(19)
(11)EP 3 733 222 A1

(12)EUROPEAN PATENT APPLICATION
published in accordance with Art. 153(4) EPC

(43)Date of publication:
04.11.2020 Bulletin 2020/45

(21)Application number: 18897186.5

(22)Date of filing:  31.10.2018
(51)International Patent Classification (IPC): 
A61L 31/14(2006.01)
A61L 31/02(2006.01)
A61L 31/06(2006.01)
(86)International application number:
PCT/CN2018/112861
(87)International publication number:
WO 2019/128453 (04.07.2019 Gazette  2019/27)
(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
Designated Extension States:
BA ME
Designated Validation States:
KH MA MD TN

(30)Priority: 25.12.2017 CN 201711424079

(71)Applicant: Lifetech Scientific (Shenzhen) Co., Ltd
Shenzhen, Guangdong 518057 (CN)

(72)Inventors:
  • LIN, Wenjiao
    Shenzhen, Guangdong 518057 (CN)
  • CHEN, Liping
    Shenzhen, Guangdong 518057 (CN)
  • QIN, Li
    Shenzhen, Guangdong 518057 (CN)

(74)Representative: Prinz & Partner mbB 
Patent- und Rechtsanwälte Rundfunkplatz 2
80335 München
80335 München (DE)

  


(54)ABSORBABLE IRON-BASED IMPLANTABLE DEVICE


(57) An absorbable iron-based implantable device, including an iron-based substrate and an iron absorption promoter that is attached to the iron-based substrate. The iron absorption promoter is a polymer containing an antioxidant structural unit on the molecular chain thereof. The antioxidant is gradually released as the iron absorption promoter is gradually degraded or broken, and may promote the absorption of iron.


Description

FIELD



[0001] The embodiments relate to the field of implantable medical devices, in particular to an absorbable iron-based implantable device.

BACKGROUND



[0002] Currently, absorbable implantable medical materials mainly include degradable polymers and absorbable metallic materials. Absorbable metallic materials include magnesium-based alloys, iron-based alloys, zinc-based alloys, pure iron, and the like. Compared with other absorbable materials, the iron-based alloy and the pure iron have excellent mechanical properties comparable to those of permanently implantable medical metallic materials such as stainless steel, cobalt-chromium alloy and platinum-chromium alloy and the like, thus it is possible to use the iron-based alloy and the pure iron to produce an implantable medical device with smaller volume but better mechanical properties, so as to guarantee better clinical operability and effectiveness. An ideal design idea of the absorbable medical device is that the absorbable medical device can provide adequate support in the recovery period of the lesion site, and after healing of the lesion, the absorbable implantable medical device will be corroded or degraded as soon as possible and be absorbed by the body. However, for a long time, an outstanding problem of absorbable medical devices made of iron-based alloy and pure iron that has not yet been solved is that the main iron corrosion products are insoluble in body fluid, although the solid corrosion products can be absorbed and metabolized by the flow of intercellular fluid and engulfment of macrophages, but it takes a long time, resulting in a large amount of corrosion products retained in the tissue for a long time, and possibly a long-term biological risk.

[0003] The results showed that after implantation into a body, the iron-based stent was first corroded to generate Fe2+, which was easily oxidized to Fe3+ in an aerobic environment. There are both PO43- and OH- ions in tissue fluid, and thermodynamically, the generated Fe2+ will preferably bind to PO43- ions to form ferrous phosphate Fe3(PO4)2 precipitate which is more insoluble, and then bind to OH- ions to form Fe(OH)2 precipitate until complete consumption of phosphate ions in the local tissue, the Fe(OH)2 precipitate will be further oxidized to ferric hydroxide Fe(OH)3 precipitate. Thermodynamically, the generated Fe3+ ions will preferably react with hydroxide ions to generate Fe(OH)3 precipitate, due to the fact that iron phosphate is stable only at pH of less than 5, and generally the pH of body fluid is more than 5, so that Fe3+ and PO43- ions are difficult to form iron phosphate precipitate in vivo. After Fe2+ ions generated by corrosion of the iron-based stent completely consume phosphate radicals in the local tissue fluid at the implanted site, it is necessary for phosphate radicals in the tissue fluid in other sites to diffuse to the implanted site to supply, and the diffusion process will take time. In contrast, while the concentration of OH- ions is lower than that of phosphate ions in the local tissue at the implanted site, OH- ions can be rapidly supplied by water dissociation in situ, thus it is more favorable to form ferrous hydroxide kinetically.

[0004] Therefore, most of the solid corrosion products after the iron-based stent being implanted into the body are iron hydroxides and iron oxides formed after subsequent dehydration, and a very small amount of corrosion product is ferrous phosphate. In the environment of pH = 7.4 and the temperature being 37 °C(in vivo), the solubility products of Fe(OH)2 and Fe(OH)3 are 7.19 × 10-17 and 1.22 × 10-38 respectively, i.e., in this environment, the concentration of free Fe2+ when the Fe(OH)2 precipitate reaches the dissolution equilibrium is about 60 mg/L, while the concentration of free Fe3+ when the Fe(OH)3 precipitate reaches the dissolution equilibrium is a dozen orders of magnitude lower than that of Fe2+, about 4.3 x 10-14 mg/L, closing to zero. Therefore, when Fe2+ generated by corrosion of the iron-based stent is oxidized to Fe3+ in the process of diffusing to the peripheral oxygen-enriched area, a Fe(OH)3 solid corrosion product is easily and quickly formed locally, and due to a very low solubility product thereof, a free Fe3+ concentration after reaching the dissolution equilibrium is very low, subsequently it is hard to gradually dissolve and metabolize the Fe(OH)3 corrosion product by new iron ions ionized by movement of the dissolution equilibrium of Fe(OH)3 to the right after Fe3+ being diffused and absorbed and metabolized by the tissue. The only way for the body to remove Fe(OH)3, an insoluble solid corrosion product, is through phagocytosis and transportation of phagocytes, such as macrophages. In addition, if the Fe(OH)3 solid corrosion products are agglomerated together, phagocytes can only contact the outermost layer of the corrosion products, leading to a lower efficiency on phagocytizing and transporting the solid corrosion products. Thus, the removal rate of Fe(OH)3 solid corrosion products will become slower, resulting in a longer absorption period.

