Absorbable implantable device

Abstract

The present application relates to an absorbable implantable device, which comprises an absorbable metal substrate and a degradable polyester layer covering at least part of the surface of the absorbable metal substrate, the contact angle of the degradable polyester layer being greater than or equal to 150°. The degradable polyester layer has superhydrophobicity, which can form a hydrophobic barrier in the body fluid to isolate the absorbable metal substrate from the body fluid, thereby protecting the absorbable metal substrate from slow corrosion or even no corrosion in the early stage of implantation; and due to the superhydrophobicity of the degradable polyester layer, the degradation of the degradable polyester layer in the aqueous body fluid environment can be delayed, which is beneficial to slow down or avoid the formation of a local acidic environment in the early stage of implantation. Therefore, sufficient mechanical support can be provided during the repair period at the lesion site after implantation; and after the repair at the lesion site is completed, a local slightly acidic environment is formed due to the degradation of the degradable polyester itself, so that the absorbable metal substrate corrodes rapidly.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medical devices, in particular to an absorbable implantable device. BACKGROUND

[0002] After the absorbable implantable device is implanted into the human body, it supports or connects the lesion site until the lesion site recovers or returns to normal morphology and function, and then the absorbable implantable device gradually corrodes or degrades and is completely absorbed by the body. According to the different application sites, it is generally considered that the recovery period of the lesion site is 1 to 6 months. That is, the absorbable implantable device needs to maintain structural integrity and have sufficient mechanical properties to support or connect the lesion site within 1 to 6 months after implantation. After 1 to 6 months after implantation, the lesion site recovers, and the absorbable implantable device should corrode or degrade as soon as possible in a short period of time.

[0003] The absorbable implantable device made of absorbable metal material has a wide clinical application prospect because of its good mechanical properties and biocompatibility, but it must solve the design requirement problem described above.

[0004] Among them, in order to solve the problem of accelerating the corrosion of the absorbable implantable device after the repair of the lesion site is completed, the prior art sets a degradable polyester layer on the metal substrate in order to form a local acidic environment through the degradation of the degradable polyester to accelerate the corrosion of the metal substrate. However, if the early degradation rate of the degradable polyester layer cannot be effectively controlled, it will accelerate the early corrosion of the absorbable metal substrate, thereby making it difficult to maintain structural integrity or provide sufficient mechanical properties to support or connect the lesion site within 1 to 6 months after implantation. SUMMARY

[0005] Therefore, it is necessary to provide an absorbable implantable device that can provide sufficient mechanical support during the repair period of the lesion site after implantation, and can quickly corrode after the repair of the lesion site is completed.

[0006] An absorbable implantable device includes an absorbable metal substrate, and further includes a degradable polyester layer covering at least part of the surface of the absorbable metal substrate, and the contact angle of the degradable polyester layer is greater than or equal to 150°.

[0007] In one embodiment, the contact angle of the degradable polyester layer is greater than or equal to 160°.

[0008] In one embodiment, the weight average molecular weight of the degradable polyester in the degradable polyester layer is greater than or equal to 15,000.

[0009] In one embodiment, the thickness of the degradable polyester layer is 1 to 100 microns.

[0010] In one embodiment, the degradable polyester in the degradable polyester layer is at least one of polyglycolic acid, polylactic acid, polybutylene succinate, poly-β-hydroxybutyric acid, polyethylene adipate, and polylactic acid-glycolic acid copolymer; or the degradable polyester in the degradable polyester layer is a copolymer of at least two monomers selected from the group consisting of monomers of polyglycolic acid, polylactic acid, polybutylene succinate, poly-β-hydroxybutyric acid, and polyethylene adipate.

[0011] In one embodiment, the absorbable metal substrate is pure iron, pure zinc, pure magnesium, iron-based alloy, magnesium-based alloy, or zinc-based alloy.

[0012] A method for preparing an absorbable implantable device, comprising the following steps:

[0013] providing an absorbable metal substrate;

[0014] dissolving a degradable polyester and a polymer in a first solvent to obtain a mixed polymer coating solution;

[0015] coating the mixed polymer coating solution on the surface of the absorbable metal substrate and drying to form a mixed polymer coating layer on the surface of the absorbable metal substrate; and

[0016] immersing the absorbable metal substrate with the mixed polymer coating layer on the surface in a second solvent to dissolve the polymer and not dissolve the degradable polyester, taking out and drying to form a degradable polyester layer on the surface of the absorbable metal substrate, thereby obtaining the absorbable implantable device, wherein the contact angle of the degradable polyester layer is greater than or equal to 150°.

[0017] In one embodiment, the mass ratio of the degradable polyester to the polymer in the coating solution is 1:1 to 9:1.

[0018] In one embodiment, the first solvent is at least one selected from the group consisting of chloroform, dichloromethane, chlorobenzene, dimethylacetamide, tetrahydrofuran, and hexafluoroisopropanol, and the second solvent is at least one selected from the group consisting of ethyl acetate, dimethylformamide, and dimethyl sulfoxide.

[0019] In one embodiment, the polymer is at least one selected from the group consisting of degradable polymers and non-degradable polymers, or at least one selected from the group consisting of copolymers of at least one monomer forming the degradable polymer and at least one monomer forming the non-degradable polymer.

[0020] In one embodiment, the degradable polymer is selected from at least one of polylactic acid, polypropylene carbonate, polycaprolactone, polyglycolic acid and polylactic-co-glycolic acid, and the non-degradable polymer is selected from at least one of polystyrene, polymethyl methacrylate and polyethylene terephthalate.

[0021] In one embodiment, the step of immersing the absorbable metal matrix with a polymer coating on the surface in a second solvent to dissolve the polymer and not dissolve the degradable polyester has a temperature of the second solvent of 20-50°C.

