of reducing the problem;

3, the use of safety, to meet clinical needs: known, magnesium and magnesium alloy may be corroded gradually degraded under in vivo physiological conditions or absorption and metabolism of the body, its main degradation product is the desired human magnesium, a magnesium alloy material contained in the other alloying elements are within the scope of biomedical, thus preclude the preparation of pure magnesium and magnesium alloys with controlled degradation of medical implant devices is safe; Meanwhile, the biodegradable polymeric material in the living body, is gradually degraded by hydrolysis reaction, the product of C0 2 and H 2 0, degradation products are also safe to human body; improve existing biodegradable polymer stent local accumulation of acidic degradation products, affect the healing of conditions, to meet clinical needs. BRIEF DESCRIPTION

FIG 1 is a schematic structural controllable degradation metal coated stent of the present invention;

FIG 2 is a sectional view AA of FIG. 1 in an enlarged portion of FIG. I; Preparation method of the present invention. FIG. 3 is controlled degradation flowchart metal coated stents.

In FIG: 1, a stent; 101, the bracket body; 102, anti-corrosion coating; 103, drug coatings; 104, therapeutic drug;

FIG 4 is a comparison before and after the corrosion resistance of magnesium alloy stent coated with a biodegradable polymer film, the curve in FIG. 1 is linearly polarized after the stent surface a coating film of a biodegradable polymer profile, curve 2 is the magnesium alloy bare stent linear polarization curves. detailed description

The following examples serve to illustrate the present invention but are not intended to limit the scope of the present invention.

1, the present invention provides Controllable Degradation of magnesium metal coated stent, a stent materials should be selected which medical purity magnesium or magnesium alloy. Magnesium alloy is a magnesium content greater than 50% of the binary, ternary or multi-element content of the magnesium alloy, a magnesium alloy alloying elements should substantially satisfy the biomedical requirements, the amount of degradation allowed during degradation should not causing the tissue toxicity dose range. The magnesium alloy include Mg-Al alloy system different series alloy, magnesium-manganese alloys, magnesium-zinc alloy series, the series magnesium alloy of zirconium, rare earth series magnesium alloy, magnesium-lithium alloy, magnesium-calcium alloy, or magnesium-silver alloy series one or a combination of these systems made binary, ternary or multi-element alloy, but is not limited thereto.

The stent 1 is formed by laser engraving or machined, in addition to a vascular stent can be made, but can also be made of bone sutures, bone screws, the bone connecting member, pushing the spine bone plate, suture anchors, hemostatic forceps , bleeding screws, plates hemostasis, the hemostatic clip, and tissue adhesives, sealants, artificial bones and other medical equipment.

2, the stent comprises a stent body 101, anti-corrosion coating 102, coating 103 drug, therapeutic drug 104 and the like; surface of the stent body 101 is provided with a anti-corrosion coating 102, coating 102 surface corrosion It is provided with a biodegradable polymer drug coating film 103, 104 carrying the therapeutic drug on drug coating 103.

The anti-corrosion coating 102 may be magnesium oxide, but is not limited thereto.

The biodegradable polymer drug coating film 103 comprises one or more substances: polylactic acid (PLA), poly-L-lactic acid (PLLA), polyglycolide, or polyglycolic acid (PGA), polycyanoacrylates (PACA), polycaprolactone (PCL), polyanhydrides: include aliphatic polyanhydrides, aromatic polyanhydrides, heterocyclic polyanhydrides, polyglycolic acid anhydride, and the like may be crosslinked polyanhydrides, polylactic acid copolymer (PLGA), polyhydroxybutyrate valerate (PHBV), poly acetylglutamate (PAGA), polyorthoesters (POE), polyethyleneoxide / polybutylene copolymer (PEO / PBTP), poly polyorthoesters, polycaprolactone, polyglycolic acid, polyethylene oxide / polybutylene terephthalate copolymer, or methacrylate ester, acrylate or methacrylate, polyurethane, silicone, poly vinyl alcohol, vinyl alcohol, polyglycolic acid, polyphosphate enzymes, and a copolymer between the polymer, in addition to collagen, gelatin, chitin and other natural biodegradable polymer materials, but is not limited thereto .