[0005] For the problem that the iron corrosion products are difficult to absorb in vivo and need a long absorption period, the prior art adopts a method of adding an antioxidant to promote the generation of the soluble iron corrosion product, the antioxidant being, for example, water-soluble polyphenol, tocopherol, sodium tripolyphosphate and the like, however, the above mentioned antioxidants has the following disadvantages: 1. the antioxidant has a poor stability, and the chemical property thereof is easy to change under the conditions of illumination, oxygen enrichment or specific pH, leading to a loss of the antioxidation effect; 2. the water-soluble antioxidant is dissolved in blood and water-based tissue fluid both in the transportation process and after implantation to lose a large amount itself, and the liposoluble antioxidant is too difficult to dissolve in the water-soluble tissue fluid, leading to a poor anti-oxidation effect, thus it is difficult to promote the generation of the iron corrosion product Fe(OH)2 having a higher solubility product; 3. most of these antioxidants have a fast release rate initially, while iron-based alloy implantable medical devices usually start to corrode in large in 3 months or so in order to ensure the stability of mechanical properties at the earlier stage. Therefore, the antioxidants have already completely been consumed while the iron substrates haven't subjected corrosion yet, and have no effect on promoting the iron absorption.

SUMMARY



[0006] In consideration of this, it is necessary to provide an absorbable iron-based implantable device capable of promoting a long-acting iron absorption.

[0007] An absorbable iron-based implantable device includes an iron-based substrate and an iron absorption promoter that is attached to the iron-based substrate, where the iron absorption promoter is a polymer containing an antioxidant structural unit on the molecular chain thereof.

[0008] In one embodiment, the iron absorption promoter is capable of being degraded to release of antioxidants.

[0009] In one embodiment, the antioxidant is at least one selected from ascorbic acid, procyanidin, vitamin E, glutathione, and lipoic acid.

[0010] In one embodiment, the weight-average molecular weight of the iron absorption promoter is 1,000-500,000.

[0011] In one embodiment, the iron absorption promoter is a procyanidin polymer.

[0012] In one embodiment, the iron absorption promoter further includes at least one degradable polymeric structural unit.

[0013] In one embodiment, the iron absorption promoter further includes at least one non-degradable polymeric structural unit.

[0014] In one embodiment, the degradable polymer is at least one selected from degradable polyester, polyamino acid, polyanhydride and glucan.

[0015] In one embodiment, the degradable polyester is at least one selected from polylactic acid, polyglycolic acid, poly succinate, poly(β-hydroxybutyrate), polycaprolactone, and polyethylene adipate.

[0016] In one embodiment, polyamino acid is at least one selected from polylysine, polyaspartic acid, polycysteine, polymethionine, polyornithine, and polyglutamic acid.

[0017] In one embodiment, the polyanhydride is at least one selected from polyoxalate anhydride, polybutanedioic anhydride, polyadipic anhydride, polysebacic anhydride, polydodecanoic anhydride, polycitric anhydride, polymalic anhydride, polysuccinic anhydride, polytartaric anhydride, polyitaconic anhydride, and polymaleic anhydride.

[0018] In one embodiment, the non-degradable polymer is at least one selected from polyethylene glycol, polyacrylate, poly succinate, polycarbonate, polyethylene vinyl acetate, poly(n-butyl methacrylate), polystyrene, polyvinylidene fluoride, polyvinyl pyrrolidone, and polyhexafluoroethylene.

[0019] In one embodiment, the mass ratio of the iron absorption promoter to the iron-based substrate is 0.05∼3:1.

[0020] In one embodiment, the mass ratio of the iron absorption promoter to the iron-based substrate is 0.15∼1:1.

[0021] In one embodiment, the iron absorption promoter is attached to the surface of the iron-based substrate; alternatively, the iron absorption promoter is filled inside of the iron-based substrate.

[0022] In one embodiment, the absorbable iron-based implantable device is a cardiovascular stent, a cerebrovascular stent, a peripheral vascular stent, a biliary stent, an esophageal stent, an airway stent, an occluding device, or an orthopedic implant.

[0023] In one embodiment, the absorbable iron-based implantable device further includes an active drug attached to the iron-based substrate which is at least one selected from antiangiogenic drugs, antiplatelet drugs, antithrombotic drugs, anti-inflammatory drugs, and anti-sensitizing drugs.

[0024] An iron absorption promoter is attached to the iron-based substrate of the absorbable iron-based implantable device described above, the iron absorption promoter is a polymer containing an antioxidant structural unit, and after the absorbable iron-based implantable device is implanted into a body, the antioxidant is gradually released as the iron absorption promoter is gradually degraded or broken, and may promote the iron absorption.