[0022] The contact angle of the degradable polyester layer of the absorbable implantable device is greater than or equal to 150°, so that the degradable polyester layer has superhydrophobicity, can form a hydrophobic barrier in a body fluid to isolate the absorbable metal matrix from the body fluid, thereby protecting the absorbable metal matrix from slow corrosion or even no corrosion in the early stage of implantation; and due to the superhydrophobicity of the degradable polyester layer, the degradation of the degradable polyester layer in an aqueous body fluid environment can be delayed, which is beneficial to delay or avoid the formation of a local micro-acidic environment in the early stage of implantation. Therefore, sufficient mechanical support can be provided during the repair period at the lesion site after implantation; and after the repair at the lesion site is completed, a local micro-acidic environment is formed due to the degradation of the degradable polyester itself, so that the absorbable metal matrix corrodes rapidly. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 Flow chart of the method for preparing the absorbable implantable device of one embodiment. DETAILED DESCRIPTION

[0024] In order to make the above objectives, characteristics and advantages of the present application more apparent and comprehensible, the specific embodiments of the present application will be described in detail below with reference to the accompanying drawings. In the following description, a large number of specific details are set forth in order to fully understand the present application. However, the present application can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without departing from the scope of the present application, so the present application is not limited by the specific embodiments disclosed below.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0026] The absorbable implantable device of one embodiment includes an absorbable metal matrix and a degradable polyester layer arranged on the surface of the absorbable metal matrix.

[0027] The absorbable metal substrate can be a lumen substrate or a substrate of other structures. It can be understood that the specific shape of the absorbable metal substrate can be adjusted according to the actual application site. The material of the absorbable metal substrate can be any metal material with bioabsorbable properties and certain mechanical support properties. For example, the material of the absorbable metal substrate can be pure iron, pure zinc, pure magnesium, iron-based alloy, magnesium-based alloy, or zinc-based alloy, etc.

[0028] To ensure sufficient mechanical support and corrosion as soon as possible after the repair at the lesion site is completed, the thickness of the absorbable metal substrate is 30-300 microns.

[0029] The degradable polyester layer is arranged on the outer surface, the inner surface, or both the outer surface and the inner surface of the absorbable metal substrate. The degradable polyester layer can partially cover the outer surface or the inner surface of the absorbable metal substrate, or can completely cover the outer surface, the inner surface, or both the outer surface and the inner surface of the absorbable metal substrate.

[0030] The material of the degradable polyester layer includes degradable polyester. The contact angle of the degradable polyester layer is greater than or equal to 150°, so that the degradable polyester layer has super-hydrophobic properties, can better isolate the absorbable implantable device from the body fluid, so that in the early stage after implantation, the body fluid in contact with the absorbable metal substrate and the body fluid infiltrating the degradable polyester layer can be reduced, thereby better protecting the absorbable metal substrate and slowing down or avoiding corrosion of the absorbable metal substrate in the early stage after implantation.

[0031] The definition of the contact angle is that the tangent of the gas-liquid interface at the three-phase intersection of solid, liquid, and gas in the liquid side and the solid-liquid intersection line form an angle, which is one of the important characteristics of the wetting properties of the solid surface. The contact angle mentioned in this paper refers to the static contact angle unless otherwise specified. The super-hydrophobic coating refers to a coating with a static contact angle greater than 150°.

[0032] The degradable polyester with super-hydrophobic properties degrades relatively slowly, and the acidic environment around the absorbable implantable device is relatively weak, so that the corrosion rate of the absorbable implantable device is moderate within 6 months after implantation in the body, and the absorbable implantable device can maintain effective support for 6 months under the protection of the super-hydrophobic coating, which can meet the clinical requirements for the mechanical properties of the absorbable implantable device in the early stage after implantation.

[0033] The contact angle of the degradable polyester layer of the absorbable implantable device is greater than or equal to 150°, so that the degradable polyester layer has superhydrophobicity, can form a hydrophobic barrier in a body fluid to isolate the absorbable metal matrix from the body fluid, thereby protecting the absorbable metal matrix from slow corrosion or even no corrosion in the early stage of implantation; and due to the superhydrophobicity of the degradable polyester layer, the degradation of the degradable polyester layer in the aqueous body fluid environment can be delayed, which is beneficial to delay or avoid the formation of a local acidic environment in the early stage of implantation to accelerate the corrosion of the absorbable metal matrix. During the repair period at the lesion site after implantation, sufficient mechanical support can be provided. After the repair at the lesion site is completed, the local slightly acidic environment generated by the degradation of the degradable polyester makes the absorbable metal matrix corrode quickly.

[0034] Preferably, the contact angle of the degradable polyester layer is greater than or equal to 160°, so that the superhydrophobicity of the degradable polyester layer is stronger, which can better protect the absorbable implantable device and avoid insufficient support due to corrosion during the repair period at the lesion site.

[0035] Preferably, the weight average molecular weight of the degradable polyester in the degradable polyester layer is greater than or equal to 15,000, so as to ensure that the degradation of the degradable polyester layer itself can be maintained for a certain period of time, so that the absorbable implantable device can maintain effective support for 1-6 months, and there is still a residual degradable polyester layer on the absorbable implantable device within 6 months after implantation, that is, the mass retention rate of the degradable polyester layer is appropriate, and the residual degradable polyester layer continues to degrade to maintain a local acidic environment to accelerate the corrosion of the absorbable metal matrix in the later stage.

[0036] Further preferably, the weight average molecular weight of the degradable polyester in the degradable polyester layer is greater than or equal to 20,000.

[0037] The degradable polyester in the degradable polyester layer is selected from at least one of polyglycolic acid (PGA), polylactic acid (PLA), polybutylene succinate (PBS), poly-β-hydroxybutyric acid (PHB), polyethylene glycol adipate (PEGA), and polylactic acid-glycolic acid copolymer (PLGA). Alternatively, the degradable polyester in the degradable polyester layer is selected from at least two monomers copolymerized from monomers constituting polyglycolic acid, polylactic acid, polybutylene succinate, poly-β-hydroxybutyric acid, and polyethylene glycol adipate.

[0038] The above-mentioned degradable polyester has good biocompatibility with the human body, and a moderate degradation rate in the body, which can meet the requirements of slow or no corrosion of the absorbable implantable device in the early stage, and faster corrosion in the later stage.