The therapeutic drug 104 comprises one or more of: antiproliferative agents, antibiotics, antimetabolites, hormone drugs, anticoagulant drugs, drugs suppressing the secretion of, but is not limited thereto.

The method of the present invention is prepared as shown in the controlled degradation of magnesium metal coated stent flowchart of FIG. 3, the method mainly includes: ① From made by laser engraving or machining the bracket body; ② surface cleaning; ③ surface corrosion treatment; ④ degradable polymer coated drug coating film; ⑤ therapeutic drug coating process step, wherein:

② surface cleaning: comprises mechanical cleaning and chemical cleaning;

Specific mechanical cleaning and chemical cleaning methods are:

. A surface of the stent body 101 is by belt sanding, mechanical removal of the surface oxide, adjusting the surface roughness;

. B on the stent surface by ultrasonic cleaning to remove surface impurities stent body 101, the ultrasonic frequency of 28 ~ 100khz, the washing time is 5-15 minutes; cleaning step comprises a) a concentration of 75% ethanol solvent cleaning of medical; 2 ) with a concentration of 99.5% solution of analytically pure acetone wash; 3) was washed with deionized water;

c The stent body 101 is placed in a concentration of 15 ~ 60 g / L, a sodium hydroxide solution to a temperature of 343 ~ 373K immersed 5-10 minutes to remove oils and oxide; and then washed with deionized water; and after cleaning the stent body 101 is placed in a vacuum drier, temperature is set at 30 ~ 40 ° C, dried for 30 to 60 minutes after removal.

③ surface corrosion treatment: treatment comprises chemical oxidation, anodic oxidation treatment, wherein the selection of either;

Specific methods are:

. A chemical oxidation treatment bath composition is: potassium dichromate 15 ~ 20g / L, nitric acid 15 ~ 25g / L, sodium chloride 0.75 ~ 1.25 g / L; the stent body 101 is immersed in the above solution, the temperature selected 343 ~ 353K, the oxidation time is 0.5 to 2.0 minutes, to generate a surface oxide film; B preclude the use of alternating current anodized oxide, magnesium alloy stent mounting same on both the electrodes 1, with the anodic oxidation treatment bath composition is: potassium permanganate 15 ~ 20g / L, trisodium phosphate, 15 ~ 55 g / L, potassium fluoride 25 ~ 55 g / L, potassium hydroxide, 65 ~ 165 g / L, aluminum hydroxide 15 65 g / L; temperature select 293 -333K, oxidation time is 10 to 50 minutes, a current density of 0.1 ~ 10A / dm 2, the AC voltage employed is 50 ~ 90V, to generate a surface oxide film;

In addition to the chemical oxidation treatment, anodizing treatment, it may preclude the use of ion implantation, laser surface treatment, thermal diffusion, any of a variety of anti-corrosion treatment of metal plating, vapor deposition, organic coatings or a combination thereof, to generate a surface corrosion film, these techniques are embalmed prior art, not described in detail here.

④ Preparation of biodegradable polymer drug coating film;

Selection of any of the following methods for the preparation of:

a. After the stent is placed in a preservative treated at a concentration of 1.0 mg / mL of the biodegradable polymer material polylactic acid (PLA) was immersed 5 to 15 minutes, in Feige TGL- 16G centrifuge at 1000 rpm / minute speed centrifuged for 3 minutes and then drying the stent 1 into a vacuum oven temperature was set at 30 ~ 40 ° C, 30 to 60 minutes after drying it out;

b. Insert the holder into a preservative treatment concentration 1.0mg / mL of polyglycolic acid (PGA) was soaked for 20 minutes in a centrifuge Feige TGL- 16G, at a speed of 1000 revolutions / min for 3 minutes, centrifuged , the stent 1 is then placed in an oven and dried in vacuo, temperature was set at 30 ~ 40 ° C, dried 30-- removed after 60 min;

⑤ coating therapeutic drug;

Biodegradable Polymer 1 polymer film surface of the stent after the drug coating 103 is fixed, any one of a method selected therapeutic drug coating:

a. methanol as solvent, was added at a concentration of 1 ~ 15μ ^ πι1 rapamycin or paclitaxel solution to the surface of the stent 1 is ultrasonic spraying orientation, uniform rotation bracket 1 according to claim 1 drug content coating surface of the stent 1 to 15 times ;

. B in tetrahydrofuran as the organic solvent, added at a concentration of l ~ 15 g / ml rapamycin, the stent 1 described above was immersed in the solution for 5 - 10 mins, dipping was repeated four times.