DETAILED DESCRIPTION OF THE EMBODIMENTS



[0025] The foregoing objects, features and advantages of the embodiments will become more apparent from the following detailed description when taken in conjunction with the accompanying drawings. In the following, numerous details are set forth to describe the embodiments. However, the embodiments may be implemented by many other manners different than those described herein and similar modifications may be made by those of ordinary skill in the art without departing from the spirit of the embodiments, thus the embodiments should not be construed as limiting.

[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. The terms used herein in the description of the present disclosure are for the purpose of describing particular embodiments only and not intended to be limiting of the present disclosure.

[0027] In one embodiment, an absorbable iron-based implantable device includes an iron-based substrate and an iron absorption promoter attached to the iron-based substrate, the iron absorption promoter being a polymer containing an antioxidant structural unit on the molecular chain thereof, and being capable of being degraded to release the antioxidant.

[0028] The iron-based substrate may be a pure iron substrate or an iron-based alloy substrate. For example, the material of iron-based alloy substrate is an iron-based alloy having a carbon content of not higher than 2.11 wt.%.

[0029] The iron absorption promoter may be attached to the surface of the iron-based substrate in a film forming manner. For example, the iron absorption promoter is attached to the outer surface, the inner surface or the side of the iron-based substrate. Alternatively, the iron absorption promoter is attached to the outer surface, the inner surface and the side surface of the iron-based substrate at the same time. Or the iron absorption promoter is attached to the outer and inner surfaces of the iron-based substrate, etc. That is, the position of the film formed by the iron absorption promoter on the iron-based substrate is not limited. Also, the distribution of the iron absorption promoter on the surface of the iron-based substrate may be either uniform or non-uniform.

[0030] In a further embodiment, the iron absorption promoter may be filled inside of the iron-based substrate. Gaps, pores, grooves, through-holes or inner cavities and the like can be formed on the iron-based substrate, so that the iron absorption promoter is filled into the corresponding gaps, pores, grooves, through-holes or inner cavities, so that the iron absorption promoter is filled inside of the iron-based substrate.

[0031] For example, the antioxidant is at least one selected from ascorbic acid, procyanidine, vitamin E, glutathione and lipoic acid. An antioxidant is polymerized to form an iron absorption promoter through a polymerization reaction, an antioxidant structural unit being a repeating unit on the molecular chain of the iron absorption promoter, and the antioxidant structural units being connected through chemical bonds. The antioxidant is released as the iron absorption promoter is degraded or broken.

[0032] The antioxidant released from the iron absorption promoter is at least one selected from ascorbic acid, procyanidin, vitamin E, glutathione and lipoic acid. The antioxidant released from the iron absorption promoter is a small molecule in the normal metabolic process of human tissue cells or a daily nutrient which can be safely untaken, such that the degraded or released product of the iron absorption promoter in vivo has a good biocompatibility with a human body, and harmful substance to the human body is not generated.

[0033] The antioxidant released during degradation of the above iron absorption promoter is an antioxidant showing a strong reduction effect, and when the iron absorption promoter is degraded or broken in vivo to release the antioxidant, oxygen in situ and near the absorbable iron-based implantable device can be consumed, to ensure that Fe2+ generated by corrosion is not immediately oxidized into Fe3+, but exists in the form of Fe2+ and precipitate thereof having a higher solubility, thereby facilitating diffusion and absorption of the iron corrosion product. Moreover, the iron absorption promoter can delay the conversion of Fe2+ to Fe3+, and free Fe2+ can diffuse out along with tissue fluid. The farther away from the iron-based substrate, the higher the concentration of oxygen ions in the tissue, until the level of oxygen concentration in normal tissues is recovered. The diffused Fe2+ ions are continuously oxidized to Fe3+ ions in oxygen-enriched tissues far away from the iron-based substrate, the Fe3+ ions are precipitated into dispersive Fe(OH)3 solid corrosion products in surrounding tissues in which the iron-based substrate is implanted in situ. The more dispersive the Fe(OH)3 solid corrosion product is, the more beneficial to improve the efficiency of phagocytosis and transportation and metabolism of ferric corrosion products by phagocytic cells, so that the absorption period of the absorbable iron-based implantable device in vivo is shortened.

[0034] In addition, in a physiological environment, after the absorbable iron-based implantable device is implanted into a body, the antioxidant is gradually released as the iron absorption promoter is gradually degraded or broken, so that the release rate of the antioxidant is delayed, the utilization rate of the antioxidant is improved, and the effect for promoting the long-acting iron absorption is achieved.

[0035] In a simulated physiological environment, such as in a saline solution, the iron absorption promoter may also be gradually degraded or broken to gradually release the antioxidant.

[0036] It can be appreciated that the antioxidant forming the iron absorption promoter may be any other antioxidant that shows antioxidant capacity and good biocompatibility with the human body.

[0037] If the molecular weight of the iron absorption promoter is too low, the release rate of the antioxidant will be too fast to facilitate improving the long-acting iron absorption promoting effect thereof, while if the molecular weight of the iron absorption promoter is too high, it will make the synthesis difficult and mechanical properties too poor to coat on the surface of the iron-based substrate. Thus, the weight-average molecular weight of the iron absorption promoter is from 1,000 to 500,000. For example, the weight-average molecular weight of the iron absorption promoter is from 3,000 to 300,000.