[0039] It can be understood that the above-mentioned degradable polyester can be crystalline or amorphous.

[0040] It can be understood that when the degradable polyester layer comprises at least two degradable polyesters, the above-mentioned weight average molecular weight refers to the average weight average molecular weight.

[0041] Preferably, the coverage of the degradable polyester layer on the surface of the absorbable metal substrate is greater than or equal to 10%, and the percentage of the mass of the degradable polyester layer to the mass of the absorbable metal substrate is greater than or equal to 5%, on the one hand, the coverage area of the hydrophobic barrier formed by the degradable polyester layer is large enough to provide sufficient hydrophobic protection to protect the absorbable metal substrate in the early stage and slow down or avoid the corrosion of the absorbable metal substrate; on the other hand, after the repair of the lesion site is completed, the corrosion of the absorbable metal substrate can be accelerated.

[0042] Preferably, the thickness of the degradable polyester layer is 1-100 microns, so that the mass retention rate of the degradable polyester layer is greater than or equal to 30% when the absorbable implantable device is implanted for 1-6 months, so as to ensure that there is still sufficient degradable polyester after 1-6 months of implantation, and the degradation of the degradable polyester can maintain a certain acidic environment for the tissue environment around the absorbable implantable device, which can accelerate the corrosion of the absorbable metal substrate, thereby reducing the possibility of adverse reactions caused by long-term retention of the absorbable metal substrate in the human body.

[0043] Further preferably, considering the corrosion rate of the absorbable metal substrate and the influence of the contact angle of the degradable polyester layer greater than or equal to 150° on the degradation rate of the degradable polyester layer, the thickness of the absorbable metal substrate is preferably 50-250 microns, and the thickness of the degradable polyester layer is preferably 5-80 microns, so as to ensure that the absorbable metal substrate has sufficient radial support performance, and the corrosion period of the absorbable metal substrate and the degradation period of the degradable polyester layer are matched, so as to obtain the effect that the absorbable metal substrate does not corrode or corrodes slowly in the early stage of implantation, and the corrosion of the absorbable metal substrate is accelerated after the repair of the lesion site is completed.

[0044] The above-mentioned absorbable implantable device at least partially covers the surface of the absorbable metal substrate by using the super-hydrophobic degradable polyester layer to protect the absorbable metal substrate in the early stage of implantation, and to accelerate the corrosion of the absorbable metal substrate in the later stage of implantation.

[0045] The above-mentioned absorbable implantable device can be a cardiovascular stent, a cerebrovascular stent, a peripheral vascular stent, a biliary stent, an esophageal stent, an airway stent, an occluder, an orthopedic implant, an andrology implant or a gynecology implant.

[0046] Please refer to Figure 1 A preparation method of an absorbable implantable device, comprising the following steps:

[0047] S110: providing an absorbable metal substrate.

[0048] The shape and material of the absorbable metal substrate are the same as described above, and will not be described again here.

[0049] S120: dissolving the degradable polyester and the polymer in a first solvent to obtain a mixed polymer coating solution.

[0050] The polymer is selected from at least one of a degradable polymer and a non-degradable polymer, or at least one of a copolymer formed from at least one monomer forming the degradable polymer and at least one monomer forming the non-degradable polymer.

[0051] Preferably, the degradable polymer is selected from at least one of poly-DL-lactic acid, polypropylene carbonate, polycaprolactone, polyglycolic acid and polylactic acid-glycolic acid copolymer, and the non-degradable polymer is selected from at least one of polystyrene, polymethyl methacrylate and polyethylene terephthalate.

[0052] It should be noted that the degradable polyester and the polymer can be the same polymer, as long as the crystallinity of the same polymer is different and the solubility in the same solvent is different. For example, two different crystallinities of PGA can be used as the degradable polyester and the polymer, respectively.

[0053] The first solvent is selected from at least one of chloroform, dichloromethane, chlorobenzene, dimethylacetamide, tetrahydrofuran and hexafluoroisopropanol. The first solvent is a good solvent for the degradable polyester and the polymer. That is, the solubility of the degradable polyester and the polymer in the first solvent is good, so that the film-forming property of the degradable polyester and the polymer is good, and a coating layer can be formed on the surface of the absorbable metal substrate.

[0054] It can be understood that, according to the selected degradable polyester and polymer, a suitable solvent can be selected in the above-mentioned first solvent, so that the first solvent has a suitable solubility for the degradable polyester and the polymer, so as to form a polymer coating layer meeting the requirements on the absorbable metal substrate.

[0055] Preferably, the first solvent is a mixed solvent of at least two of the above-mentioned solvents.

[0056] The mass ratio of the degradable polyester to the polymer is 1:1 to 9:1, and preferably 3:2 to 4:1.

[0057] In the mixed polymer coating solution, the concentration of the degradable polyester is preferably 1 to 9 mg / mL.

[0058] S130: coating the mixed polymer coating solution on the surface of the absorbable metal substrate and drying to form a mixed polymer coating layer on the surface of the absorbable metal substrate.

[0059] The coating method can be ultrasonic atomization spraying, spin coating, dip coating and the like.

[0060] The present embodiment preferably adopts the ultrasonic atomization spraying method. In the spraying process, the pump flow rate of the ultrasonic atomization spraying device is preferably 0.04-0.08 mL / min, the ultrasonic intensity is preferably 50%-70%, the rotation speed is preferably 200-250 r / min, and the advancing speed is preferably 0.3-0.6 m / s.

[0061] The drying method is natural drying or vacuum drying at room temperature. After the mixed polymer coating solution is dried, a mixed polymer coating layer is formed on the surface of the absorbable metal substrate. The material of the mixed polymer coating layer includes the degradable polyester and the polymer.

[0062] S140: The absorbable metal substrate with the mixed polymer coating layer on the surface is immersed in a second solvent to dissolve the polymer and not dissolve the degradable polyester, and after being taken out and dried, a degradable polyester layer is formed on the surface of the absorbable metal substrate to obtain an absorbable implantable device, wherein the contact angle of the degradable polyester layer is greater than or equal to 150°.