The method of coating a surface coating process ④ other degradable polymer film drug coating; ⑤ therapeutic drug coating process step in addition to dip coating, spray coating, but also preclude thermal spraying, electrostatic coating , sol-gel, supercritical liquid coating process according to any of one kind or combinations thereof.

Preferred embodiments given below.

Example 1

After selection purity magnesium polished, carved into a vascular stent with a laser;

① Surface cleaning: 1) with a concentration of 75% of medical ethanol solvent, using an ultrasonic wave surface of the stent body 101 is cleaned, cleaning time 10 minutes; 2) a concentration of 99.5% solution of analytically pure acetone wash; 3) to washed with deionized water, after cleaning the stent body 101 is placed in a vacuum drier;

② surface corrosion treatment: immersing the stent body 101 to potassium dichromate 15g / L, nitric acid 15g / L, NaCl 1.0 g / L solution, and oxidation at 80 ° C 1 minute to generate a surface oxide film;

③ Preparation of biodegradable polymer drug coating film: The preservative treated stent 1 is placed at a concentration of 1.0 mg / mL of polylactic acid (PLA) was immersed for 15 minutes in Dove TGL - 16G on the centrifuge, at 1000 r / min speed for 3 minutes, and then the stent is placed in a vacuum oven drying temperature setting of 30 ° C, taken out and dried for 60 minutes;

④ therapeutic drug coating: methanol as solvent, was added at a concentration of rapamycin 10 μβ / ιη1, the sprayed surface of the stent 1, coating was repeated 10 times.

Example 2

Selection AZ31B magnesium alloy after polishing, using a laser engraving into a blood vessel stent;

① Surface cleaning: 1) with a concentration of 75% of medical ethanol solvent, using an ultrasonic wave surface of the stent body 101 is cleaned, cleaning time 10 minutes; 2) a concentration of 99.5% solution of analytically pure acetone wash; 3) to washed with deionized water, after cleaning the stent body 101 is placed in a vacuum drier;

② surface corrosion treatment: the stent body 101 is anodized, mounting same on the stent body 101 at the two electrodes, with the anodic oxidation treatment bath composition: potassium permanganate 15g / L, sodium phosphate tribasic 15g / L, potassium fluoride 25 g / L, potassium hydroxide 65 g / L, aluminum hydroxide 15 g / L, at a temperature of 30 ° C, 15 minutes oxide, current density of 3A / dm 2, voltage of 60V AC, i.e., the surface an oxide film may be generated;

③ Preparation of biodegradable polymer drug coated membrane: corrosion treatment after the stent is placed in a 1.0mg / mL polyglycolic acid (PGA) was immersed for 20 minutes in Feige TGL - 16G on the centrifuge, 1000 rpm / min for 3 minutes, centrifuged, dried and then the stent 1 into a vacuum oven temperature was set at 40 ° C, taken out and dried for 40 minutes;

④ therapeutic drug coating: tetrahydrofuran as the organic solvent, added at a concentration of lO g / ml rapamycin, the stent body 1 is immersed in the above solution for 5 minutes, dipping was repeated four times.

Experimental Example 1

The present embodiment used to investigate the degradation of the preservative treatment using the stent.

Materials and Methods

Example 2 Preparation of the stent as subjects, comparing the stent may be coated with the corrosion resistance before and after the change of degradable polymer films. M2273 linear scan function of the potentiostat, the stent is placed in pH7.4 phosphate buffer solution, test and linear polarization curve bare stent coated stent a polymer film at room temperature, the results shown in FIG. Curve 2 in FIG. 4 is a magnesium alloy stent pH7.4 PBS linear polarization curve of curve 1 is a rear bracket applied to the surface of the biodegradable polymer film linear polarization curve. It is seen from Figure 4:

1, the magnesium alloy stent coated with a biodegradable polymer positively shift the membrane potential, improved corrosion resistance; at the same time, significantly reduced the corrosion current.