[0038] Meanwhile, the above iron absorption promoter is a polymer containing antioxidant structural units and has the advantage of high stability comparing to most natural antioxidants. Under illumination, oxygen enrichment or a specific pH environment, the chemical property of the above iron absorption promoter is difficult to change, enabling a long-acting and stable existence. In addition, the iron absorption promoter has a poor solubility in water. Therefore, the iron absorption promoter can exist stably in a body, and after the absorbable iron-based implantable device is implanted into the body, the iron absorption promoter is difficult to dissolve in aqueous tissue fluid, resulting in a little lose and thereby promoting the absorption of iron in long term.

[0039] Moreover, the iron absorption promoter has good stability and low environmental requirement on product storage, so that the product failure caused by the failure of the iron absorption promoter during storage is avoided, and the shelf life is prolonged.

[0040] In one embodiment, the iron absorption promoter further includes at least one degradable polymeric structural unit. The iron absorption promoter is formed by polymerization of a degradable polymer monomer and the above antioxidant. On the molecular chain of the iron absorption promoter, the degradable polymer structural unit is connected with the antioxidant structural unit through a chemical bond. Here, the degradable polymer structural unit refers to the repeating unit in the degradable polymer molecular chain.

[0041] In one embodiment, the degradable polymer is selected from at least one forming degradable polyester, polyamino acid, polyanhydride and glucan.

[0042] In one embodiment, the degradable polyester is at least one selected from polylactic acid, polyglycolic acid, poly succinate, poly(β-hydroxybutyrate), polycaprolactone, and polyethylene adipate.

[0043] In one embodiment, polyamino acid is at least one selected from polylysine, polyaspartic acid, polycysteine, polymethionine, polyornithine, and polyglutamic acid.

[0044] In one embodiment, the polyanhydride is at least one selected from polyoxalate anhydride, polybutanedioic anhydride, polyadipic anhydride, polysebacic anhydride, polydodecanoic anhydride, polycitric anhydride, polymalic anhydride, polysuccinic anhydride, polytartaric anhydride, polyitaconic anhydride, and polymaleic anhydride.

[0045] Polymerization of the degradable polymer monomer and the antioxidant facilitates improving the stability of the antioxidant, further delaying the release rate of the antioxidant, such that after the absorbable iron-based implantable device is implanted into a body, the antioxidant is gradually and slowly released to keep consistent with the degradation period of the iron-based substrate as far as possible, enabling a long-acting effect on promoting the iron absorption to a maximum level, and the chain segment formed by the degradable polymer is gradually degraded and absorbed as the antioxidant is released.

[0046] It can be appreciated that in other embodiments, in addition to the degradable polymer monomers listed above, other degradable polymer monomers capable of polymerizing with an antioxidant to form an iron absorption promoter and having good biocompatibility with the human body can also be used in the absorbable iron-based implantable device to promote a long-lasting absorption of iron .

[0047] In a further embodiment, the iron absorption promoter further includes at least one non-degradable polymeric structural unit. The non-degradable polymeric structural unit is a repeating unit on the non-degradable polymer molecular chain. The iron absorption promoter is formed by polymerization of a non-degradable polymer monomer with an antioxidant. In one embodiment, the non-degradable polymer is at least one selected from polyethylene glycol, polyacrylate, polysuccinate, polycarbonate, polyethylene vinyl acetate, poly(n-butyl methacrylate), polystyrene, polyvinylidene fluoride, polyvinyl pyrrolidone, and polyhexafluoroethylene.

[0048] In one embodiment, the iron absorption promoter further includes at least one degradable polymeric structural unit and at least one non-degradable polymeric structural unit. For example, the varieties of degradable and non-degradable polymers are the same as the varieties of degradable and non-degradable polymers listed above, respectively.

[0049] The addition of non-degradable polymeric structural unit may improve hydrophilicity or hydrophobicity, or mechanical properties of the iron absorption promoter, or stability and the release rate of the antioxidant.

[0050] It can be appreciated that in other embodiments, in addition to the non-degradable polymeric monomers listed above, other non-degradable polymeric monomers which are capable of polymerizing with an antioxidant or an antioxidant together with a degradable polymeric monomer to form an iron absorption promoter and are biocompatible with the human body, may also be used in the absorbable iron-based implantable devices described above to improve hydrophilicity or hydrophobicity, or mechanical properties of the iron absorption promoter, or stability and the release rate of the antioxidant.

[0051] For example, the antioxidant is copolymerized with the degradable polymer monomer and/or the non-degradable polymer monomer by random copolymerization, alternating copolymerization, block copolymerization or graft copolymerization. The iron absorption promoter formed by polymerization can be gradually release the antioxidant.

[0052] The lower mass of the iron absorption promoter has a novel effect on promoting the absorption of iron. The higher mass of the iron absorption promoter has a good effect on promoting the absorption of iron, but due to high mass and large volume thereof, physical properties of the absorbable iron-based implantable device are seriously affected. Therefore, the mass ratio of the iron absorption promoter to iron in the iron-based substrate is 0.05∼ 3:1 in combination with the iron absorption effect and physical properties. In one embodiment, the mass ratio of the iron absorption promoter to iron in the iron-based substrate is 0.15∼1:1.

[0053] In one embodiment, the absorbable iron-based implantable device further includes an active drug. The active drug may be coated directly on the iron-based substrate, or filled on the iron-based substrate, or dispersed in a film formed from the iron absorption promoter, or dispersed in the degradable polymer layer.

[0054] The active drug is at least one selected from antiangiogenic drugs, antiplatelet drugs, antithrombotic drugs, anti-inflammatory drugs, and anti-sensitizing drugs.
In particular, the antiangiogenic drug is at least one selected from taxol, rapamycin and rapamycin derivatives. The antiplatelet drug is cilostazol. The antithrombotic drug is heparin. The anti-inflammatory drug is dexamethasone. The anti-sensitizing drug is at least one selected from calcium gluconate, chlorpheniramine and cortisone.