[0063] The second solvent is selected from at least one of ethyl acetate, dimethylformamide and dimethyl sulfoxide. The second solvent is a good solvent for the above-mentioned polymer, and the second solvent is a poor solvent for the above-mentioned degradable polyester. That is, there is a difference in the solubility of the polymer and the degradable polyester in the second solvent. When the absorbable metal substrate with the polymer coating layer on the surface is immersed in the second solvent, the polymer is dissolved and the degradable polyester is not dissolved.

[0064] It should be noted that the dissolution of the polymer and the non-dissolution of the degradable polyester do not necessarily require that the polymer is completely dissolved and the degradable polyester is completely not dissolved, but rather that, within the immersion time, the solubility of the polymer in the second solvent is much greater than the solubility of the degradable polyester in the second solvent, so that after immersion, most of the degradable polyester in the polymer coating layer is retained, and due to the dissolution of the polymer, the surface roughness of the polymer coating layer, i.e. the degradable polyester layer, is improved, thereby improving the hydrophobicity of the degradable polyester layer.

[0065] It should also be noted that the second solvent should be reasonably selected from the above-mentioned various second solvents according to the selected degradable polyester and polymer, so that there is a large difference in the solubility of the degradable polyester and the polymer in the second solvent.

[0066] Preferably, the second solvent is a mixed solvent of at least two of the above-mentioned solvents.

[0067] When the absorbable metal substrate with the mixed polymer coating layer on the surface is immersed in the second solvent, the temperature of the second solvent is 20-50°C. The immersion time is 10-15 min.

[0068] The drying method is natural drying or vacuum drying at room temperature.

[0069] The above-mentioned method for preparing an absorbable implantable device first forms a mixed polymer coating containing biodegradable polyester and polymer on the surface of an absorbable metal substrate. Then, the mixed polymer coating is immersed in a suitable second solvent to dissolve the polymer while leaving the biodegradable polyester undissolved. This results in the coating containing only biodegradable polyester or mainly containing biodegradable polyester, and a rough surface is formed in the coating. As a result, a superhydrophobic biodegradable polyester layer with a contact angle greater than or equal to 150° is formed on the surface of the absorbable metal substrate.

[0070] The aforementioned method for preparing absorbable implantable devices, by adding a second solvent for redissolution, can remove some small molecules and residual monomers from the biodegradable polyester, resulting in more uniform corrosion of the absorbable implantable device in the early stages of implantation. This helps avoid uneven corrosion of the absorbable metal matrix. Simultaneously, during the early corrosion process of the absorbable implantable device, the superhydrophobic properties of the biodegradable polyester layer prevent the rapid generation of large amounts of degradation products. Therefore, it can effectively prevent the reduction in the effectiveness or biological safety risks of the implantable device due to rapid and uneven corrosion in the early stages of implantation, thereby reducing the possibility of harm to the human body.

[0071] The above-mentioned methods for preparing absorbable implantable devices are simple and have low manufacturing costs.

[0072] The above-mentioned absorbable implantable device will be further illustrated below through specific embodiments.

[0073] The following examples use the following test methods:

[0074] 1. Contact angle testing method:

[0075] Contact angle through Germany The company's DSA100 droplet shape analyzer was used for testing under normal pressure, with the test environment controlled at room temperature and relative humidity of 55%–60%. 5 μL of distilled water was used as the probe solution, and measurements were taken at 5 different points on each sample. During each measurement, the probe solution remained on the sample surface for no more than 1 minute, and the average value was taken as the static contact angle.

[0076] 2. Test method for polymer weight-average molecular weight:

[0077] The weight average molecular weight of the polymer is detected by using the GPC-multiple angle laser light scattering instrument system of Wyatt Company in the United States. The test system comprises a liquid phase pump and a sample injector of Agilent Company in the United States, an Agilent PL MIXED-C type GPC column (size: 7.5*300 mm, 5 microns) of Agilent Company in the United States, a multiple angle laser light scattering instrument and a differential detector of Wyatt Company in the United States. The detection conditions are as follows: mobile phase: tetrahydrofuran; pump flow rate: 1 mL / min; sample amount: 100 μL; laser wavelength: 663.9 nm; test temperature: 35 °C.

[0078] 3. Test method of coating thickness.

[0079] First, a conductive layer (for example, gold, silver, etc.) is sprayed on the surface of the absorbable implantable device, then the part of the absorbable implantable device with the coating is embedded with resin, and is ground and polished on a metallographic sample pre-grinder until a cross section of the implantable device with the coating is exposed. At least three cross sections perpendicular to the surface of the device are selected, and then the cross sections are observed by using SEM. The thickness of the coating at at least three positions along the surface normal direction of the implantable device is detected. The average value obtained by adding the thickness of the coating at multiple positions in each cross section is the thickness of the coating.

[0080] wherein SEM is a JSM6510 scanning electron microscope of JEOL Company in Japan.

[0081] 4. Test method of radial support force of vascular stent

[0082] The absorbable implantable device is implanted into the blood vessel of a test animal. Then at a predetermined observation time point, such as 1 month, 3 months, 6 months, the absorbable implantable device and the surrounding tissue are taken out. After the surface moisture is absorbed, the radial support force test is directly performed. The RX550 radial support force tester is used for detection. The detection conditions are as follows: compression mode: Ramp; initial outer diameter: OD+(0.5-1) mm; end outer diameter: OD-(0.5-1) mm; rate: 0.1 mm / s; holding time: 1 s.