2, linear polarization resistance curve 2 is 656.3 ohms, linear polarization resistance curve 1 is 9574.6 ohms, which represents the reciprocal polarization resistance of the corrosion rate of the metal material. After the coated surface of the stent so that the biodegradable polymer film can significantly improve the corrosion resistance, service life was extended magnesium alloy stents.

Although the foregoing has been a general description and specific embodiments of the present invention is described in detail, but the present invention is based on, you can make some modifications or improvements, which will be apparent to those skilled in the art. Accordingly, such modifications without departing from the spirit of the present invention is based on the improvement made or, belong to the scope of the invention as claimed. Industrial Applicability

Pure magnesium or magnesium alloy of the present invention after the stent surface corrosion after treatment, delay magnesium alloy corrosion, extend the service life of the stent, which greatly reduces the rate of degradation of the magnesium alloy and controlling the drug release, due to avoiding the use of function caused by the degradation of the stent reduce the problem by modifying degradable polymer materials, the degradation of controllability of good processing stability, easy processing, its strength, stiffness and rigidity to meet the medical requirements. Preparation of pure magnesium and magnesium alloy implantable medical device controlled degradation is safe, practical.

Claims

Claims
A controlled degradation of magnesium metal coated stent, which is a medical stent body made of high-purity magnesium or magnesium alloy, wherein the surface of the body of the stent is coated with anti-corrosion coating, anti-corrosion coating may be applied on the surface degradation of polymer film coated drug, the drug coating carrying therapeutic drugs.
The controlled degradation of the magnesium metal coated stent according to claim 1, wherein said anti-corrosion coating is magnesium oxide.
The controlled degradation of the magnesium metal coated stent according to claim 1, wherein the degradable polymer film drug coating comprises one or more substances: polylactic acid, poly-L-lactic acid , polyglycolide, polyglycolic acid, poly cyanoacrylates, polycaprolactone, polyanhydrides, polylactic acid copolymer, poly-hydroxy valerate, poly-acetyl acid, polyorthoesters, polyethylene oxide ethylene, polybutene copolymers, polyorthoesters, polycaprolactone, polyglycolic acid, polyethylene oxide, polybutylene terephthalate copolymer, or methacrylate esters, methacrylic acid esters or salts, between polyurethane, silicone resin, polyvinyl alcohol, vinyl alcohol, polyglycolic acid, poly phosphatase, the above-described polymers and copolymers, collagen, gelatin, chitin.
The controlled degradation of the magnesium metal coated stent according to claim 1, wherein said therapeutic agent comprises one or more of the following: antiproliferative agents, antibiotics, antimetabolites, hormonal drugs, anticoagulant drugs, inhibit the secretion of drugs.
The controlled degradation of one of the magnesium metal coated stent according to any of claims 1 to 4, wherein the Mg-Al series alloy is a magnesium alloy, magnesium-manganese alloys, magnesium-zinc alloy series, magnesium zirconium alloys, rare earth series magnesium alloy, magnesium-lithium alloy, magnesium alloy series calcium or magnesium silver alloy or a series combination of these systems made binary, ternary or multi-element alloy, any of the above species magnesium alloy magnesium content greater than 50%.
Controlled degradation according to claim magnesium metal coated stent according to any of 1 ~ 4, wherein said magnesium alloy is made into a stent comprising: a vascular stent, bone sutures, bone screws, bone connecting member, pushing the spine bone plate, suture anchors, hemostatic forceps, hemostatic screws, plates hemostasis, the hemostatic clip, and tissue adhesives, sealants, artificial bone with a medical stent.
7. The method according to any one of the bracket for preparing claims 1~6, comprising the steps of:
The stent body for corrosion protection, anti-corrosion coating is formed to the surface; the surface coating anticorrosive coatings of biodegradable polymer drug coating film; in the drug coating layer of the coated surface treatment drug.