[0055] An iron absorption promoter is attached to the iron-based substrate of the absorbable iron-based implantable device described above, the iron absorption promoter being a polymer containing an antioxidant structural unit. After the absorbable iron-based implantable device is implanted into a body, as the absorbable iron-based implantable device is gradually and slowly degraded, an antioxidant is gradually released, thereby enabling a long-acting effect and effectively delaying the release rate of the antioxidant, and the antioxidant which is released by the iron absorption promoter is interacted with an iron corrosion product more fully during the gradual corrosion process of the iron-based substrate, thereby promoting the absorption of the iron corrosion product.

[0056] The absorbable iron-based implantable device is a cardiovascular stent, a cerebrovascular stent, a peripheral vascular stent, a biliary tract stent, an esophageal stent, an airway stent, an occluding device, an orthopaedic implant and the like.

[0057] For preparation of the above-mentioned absorbable iron-based implantable device, first an iron-based substrate is prepared, and then an iron absorption promoter and/or a drug-containing degradable polymer layer and the like are formed on the iron-based substrate. For example, a lumen iron-based substrate may be formed by laser cutting, and then an iron absorption promoter and/or drug-containing degradable polymer layer may be formed on the iron-based substrate by plasma spraying, ultrasonic atomization spraying, and the like.

[0058] The above-mentioned iron absorption promoter is commercially available or is obtained by polymerization using a polymerization method. For instance, a melt polymerization process is used to copolymerize an antioxidant and a polymer monomer to form an iron absorption promoter, for example, the melt polymerization process is used to form a polylactic acid vitamin E copolymer. Alternatively, a ring-opening polymerization is used to form a copolymer of an antioxidant and a polymer monomer, for example, ascorbic acid is used as an initiator to initiate ring-opening polymerization of caprolactone to form ascorbic acid polycaprolactone copolymer. As another example, vitamin C (ascorbic acid), anhydrous potassium carbonate, and N, N-dimethylformamide are dissolved and mixed to react to form a benzyl-protected vitamin C precursor. After the benzyl protected vitamin C precursor is dissolved in dichloromethane, the solution of acrylamide is slowly added dropwise to form an acrylate-modified benzyl-protected vitamin C monomer. A polylactic acid homopolymer is formed by ring-opening polymerization of L-type lactide. The homopolymer and the vitamin C precursor are synthesized under the condition of copper bromide and anhydrous toluene to form a block compolyer which is then debenzylated by hydrogen to obtain polylactic acid-block-polyascorbic acid acrylate copolymer.

[0059] The absorbable iron-based implantable device described above are further illustrated by the following examples.

[0060] The following characterization and test methods are employed in the following embodiments:

1. Characterization of the effect of promoting the iron absorption



[0061] Taking an iron-based alloy vascular stent containing an iron absorption promoter as an example, a test that an iron-based alloy stent containing the iron absorption promoter was implanted into a healthy mini porcine coronary artery model was performed to detect the absorption/metabolism percentage of iron in a blood vessel where the iron-based alloy vascular stent was positioned, and the effect of promoting the iron absorption by the iron absorption promoter in vivo is evaluated by the absorption/metabolism percentage of iron. The method was as follows: measuring the mass of iron in the implanted iron-based alloy vascular stent as Mo, then implanting iron-based alloy vascular stent containing the iron absorption promoter in the same batch and same specification into a porcine coronary artery, taking out the iron-based alloy vascular stent and a blood vessel segment where the iron-based alloy vascular stent was positioned after 36 months, carefully trimming redundant matters such as adipose tissue and myocardial tissue surrounding the outer membrane of the blood vessel to ensure the length of the blood vessel equivalent to that of the iron-based alloy vascular stent implanted therein, measuring the iron content in the iron-based alloy vascular stent as well as the blood vessel segment where the iron-based alloy vascular stent was positioned as M1, and the iron ion content in the blank blood vessel was too low and can be ignored herein. Thus during the implantation period, the iron absorption/metabolism percentage was W, W = (M0 - M1)/M0100%.

[0062] Here, the method for testing the iron content was as follows: digesting the stent or the stent together with the blood vessel in a microwave digestion instrument by using concentrated nitric acid, then testing the concentration of iron ion in the solution by using an Agilent 240FS atomic absorption spectrometer under the conditions of a wavelength of 248.3 nm, a slit of 0.2 nm, acetylene as combustion-supporting gas and a flow rate of 2.0 L/min, and further calculating the mass of iron in the sample.

[0063] The better the effect of promoting iron absorption by the iron absorption promoter, the higher the percentage of iron absorption/metabolism. For an iron-based alloy implantable device without an antioxidant or an iron-based alloy implantable device containing a small molecular antioxidant, the iron absorption/metabolism percentage was generally within 15% after implantation into a porcine coronary artery for 36 months, while after adding a high molecular iron absorption promoter, the iron absorption/metabolism percentage was more than 15%, and the most desirable effect of promoting iron absorption was that the iron absorption/metabolism percentage equaled to 100%.

2. The method for detecting the weight-average molecular weight of the polymer:



[0064] The weight-average molecular weight of the polymer was detected using a GPC-multi-angle light scattering detector from Wyatt, USA, combined with a molecular weight test system. The test system included a liquid phase pump and a sample injector from Agilent, USA, an Agilent PL MIXED-C type GPC column (size: 7.5 X 300mm, 5 microns) from Agilent, USA, and a multi-angle light scattering detector and a differential detector from Wyatt, USA. the detection condition was as follows: fluid phase: tetrahydrofuran; pump rate: 1 mL/min; loading volume of sample: 100 µL; laser wavelength: 663.9 nm; test temperature: 35 °C.