[0083] 5. Test method of mass retention rate of degradable polyester

[0084] The mass of the degradable polyester is detected by the following weight loss method: the total mass M0 of the absorbable implantable device is weighed, then the degradable polyester on the surface of the substrate is removed by using a good solvent of the degradable polyester, and the mass M1 of the residual absorbable implantable device is weighed. Then, the mass M of the degradable polyester is (M0-M1). 聚酯

[0085] ​The mass retention rate of the degradable polyester refers to the ratio between the mass of the degradable polyester remaining on the absorbable implantable device after corrosion of the device and the total mass of the degradable polyester before corrosion. The determination of the mass retention rate specifically comprises the following steps: before the absorbable implantable device is implanted, the mass M0 of the degradable polyester on the device is measured by the aforementioned weight loss method 聚酯 (M0-M1). The absorbable implantable device of the same specification is implanted into the blood vessels of the test animals. At a predetermined observation time point, such as 1 month, 3 months, 6 months, the residual device and the surrounding tissue are taken out, the water is absorbed, the extraction is constant volume, and then the aforementioned GPC-multiple angle laser light scattering detector system of Wyatt Company of the United States is used to detect the mass m of the degradable polyester remaining on the device 聚酯 . Then the mass retention rate of the degradable polyester at the observation time point is m 聚酯 / (M0-M1) x 100%.

[0086] Example 1

[0087] A pure iron lumen stent substrate with a thickness of 50 microns is prepared. Poly-DL-lactic acid (PDLLA) and poly-lactic acid (PLLA) with a mass ratio of 2:3 are mixed in trichloromethane to prepare a mixed polymer coating solution with a concentration of 4 mg / ml of PDLLA and 6 mg / ml of PLA. The mixed polymer coating solution is coated on the outer surface of the pure iron lumen stent substrate by ultrasonic atomization spraying. After vacuum drying, a mixed polymer coating layer is formed on the outer surface of the pure iron lumen stent substrate. Then the pure iron lumen stent substrate with the mixed polymer coating layer on the outer surface is immersed in medical grade ethyl acetate at room temperature for 15 min to dissolve the PDLLA in the polymer coating layer. After taking out and vacuum drying, a degradable polyester layer is formed on the surface of the pure iron lumen stent substrate, and an absorbable vascular stent of the present embodiment is obtained. The ultrasonic atomization spraying equipment is MediCoat DES4000 equipment, the pump flow rate of the equipment is 0.05 ml / min, the ultrasonic intensity is 70%, the rotating speed is 250 r / min, the forward speed is 0.3 cm / s, and the stroke is 2 times.

[0088] The contact angle of the degradable polyester layer in the absorbable vascular stent of Example 1 is measured to be 155°, the weight average molecular weight of PLA is 30,000, and the thickness of the degradable polyester layer is 12 μm.

[0089] The same raw materials and methods are used to make six identical absorbable vascular stents. The six absorbable vascular stents are implanted into the abdominal aortas of two New Zealand rabbits with similar age and weight, and three absorbable vascular stents are randomly implanted into each New Zealand rabbit. At 6 months after implantation, one New Zealand rabbit is followed up for sampling, and three absorbable vascular stents are removed. At 24 months, the other New Zealand rabbit is followed up for sampling, and three absorbable vascular stents are removed. The six removed absorbable vascular stents are subjected to radial support force testing and mass retention rate testing of the degradable polyester. The test results are as follows: at 6 months after implantation, the average radial support force of the absorbable vascular stents is 63 kPa, meeting the clinical requirements for vascular stents, and the average mass retention rate of the degradable polyester is 47%. At 24 months after implantation, the absorbable vascular stents have completely corroded.

[0090] Example 2

[0091] An iron-based alloy lumen stent base with a thickness of 55 microns is provided. Polylactic acid (PLA) and polypropylene carbonate (PPC) with a mass ratio of 4:2 are mixed in tetrahydrofuran to prepare a mixed polymer coating solution with a concentration of 2 mg / ml of PLA and 4 mg / ml of PPC. The mixed polymer coating solution is coated on the outer surface of the pure iron lumen stent base by ultrasonic atomization spraying. After vacuum drying, a mixed polymer coating layer is formed on the outer surface of the pure iron lumen stent base. Then, the pure iron lumen stent with the mixed polymer coating layer on the outer surface is immersed in dimethyl sulfoxide at 40°C for 10 min to dissolve the PPC. After removal and natural drying, a degradable polyester layer is formed on the surface of the pure iron lumen stent base, and an absorbable vascular stent of the present embodiment is obtained. The ultrasonic atomization spraying equipment is MediCoat DES4000 equipment, the pump flow rate of the equipment is 0.06 ml / min, the ultrasonic intensity is 70%, the rotation speed is 200 r / min, the forward speed is 0.3 cm / s, and the stroke is 2 times.

[0092] The contact angle of the degradable polyester layer in the absorbable vascular stent provided in Example 2 is measured to be 162°, the weight average molecular weight of PLA is 15,000, and the thickness of the degradable polyester layer is 16 μm.

[0093] The same raw materials and methods are used to make six identical absorbable vascular stents. The six absorbable vascular stents are implanted into the abdominal aortas of two New Zealand rabbits of similar age and weight, and three absorbable vascular stents are randomly implanted into each New Zealand rabbit. Then, one of the New Zealand rabbits is followed up and sampled at 6 months and 24 months, respectively, and the radial support force test and the mass retention rate test of the degradable polyester are performed on the three absorbable vascular stents taken out at each sampling time, respectively. The test results are as follows: at 6 months after implantation, the average radial support force of the absorbable vascular stent is 84 kPa, meeting the clinical requirements for vascular stents, and the average mass retention rate of the degradable polyester is 63%. At 24 months after implantation, the absorbable stent has completely corroded.

[0094] Example 3

[0095] A magnesium-based alloy lumen stent base with a thickness of 60 microns is provided, and poly-β-hydroxybutyric acid (PHB) and polypropylene carbonate (PPC) with a mass ratio of 3:2 are mixed and dissolved in chlorobenzene to prepare a mixed polymer coating solution with a concentration of 2 mg / ml of PHB and 3 mg / ml of PPC, respectively. The mixed polymer coating solution is coated on the outer surface of the pure iron lumen stent base by ultrasonic atomization spraying, and a mixed polymer coating layer is formed on the outer surface of the pure iron lumen stent base after vacuum drying. Then, the pure iron lumen stent with the mixed polymer coating layer on the outer surface is immersed in dimethyl sulfoxide at 40°C for 12 min to dissolve the PPC, taken out, and naturally dried to form a degradable polyester layer on the surface of the pure iron lumen stent base, thereby obtaining the absorbable vascular stent of the present example. The ultrasonic atomization spraying equipment is MediCoat DES4000 equipment, the pump flow rate of the equipment is 0.06 ml / min, the ultrasonic intensity is 70%, the rotation speed is 200 r / min, the forward speed is 0.3 cm / s, and the stroke is 2 times.