8. A method as claimed in claim 7, wherein said stent body by laser engraving or machining system.
9. The method according to claim 7, characterized in that, prior to the step of anticorrosion treatment further comprises mechanical cleaning and chemical cleaning of the surface of the stent body.
10. A method as claimed in claim 7, wherein said anti-corrosion treatment is a chemical oxidation treatment or anodizing treatment.
11. The method according to claim 10, wherein said chemical oxidation processing in the bath with a chemical oxidation process comprising: potassium dichromate 15 ~ 20g / L, nitric acid 15 ~ 25 g / L, chloride sodium 0.75 1.25 g / L; the stent body is immersed in the chemical oxidation treatment bath, a temperature of 343 - 353K, the oxidation time is 0.5 - 2.0 minutes.
12. The method according to claim 10, wherein said alternating current anodizing treatment using oxidation, bracket body mounting same on both electrodes, anodizing treatment bath containing: Potassium permanganate 15 ~ 20g / L, sodium phosphate tribasic 15 ~ 55 g / L, potassium fluoride 25 ~ 55 g / L, potassium hydroxide, 65 ~ 165 g / L, aluminum hydroxide, 15 ~ 65 g / L; temperature of 293 ~ 333K, oxidation time 10 50 minutes, a current density of 0.1 ~ 10A / dm 2, preclude the use of the AC voltage is 50 ~ 90V.
13. The method as claimed in claim 9, characterized in that said mechanical cleaning steps of: a stent body belt surface is polished for removing the oxide surface, adjusting the surface roughness; surface of the stent body using an ultrasonic wave cleaning, for removing the impurities of the surface of the stent body.
14. The method as claimed in claim 9, wherein said chemical cleaning step: ethanol solvent cleaning of medical use; AR was washed with acetone; finally washed with deionized water.
15. The method as recited in claim 14, characterized in that, after the chemical cleaning of the surface of said bracket body further comprises the steps of:
The stent body immersed into the alkaline solution, for removing fat and oxide; and then washed with deionized water, and dried in vacuo.
16. The method according to claim 7, wherein said surface coating anticorrosive coatings of biodegradable polymer film coating, the choice of any one of the following: discharge said stent body having a concentration of 1.0 mg / mL of the biodegradable polymer material soaked in a solution of polylactic acid 5 15 minutes at 1000 r / min speed for 3 minutes, drying the stent body into a vacuum oven temperature was set at ~ 30 40 ° C, 30 ~ 60min removed after drying;
Dipping the stent into the body at a concentration of 1.0mg / mL of polyglycolic acid solution for 20 minutes, at a speed of 1000 revolutions / minute and centrifuged for 3 minutes into the stent body was dried in a vacuum oven, set at a temperature 30 ~ 40 ° C, 30 ~ 60min removed after drying.
17. The method according to claim 7, characterized in that the polymer film coating method of coating the surface of said therapeutic drug in biodegradable, use of any one of the following: methanol as solvent, with concentration of l ~ 15 g / ml solution of rapamycin on the stent surface orienting body ultrasonic spray coating, uniform rotation of the stent body, the drug content of the stent body according to claim surface coating 1 to 15 times;
In tetrahydrofuran as the organic solvent, to a concentration of l ~ 15 g / ml solution of rapamycin, the stent body was immersed in the solution for 5-10 minutes, dipping was repeated four times.
18. The method according to claim 7, characterized in that the coating process the coated biodegradable polymer coating or film coated drug therapeutic medicine, the selection of any one or a combination of the following: dipping, spraying, thermal spraying, electrostatic coating, sol-gel, supercritical liquid
19. The method according to claim 7, wherein the anti-corrosion treatment method for preserving the following preclude the use of any one or more of: ion implantation, laser surface treatment, thermal diffusion, metal plating, vapor deposition, an organic coating Floor.
PCT/CN2008/001313 2008-01-03 2008-07-14 A controlled degradation magnesium metal coating scaffold and its preparation method WO2009082876A1 (en)

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