Embodiment 1



[0065] Proanthocyanidin polymer having a weight-average molecular weight of 1000 was dissolved in ethyl acetate to formulate a solution having the concentration of the proanthocyanidin polymer of 10 mg/mL, the formulated solution was then uniformly sprayed on the inner surface and the outer surface of an iron-based alloy coronary stent substrate having a nominal diameter of 4.0 mm and a wall thickness of 60 microns to form an iron absorption promoter coating having a thickness of 5 microns, thus obtaining an iron-based alloy coronary stent. Here, the mass ratio of the iron absorption promoter to iron in the iron-based alloy coronary stent substrate was 0.05: 1. A polylactic acid (having a weight-average molecular weight of 20,000) rapamycin-loaded coating having a thickness of 3 microns was continuously sprayed on the surface of the iron absorption promoter coating to obtain the iron-based alloy coronary stent. The prepared iron-based alloy coronary stent was implanted into a mini porcine coronary artery, maintaining an overdilation ratio in the range of 1.1: 1 to 1.2: 1 in the implantation process. A follow-up was performed 36 months after implantation, the remaining iron-based alloy coronary stent and surrounding vascular tissue thereof were removed, and the percentage of iron metabolized by the tissue tested as described above was 20%.

Embodiment 2



[0066] Tocopherol polyethylene glycol maleate having a weight-average molecular weight of 5000 was dissolved in ethyl acetate to formulate a solution having the concentration of tocopherol polyethylene glycol maleate of 10 mg/mL, the formulated solution was then uniformly sprayed on the inner surface and the outer surface of an iron-based alloy coronary stent substrate having a nominal diameter of 3.0 mm and a wall thickness of 50 microns to form an iron absorption promoter coating having a thickness of 10 microns, thus obtaining an iron-based alloy coronary stent. Here, the mass ratio of the iron absorption promoter to iron in the iron-based alloy coronary stent substrate was 0.15: 1. The prepared iron-based alloy coronary stent was implanted into a mini porcine coronary artery, maintaining an overdilation ratio in the range of 1.1: 1 to 1.2: 1 in the implantation process. A follow-up was performed 36 months after implantation, the remaining iron-based alloy coronary stent and surrounding vascular tissue thereof were removed, and the percentage of iron metabolized by the tissue tested as described above was 26%.

Embodiment 3



[0067] Polylactic acid block polycysteine coupled glutathione having a weight-average molecular weight of 10,000 was dissolved in ethyl acetate to formulate a solution having a concentration of 5 mg/mL, the formulated solution was then uniformly sprayed on the inner surface and the outer surface of an iron-based alloy coronary stent substrate having a nominal diameter of 3 mm and a wall thickness of 50 microns to form an iron absorption promoter coating having a thickness of 15 microns, thus obtaining an iron-based alloy coronary stent. Here, the mass ratio of the iron absorption promoter to iron in the iron-based alloy coronary stent substrate was 0.25: 1. The prepared iron-based alloy coronary stent was implanted into a mini porcine coronary artery, maintaining an overspread ratio in the range of 1.1: 1 to 1.2: 1 in the implantation process. A follow-up was performed 36 months after implantation, the remaining iron-based alloy coronary stent and surrounding vascular tissue thereof were removed, and the percentage of iron metabolized by the tissue tested as described above was 30%.

Embodiment 4



[0068] Polylactic acid vitamin E copolymer having a weight-average molecular weight of 50,000 was dissolved in dichloromethane to formulate a solution having the concentration of 5 mg/mL, the formulated solution was then uniformly sprayed on the inner surface and the outer surface of an iron-based alloy coronary stent substrate having a nominal diameter of 3.0 mm and a wall thickness of 50 microns to form an iron absorption promoter coating having a thickness of 15 microns, a polylactic acid (having a weight-average molecular weight of 20,000) paclitaxel-loaded drug layer having a thickness of 3 microns was continuously sprayed on the surface of the iron absorption promoter coating to obtain an iron-based alloy coronary stent. Here, the mass ratio of the iron absorption promoter to iron in the iron-based alloy coronary stent substrate was 0.25: 1. The prepared iron-based alloy coronary stent was implanted into a mini porcine coronary artery, maintaining an overdilation ratio in the range of 1.1: 1 to 1.2: 1 in the implantation process. A follow-up was performed 36 months after implantation, the remaining iron-based alloy coronary stent and surrounding vascular tissue thereof were removed, and the percentage of iron metabolized by the tissue tested as described above was 35%.

Embodiment 5



[0069] Lipoic acid polylysine polyethylene glycol copolymer having a weight-average molecular weight of 100,000 was dissolved in ethyl acetate to formulate a solution having the concentration of 10 mg/mL, the formulated solution was then uniformly sprayed on the inner surface and the outer surface of an iron-based alloy coronary stent substrate having a nominal diameter of 3.0 mm and a wall thickness of 50 microns to form an iron absorption promoter coating having a thickness of 25 microns, thus obtaining an iron-based alloy coronary stent. Here, the mass ratio of the iron absorption promoter to iron in the iron-based alloy coronary stent substrate was 0.5: 1. The prepared iron-based alloy coronary stent was implanted into a mini porcine coronary artery, maintaining an overdilation ratio in the range of 1.1: 1 to 1.2: 1 in the implantation process. A follow-up was performed 36 months after implantation, the remaining iron-based alloy coronary stent and surrounding vascular tissue thereof were removed, and the percentage of iron metabolized by the tissue tested as described above was 40%.