[0096] The contact angle of the degradable polyester layer in the absorbable vascular stent provided in Example 3 is measured to be 158°, the weight average molecular weight of PHB is 33,000, and the thickness of the degradable polyester layer is 15 μm.

[0097] The same raw materials and methods are used to make six identical absorbable vascular stents. The six absorbable vascular stents are implanted into the abdominal aortas of two New Zealand rabbits with similar age and weight, and three absorbable vascular stents are randomly implanted into each New Zealand rabbit. Then one of the New Zealand rabbits is followed up and sampled at 6 months and 24 months, respectively, and the radial support force test and the mass retention rate test of the degradable polyester are performed on the three absorbable vascular stents taken out at each sampling time. The test results are as follows: at 6 months after implantation, the average radial support force of the absorbable vascular stent is 71 kPa, meeting the clinical requirements for vascular stents, and the average mass retention rate of the degradable polyester is 43%. At 24 months after implantation, the absorbable stent has completely corroded.

[0098] Example 4

[0099] A pure iron lumen stent base with a thickness of 90 microns is provided, and polybutylene succinate (PBS), polyethylene glycol adipate (PEGA), and polypropylene carbonate (PPC) with a mass ratio of 4:5:1 are mixed in trichloromethane to prepare a mixed polymer coating solution with concentrations of 2 mg / ml of PBS, 2.5 mg / ml of PEGA, and 0.5 mg / ml of PPC. The mixed polymer coating solution is coated on the outer surface of the pure iron lumen stent base by ultrasonic atomization spraying, and a mixed polymer coating layer is formed on the outer surface of the pure iron lumen stent base after vacuum drying. Then the pure iron lumen stent with the mixed polymer coating layer on the outer surface is soaked in dimethylformamide at 40°C for 12 min to dissolve the PPC, taken out, and naturally dried to form a degradable polyester layer on the surface of the pure iron lumen stent base, thereby obtaining the absorbable vascular stent of the present embodiment. The ultrasonic atomization spraying equipment is MediCoat DES4000 equipment, the pump flow rate of the equipment is 0.04 ml / min, the ultrasonic intensity is 70%, the rotation speed is 250 r / min, the forward speed is 0.3 cm / s, and the stroke is 1 time.

[0100] The contact angle of the degradable polyester layer in the absorbable vascular stent provided in Example 4 is measured to be 161°, the average weight average molecular weight of polybutylene succinate and polyethylene glycol adipate is 20,000, and the thickness of the degradable polyester layer is 1 μm.

[0101] The same raw materials and methods are used to make six identical absorbable vascular stents. The six absorbable vascular stents are implanted into the abdominal aortas of two New Zealand rabbits of similar age and weight, and three absorbable vascular stents are randomly implanted into each New Zealand rabbit. Then, one of the New Zealand rabbits is followed up and sampled at 6 months and 24 months, respectively, and the radial support force test and the mass retention rate test of the degradable polyester are performed on the three absorbable vascular stents taken out at each sampling time, respectively. The test results are as follows: at 6 months after implantation, the average radial support force of the absorbable vascular stent is 78 kPa, which meets the clinical requirements for vascular stents, and the average mass retention rate of the degradable polyester is 30%. At 24 months after implantation, the absorbable stent has completely corroded.

[0102] Example 5

[0103] A pure iron lumen stent base with a thickness of 30 microns is provided, and polyglycolic acid (PGA) and poly-DL-lactic acid (PDLLA) with a mass ratio of 9:1 are mixed in hexafluoroisopropanol to prepare a mixed polymer coating solution with a concentration of 9 mg / ml of PGA and 1 mg / ml of PDLLA. The mixed polymer coating solution is coated on the outer surface of the pure iron lumen stent base by ultrasonic atomization spraying, and a mixed polymer coating layer is formed on the outer surface of the pure iron lumen stent base after vacuum drying. Then, the pure iron lumen stent with the mixed polymer coating layer on the outer surface is soaked in ethyl acetate at room temperature for 10 min to dissolve the PDLLA, taken out, and naturally dried to form a degradable polyester layer on the surface of the pure iron lumen stent base, thereby obtaining the absorbable vascular stent of the present embodiment. The ultrasonic atomization spraying equipment is MediCoat DES4000 equipment, the pump flow rate of the equipment is 0.06 ml / min, the ultrasonic intensity is 70%, the rotation speed is 200 r / min, the forward speed is 0.3 cm / s, and the stroke is 8 times.

[0104] The contact angle of the degradable polyester layer in the absorbable vascular stent provided in Example 5 is measured to be 170°, the weight average molecular weight of PGA is 25,000, and the thickness of the degradable polyester layer is 100 μm.

[0105] The same raw materials and method are used to make six identical absorbable vascular stents. The six absorbable vascular stents are implanted into the abdominal aortas of two New Zealand rabbits with similar age and weight, and three absorbable vascular stents are randomly implanted into each New Zealand rabbit. Then, one of the New Zealand rabbits is followed up and sampled at 6 months and 24 months, respectively, and the radial support force test and the mass retention rate test of the degradable polyester are performed on the three absorbable vascular stents taken out at each sampling time. The test results are as follows: at 6 months after implantation, the average radial support force of the absorbable vascular stent is 75 kPa, which meets the clinical requirements for vascular stents, and the average mass retention rate of the degradable polyester is 71%. At 24 months after implantation, the absorbable stent has completely corroded.

[0106] Example 6

[0107] A pure iron tubular stent base with a thickness of 50 microns is provided. Polylactic acid-glycolic acid copolymer (PLGA, LA:GA=2:8 (mass ratio)) and polymethyl methacrylate (PMMA) with a mass ratio of 1:1 are mixed and dissolved in chloroform to prepare a mixed polymer coating solution with a concentration of 2 mg / ml of PLGA and 2 mg / ml of PMMA. The mixed polymer coating solution is coated on the outer surface of the pure iron tubular stent base by ultrasonic atomization spraying, and a mixed polymer coating layer is formed on the outer surface of the pure iron tubular stent base after vacuum drying. Then, the pure iron tubular stent with the mixed polymer coating layer on the outer surface is soaked in ethyl acetate at 30°C for 10 min to dissolve the PMMA, taken out, and naturally dried to form a degradable polyester layer on the surface of the pure iron tubular stent base, thereby obtaining the absorbable vascular stent of the present embodiment. The ultrasonic atomization spraying equipment is MediCoat DES4000 equipment, the pump flow rate of the equipment is 0.06 ml / min, the ultrasonic intensity is 70%, the rotation speed is 200 r / min, the forward speed is 0.3 cm / s, and the stroke is 4 times.

[0108] The contact angle of the degradable polyester layer in the absorbable vascular stent provided in Example 6 is measured to be 155°, the weight average molecular weight of PLGA is 20,000, and the thickness of the degradable polyester layer is 34 μm.

[0109] ​The same raw materials and methods are used to make six identical absorbable vascular stents. The six absorbable vascular stents are implanted into the abdominal aortas of two New Zealand rabbits with similar age and weight, and three absorbable vascular stents are randomly implanted into each New Zealand rabbit. Then, one of the New Zealand rabbits is followed up and sampled at 6 months and 24 months, respectively, and the radial support force test and the mass retention rate test of the degradable polyester are performed on the three absorbable vascular stents taken out at each sampling time. The test results are as follows: at 6 months after implantation, the average radial support force of the absorbable vascular stent is 83 kPa, meeting the clinical requirements for vascular stents, and the average mass retention rate of the degradable polyester is 30%. At 24 months after implantation, the absorbable stent has completely corroded.

[0110] Example 7

[0111] A pure iron lumen stent base with a thickness of 45 microns is provided, and polyethylene glycol adipate (PEGA), poly-racemic lactic acid (PDLLA), and polycaprolactone (PCL) with a mass ratio of 4:1 are mixed in a mixed solvent of chloroform and chlorobenzene (the volume ratio of chloroform to chlorobenzene is 1:1) to prepare a mixed polymer coating solution with a concentration of 8 mg / ml of PEGA, 1 mg / ml of PDLLA, and 1 mg / ml of PCL. The mixed polymer coating solution is coated on the outer surface of the pure iron lumen stent base by ultrasonic atomization spraying, and a mixed polymer coating layer is formed on the outer surface of the pure iron lumen stent base after vacuum drying. Then, the pure iron lumen stent with the mixed polymer coating layer on the outer surface is immersed in a mixed solvent of dimethylformamide and dimethyl sulfoxide (the volume ratio of dimethylformamide to dimethyl sulfoxide is 1:1) at 50°C for 13 min to dissolve PDLLA and PCL, and then taken out and naturally dried to form a degradable polyester layer on the surface of the pure iron lumen stent base, thereby obtaining the absorbable vascular stent of the present example. The ultrasonic atomization spraying equipment is MediCoat DES4000 equipment, the pump flow rate of the equipment is 0.04 ml / min, the ultrasonic intensity is 70%, the rotation speed is 200 r / min, the forward speed is 0.3 cm / s, and the stroke is 3 times.

[0112] The contact angle of the degradable polyester layer in the absorbable vascular stent provided in Example 7 is measured to be 156°, the weight average molecular weight of PEGA is 20,000, and the thickness of the degradable polyester layer is 12 μm.

[0113] The same raw materials and methods are used to make a total of six identical absorbable vascular stents. The six absorbable vascular stents are implanted into the abdominal aortas of two New Zealand rabbits that are similar in age and weight, and three absorbable vascular stents are randomly implanted into each New Zealand rabbit. Then, at 6 months and 24 months after implantation, one of the New Zealand rabbits is followed up and sampled, and the radial support force test and the mass retention rate test of the degradable polyester are performed on the three absorbable vascular stents taken out at each sampling time. The test results are as follows: at 6 months after implantation, the average radial support force of the absorbable vascular stent is 75 kPa, which meets the clinical requirements for vascular stents, and the average mass retention rate of the degradable polyester is 55%. At 24 months after implantation, the absorbable stent has completely corroded.

[0114] Comparative Example 1

[0115] A pure iron tubular stent base with a thickness of 50 microns is provided, polylactic acid (PLA) is mixed in chloroform to prepare a coating solution of PLA with a concentration of 6 mg / ml, and the coating solution is coated on the outer surface of the pure iron tubular stent base by ultrasonic atomization spraying, and after vacuum drying, a polylactic acid coating is formed on the outer surface of the pure iron tubular stent base, thereby obtaining an absorbable vascular stent. The ultrasonic atomization spraying equipment is MediCoat DES4000 equipment, the pump flow rate of the equipment is 0.05 ml / min, the ultrasonic intensity is 70%, the rotation speed is 250 r / min, the forward speed is 0.3 cm / s, and the stroke is 2 times.

[0116] It is measured that the weight average molecular weight of PLA in the absorbable vascular stent of this comparative example 1 is 15,000, and the thickness of the degradable polyester layer is 12 μm.

[0117] The same raw materials and methods are used to make a total of six identical absorbable vascular stents. The six absorbable vascular stents are implanted into the abdominal aortas of two New Zealand rabbits that are similar in age and weight, and three absorbable vascular stents are randomly implanted into each New Zealand rabbit. At 6 months after implantation, one of the New Zealand rabbits is followed up and sampled, and three absorbable vascular stents are taken out. At 24 months, the other New Zealand rabbit is followed up and sampled, and three absorbable vascular stents are taken out. The radial support force test and the mass retention rate test of the degradable polyester are performed on the six absorbable vascular stents taken out. The test results are as follows: at 6 months after implantation, the average radial support force of the absorbable vascular stent is 29 kPa, which is difficult to meet the clinical requirements for vascular stents, and the average mass retention rate of the degradable polyester is only 23%. At 24 months after implantation, the absorbable vascular stent completely corrodes.