Embodiment 6



[0070] Ascorbic acid polycaprolactone copolymer having a weight-average molecular weight of 300,000, polylactic acid having a weight-average molecular weight of 100,000 and dexamethasone were dissolved in ethyl acetate based on a blending ratio of 1: 1: 1 by mass to formulate a solution having a total concentration of 6 mg/mL, the formulated solution was then uniformly sprayed on the inner surface and the outer surface of an iron-based alloy coronary stent substrate having a nominal diameter of 3.0 mm and a wall thickness of 50 microns to form a blended coating containing an iron absorption promoter with a thickness of 25 microns, thus obtaining an iron-based alloy coronary stent. Here, the mass ratio of the iron absorption promoter to iron in the iron-based alloy coronary stent substrate was 0.5: 1. The prepared iron-based alloy coronary stent was implanted into a mini porcine coronary artery, maintaining an overdilation ratio in the range of 1.1: 1 to 1.2: 1 in the implantation process. A follow-up was performed 36 months after implantation, the remaining iron-based alloy coronary stent and surrounding vascular tissue thereof were removed, and the percentage of iron metabolized by the tissue tested as described above was 45%.

Embodiment 7



[0071] Polylactic acid block polyascorbic acid acrylate having a weight-average molecular weight of 500,000 was dissolved into trichloromethane to formulate a solution having a concentration of 1.5 mg/mL, the formulated solution was then uniformly sprayed on the inner surface and the outer surface of an iron-based alloy coronary stent substrate having a nominal diameter of 2.5 mm and a wall thickness of 40 microns to form an iron absorption promoter coating having a thickness of 33 microns, thus obtaining an iron-based alloy coronary stent. Here, the mass ratio of the iron absorption promoter to iron in the iron-based alloy coronary stent substrate was 1: 1. The prepared iron-based alloy coronary stent was implanted into a mini porcine coronary artery, maintaining an overdilation ratio in the range of 1.1: 1 to 1.2: 1 in the implantation process. A follow-up was performed 36 months after implantation, the remaining iron-based alloy coronary stent and surrounding vascular tissue thereof were removed, and the percentage of iron metabolized by the tissue tested as described above was 55%.

Embodiment 8



[0072] Lipoic acid glucan copolymer having a weight-average molecular weight of 500,000 was dissolved in ethyl acetate to formulate a solution having the concentration of the lipoic acid glucan copolymer of 2 mg/mL, the formulated solution was then uniformly sprayed on the inner surface and the outer surface of an iron-based alloy coronary stent substrate having a nominal diameter of 2.5 mm and a wall thickness of 40 microns to form an iron absorption promoter coating having a thickness of 50 microns, thus obtaining an iron-based alloy coronary stent. Here, the mass ratio of the iron absorption promoter to iron in the iron-based alloy coronary stent substrate was 2: 1. The prepared iron-based alloy coronary stent was implanted into a mini porcine coronary artery, maintaining an overdilation ratio in the range of 1.1: 1 to 1.2: 1 in the implantation process. A follow-up was performed 36 months after implantation, the remaining iron-based alloy coronary stent and surrounding vascular tissue thereof were removed, and the percentage of iron metabolized by the tissue tested as described above was 60%.

Embodiment 9



[0073] Lipoic acid polyaspartic acid polyethylene glycol copolymer having a weight-average molecular weight of 100,000 (the preparation method is performed according to the method disclosed in CN1055242722 A) is dissolved in ethyl acetate to formulate a solution having the concentration of 10 mg/mL, the formulated solution was then uniformly sprayed on the inner surface and the outer surface of an iron-based alloy coronary stent substrate having a nominal diameter of 2.5 mm and a wall thickness of 30 microns to form an iron absorption promoter coating having a thickness of 50 microns, thus obtaining an iron-based alloy coronary stent. Here, the mass ratio of the iron absorption promoter to iron in the iron-based alloy coronary stent substrate was 3: 1. The prepared iron-based alloy coronary stent was implanted into a mini porcine coronary artery, maintaining an overdilation ratio in the range of 1.1: 1 to 1.2: 1 in the implantation process. A follow-up was performed 36 months after implantation, the remaining iron-based alloy coronary stent and surrounding vascular tissue thereof were removed, and the percentage of iron metabolized by the tissue tested as described above was 60%.

Comparative Example 1



[0074] Proanthocyanidin having a molecular weight of 594 was dissolved in ethanol to formulate a solution having a concentration of the proanthocyanidin of 10 mg/mL, the formulated solution was then uniformly sprayed on the inner surface and the outer surface of an iron-based alloy coronary stent substrate having a nominal diameter of 4.0 mm and a wall thickness of 60 microns to form an iron absorption promoter coating having a thickness of 5 microns, thus obtaining an iron-based alloy coronary stent. Here, the mass ratio of proanthocyanidin to iron in the iron-based alloy coronary stent substrate was 0.05: 1. The prepared iron-based alloy coronary stent was implanted into a mini porcine coronary artery, maintaining an overdilation ratio in the range of 1.1: 1 to 1.2: 1 in the implantation process. A follow-up was performed 36 months after implantation, the remaining iron-based alloy coronary stent and surrounding vascular tissue thereof were removed, and the percentage of iron metabolized by the tissue tested as described above was 10%.