[0118] Comparative Examples 1-7 and Comparative Example 1, because the degradable polyester layer is hydrophobically modified, the protection effect of the degradable polyester layer on the absorbable metal base is improved.

[0119] Any combination of the technical features in the above-described embodiments can be made, and for the sake of brevity, not all possible combinations are described, however, as long as the combination of the technical features does not exist in contradiction, it shall be considered within the scope of the present disclosure.

[0120] The above-described embodiments only express several implementation manners of the present application, and the description is relatively specific and detailed, but it shall not be understood as a limitation on the patent scope of the present application. It shall be pointed out that, for ordinary skilled persons in the art, several modifications and improvements can be made without departing from the concept of the present application, and these shall be within the protection scope of the present application. Therefore, the protection scope of the present application patent shall be subject to the appended claims.

Claims

1. An absorbable implantable device comprising an absorbable metal matrix, characterized in that, Further comprising a degradable polyester layer at least partially covering the surface of the absorbable metal matrix, the degradable polyester layer having a contact angle greater than or equal to 150°; the degradable polyester layer being formed by immersing a mixed polymer coating of the degradable polyester and the polymer in a second solvent, the degradable polyester layer having a rough surface; the solubility of the polymer in the second solvent being greater than the solubility of the degradable polyester in the second solvent; the second solvent being selected from at least one of ethyl acetate, dimethylformamide and dimethyl sulfoxide; the temperature of the second solvent being 20-50°C; the mass ratio of the degradable polyester to the polymer in the mixed polymer coating solution forming the mixed polymer coating being 1:1-9:

1.

2. The absorbable implantable device of claim 1, wherein, The contact angle of the degradable polyester layer is greater than or equal to 160°.

3. The absorbable implantable device of claim 1, wherein, The weight average molecular weight of the degradable polyester in the degradable polyester layer is greater than or equal to 15,000.

4. The absorbable implantable device of claim 1, wherein, The thickness of the degradable polyester layer is 1-100 microns.

5. The absorbable implantable device of claim 1, wherein, The degradable polyester in the degradable polyester layer is at least one of polyglycolic acid, polylactic acid, polybutylene succinate, poly-β-hydroxybutyric acid and poly(lactic-co-glycolic acid); or, the degradable polyester in the degradable polyester layer is formed by copolymerization of at least two of the monomers forming polyglycolic acid, polylactic acid, polybutylene succinate, poly-β-hydroxybutyric acid and polyethylene adipate.

6. The absorbable implantable device of claim 1, wherein, The material of the absorbable metal matrix is pure iron, pure zinc, pure magnesium, iron-based alloy, magnesium-based alloy or zinc-based alloy.

7. The absorbable implantable device of claim 1, wherein, The mass ratio of the degradable polyester to the polymer in the mixed polymer coating solution forming the mixed polymer coating is 3:2-4:

1.

8. The absorbable implantable device of claim 1, wherein, The coverage of the degradable polyester layer on the surface of the absorbable metal matrix is greater than or equal to 10%; the mass percentage of the degradable polyester layer to the mass of the absorbable metal matrix is greater than or equal to 5%.

9. The absorbable implantable device of claim 4, wherein, The mass retention rate of the degradable polyester layer is greater than or equal to 30% when the absorbable implantable device is implanted for 1-6 months.

10. The absorbable implantable device of claim 1, the polymer being at least one of a degradable polymer and a non-degradable polymer, or at least one of a copolymer formed by at least one monomer forming the degradable polymer and at least one monomer forming the non-degradable polymer.

11. The absorbable implantable device of claim 10, wherein, The degradable polymer is at least one of poly-D,L-lactic acid, polypropylene carbonate, polycaprolactone, polyglycolic acid and poly(lactic-co-glycolic acid), and the non-degradable polymer is at least one of polystyrene, polymethyl methacrylate and polyethylene terephthalate.

12. A method of making an absorbable implantable device, comprising: The method comprises the following steps: providing an absorbable metal matrix; dissolving a degradable polyester and a polymer in a first solvent to obtain a mixed polymer coating solution; coating the mixed polymer coating solution on the surface of the absorbable metal matrix and drying to form a mixed polymer coating on the surface of the absorbable metal matrix; and The absorbable metal substrate with the mixed polymer coating on the surface is immersed in a second solvent to dissolve the polymer and not dissolve the degradable polyester, and after being taken out and dried, a degradable polyester layer is formed on the surface of the absorbable metal substrate to obtain the absorbable implantable device, wherein the contact angle of the degradable polyester layer is greater than or equal to 150°; the second solvent is selected from at least one of ethyl acetate, dimethylformamide and dimethyl sulfoxide; the temperature of the second solvent is 20-50°C; and the mass ratio of the degradable polyester to the polymer in the mixed polymer coating solution is 1:1-9:

1.

13. The method for preparing the absorbable implantable device according to claim 12, characterized in that, The first solvent is selected from at least one of chloroform, dichloromethane, chlorobenzene, dimethylacetamide, tetrahydrofuran and hexafluoroisopropanol.

14. The method for preparing the absorbable implantable device according to claim 12, characterized in that, The polymer is selected from at least one of a degradable polymer and a non-degradable polymer, or at least one of a copolymer formed by at least one monomer forming the degradable polymer and at least one monomer forming the non-degradable polymer.

15. The method for preparing the absorbable implantable device according to claim 14, characterized in that, The degradable polymer is selected from at least one of poly-racemic lactic acid, polypropylene carbonate, polycaprolactone, polyglycolic acid and poly(lactic-co-glycolic acid), and the non-degradable polymer is selected from at least one of polystyrene, polymethyl methacrylate and polyethylene terephthalate.

16. The method for preparing the absorbable implantable device according to claim 12, characterized in that, The mass ratio of the degradable polyester to the polymer in the mixed polymer coating solution is 3:2-4:1, and the concentration of the degradable polyester in the mixed polymer coating solution is 1-9 mg / mL.

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