Comparative Example 2



[0075] Vitamin C was dissolved in purified water to formulate a solution having a concentration of vitamin C of 10 mg/mL, the formulated solution was then uniformly sprayed on the inner surface and the outer surface of an iron-based alloy coronary stent substrate having a nominal diameter of 2.5 mm and a wall thickness of 40 microns to form an iron absorption promoter coating having a thickness of 33 microns, thus obtaining an iron-based alloy coronary stent. Here, the mass ratio of vitamin C to iron in the iron-based alloy coronary stent substrate was 1: 1. The prepared iron-based alloy coronary stent was implanted into a mini porcine coronary artery, maintaining an overdilation ratio in the range of 1.1: 1 to 1.2: 1 in the implantation process. A follow-up was performed 36 months after implantation, the remaining iron-based alloy coronary stent and surrounding vascular tissue thereof were removed and the percentage of iron metabolized by the tissue tested as described above was 15%.

[0076] It can be seen that after implantation of the iron-based alloy coronary stents of Embodiments 1-9, the percentage of iron metabolized by the tissue is higher than that of Comparative Example 1 and Comparative Example 2, indicating that the iron absorption promoter of Embodiments 1-9 does promote a long-acting iron absorption.

[0077] The various features of the above-mentioned embodiments may be combined in any way, and in order to simplify the description, not all possible combinations of the features of the above-mentioned embodiments are described, however, as long as there is no conflict between these features, they should be considered to be within the scope of the description.

[0078] The embodiments described above represent only a few embodiments of the present disclosure, the description of which is specific and detailed, but should not be construed to limit the scope of the present disclosure. It should be noted that several variations and modifications may be made by those of ordinary skill in the art without departing from the spirit of the present disclosure, which all fall within the scope of the present disclosure.


Claims

1. An absorbable iron-based implantable device, comprising:
an iron-based substrate and an iron absorption promoter attached to the iron-based substrate, wherein the iron absorption promoter is a polymer, and an antioxidant structural unit is contained in the molecular chain of the iron absorption promoter.
 
2. The absorbable iron-based implantable device of claim 1, wherein the iron absorption promoter is capable of being degraded to release an antioxidant.
 
3. The absorbable iron-based implantable device of claim 2, wherein the antioxidant is at least one selected from the group consisting of: ascorbic acid, procyanidin, vitamin E, glutathione, and lipoic acid.
 
4. The absorbable iron-based implantable device of claim 1, wherein the iron absorption promoter has a weight-average molecular weight of 1,000 to 500,000.
 
5. The absorbable iron-based implantable device of claim 1, wherein the iron absorption promoter is a procyanidin polymer.
 
6. The absorbable iron-based implantable device of claim 1, wherein the iron absorption promoter further comprises at least one degradable polymeric structural unit.
 
7. The absorbable iron-based implantable device of claim 1, wherein the iron absorption promoter further comprises at least one non-degradable polymeric structural unit.
 
8. The absorbable iron-based implantable device of claim 6, wherein the degradable polymer is at least one selected from the group consisting of: degradable polyester, polyamino acid, polyanhydride, and glucan.
 
9. The absorbable iron-based implantable device of claim 8, wherein the degradable polyester is at least one selected from the group consisting of: polylactic acid, polyglycolic acid, polysuccinate, poly(β-hydroxybutyrate), polycaprolactone, and polyethylene adipate.
 
10. The absorbable iron-based implantable device of claim 8, wherein the polyamino acid is at least one selected from the group consisting of: polylysine, polyaspartic acid, polycysteine, polymethionine, polyornithine, and polyglutamic acid.
 
11. The absorbable iron-based implantable device of claim 8, wherein the polyanhydride is at least one selected from the group consisting of: polyoxalate anhydride, polybutanedioic anhydride, polyadipic anhydride, polysebacic anhydride, polydodecanoic anhydride, polycitric anhydride, polymalic anhydride, polysuccinic anhydride, polytartaric anhydride, polyitaconic anhydride, and polymaleic anhydride.
 
12. The absorbable implantable device of claim 7, wherein the non-degradable polymer is at least one selected from the group consisting of: polyethylene glycol, polyacrylate, poly succinate, polycarbonate, polyethylene vinyl acetate, poly(n-butyl methacrylate), polystyrene, polyvinylidene fluoride, polyvinyl pyrrolidone, and polyhexafluoroethylene.
 
13. The absorbable iron-based implantable device of claim 1, wherein the mass ratio of the iron absorption promoter to iron in the iron-based substrate is 0.05∼3: 1.
 
14. The absorbable iron-based implantable device of claim 13, wherein the mass ratio of the iron absorption promoter to iron in the iron-based substrate is 0.15∼1: 1.
 
15. The absorbable iron-based implantable device of claim 1, wherein the iron absorption promoter is attached to a surface of the iron-based substrate or the iron absorption promoter is filled inside of the iron-based substrate.
 
16. The absorbable iron-based implantable device of claim 1, wherein the absorbable iron-based implantable device is a cardiovascular stent, a cerebrovascular stent, a peripheral vascular stent, a biliary stent, an esophageal stent, an airway stent, an occluding device, or an orthopedic implant.
 
17. The absorbable iron-based implantable device of claim 1, wherein the absorbable iron-based implantable device further comprises an active drug attached to the iron-based substrate, wherein the active drug is at least one selected from antiangiogenic drugs, antiplatelet drugs, antithrombotic drugs, anti-inflammatory drugs, and anti-sensitizing drugs.
 





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Cited references

REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description