Methods for making oxidation resistant polymeric material
Abstract
This record has no abstract on file.
Term
Projected expiry 30 January 2032.
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21 claims: 3 independent, 18 dependent
- 1For medical implants, A wear-resistant non-oxidizing cross-linked ultra-high molecular weight polyethylene (UHMWPE) mixture containing detectable residual radicals, according to the following steps:a) The UHMWPE substance is mixed with α-tocopherol (vitamin E), b) the UHMWPE mixture obtained in a) above is solidified, and c) the solidified UHMWPE mixture at a temperature lower than the melting point of the UHMWPE mixture from room temperature. D) From room temperature to a temperature below the melting point of the UHMWPE mixture Below a range of temperatures In, the heated solidified UHMWPE mixture is irradiated with ionizing radiation having a radiation dose of 50 kGy to 1,000 kGy to form a wear-resistant non-oxidizing crosslinked UHMWPE mixture containing detectable residual radicals, and e) step. Before and after the irradiation with d), the solidified UHMWPE mixture is machined so that α-tocopherol (vitamin E) is leached out of the UHMWPE mixture. Prevent, A wear-resistant non-oxidizing cross-linked UHMWPE mixture, which is obtained by a method comprising forming a wear-resistant non-oxidizing cross-linked UHMWPE mixture containing detectable residual radicals.
- 16For medical implants, A wear-resistant non-oxidizing cross-linked ultra-high molecular weight polyethylene (UHMWPE) mixture containing detectable residual radicals, according to the following steps:a) Solidify a UHMWPE mixture consisting of a mixture of UHMWPE substances containing one or more α-tocopherols (vitamin E), b) heat the solidified UHMWPE mixture from room temperature below the melting point of the UHMWPE mixture. C) From room temperature to a temperature below the melting point of the UHMWPE mixture. Below a range of temperatures In, the heated solidified UHMWPE mixture is irradiated with ionizing radiation having a radiation dose of 50 kGy to 1,000 kGy to form a wear-resistant non-oxidizing crosslinked UHMWPE mixture containing detectable residual radicals, and d) step. Before and after irradiation with c), the solidified UHMWPE mixture is machined so that α-tocopherol (vitamin E) is leached out of the UHMWPE mixture. Prevent, A wear-resistant non-oxidizing cross-linked UHMWPE mixture, which is obtained by a method comprising forming a wear-resistant non-oxidizing cross-linked UHMWPE mixture containing detectable residual radicals.
- 19For medical implants, A wear-resistant non-oxidizing cross-linked ultra-high molecular weight polyethylene (UHMWPE) mixture containing detectable residual radicals, according to the following steps:a) A solidified mixture of UHMWPE substances containing one or more α-tocopherols (vitamin E) is heated from room temperature to a temperature lower than the melting point of the UHMWPE mixture, and b) from room temperature to a temperature lower than the melting point of the UHMWPE mixture. For up to Below a range of temperatures In, the heated solidified UHMWPE mixture is irradiated with ionizing radiation having a radiation dose of 50 kGy to 1,000 kGy to form a wear-resistant non-oxidizing crosslinked UHMWPE mixture containing detectable residual radicals, and c) step. Before and after irradiation with b), the solidified UHMWPE mixture is machined so that α-tocopherol (vitamin E) is leached out of the UHMWPE mixture. Prevent, A wear-resistant non-oxidizing cross-linked UHMWPE mixture, which is obtained by a method comprising forming a wear-resistant non-oxidizing cross-linked UHMWPE mixture containing detectable residual radicals.
Independent claims3
225 paragraphs, as filed
Field of invention
This application claims priority to US Application No. 60 / 440,389 filed on January 16, 2003, which is incorporated herein by reference in its entirety.
The present invention relates to a method for producing an oxidation-resistant medical device containing a polymer substance. Methods of doping polyethylene with an antioxidant, such as Vitamin E, and the substances used therein are also provided.
Background of the invention
Oxidation-resistant cross-linked polymer materials, such as ultra-high molecular weight polyethylene (UHMWPE), are desired in medical devices because they significantly increase the wear resistance of the device. A preferred cross-linking method is by exposing UHMWPE to ionizing radiation. However, in addition to cross-linking, ionizing radiation also generates residual radicals that cause oxidative embrittlement. Melting is used after irradiation to remove the crystals and rebond the residual radicals to each other. Melting is used after irradiation to reduce the oxidative potential associated with residual radicals. However, post-irradiation melting reduces the crystallinity of UHMWPE, which in turn reduces the yield strength, extreme tensile strength, modulus and fatigue strength of UHMWPE. Such highly crosslinked UHMWPE (irradiated and melted) is not suitable for certain applications that require high fatigue resistance; that is, long-term fatigue damage can impair the performance of medical devices. Therefore, it is necessary to remove the residual radical or the oxidizing action of the residual radical without melting. According to such a method, the mechanical properties and fatigue resistance will be maintained while maintaining the crystallinity of the irradiated UHMWPE.
It is generally known that mixing polyethylene powder with antioxidants before consolidation can improve the oxidation resistance of polyethylene materials. Antioxidants such as vitamin E and β-carotene were mixed with UHMWPE powder or particles by several researchers in an attempt to improve wear resistance (Mori et al.p. 1017, Hand). -out at the 47th Annual Meeting, Orthopedic Res Soc, February 25-28,2001, San Francisco, CA; McKellop et al. WO01 / 80778; Schaffner et al. EP0995450; Hahn D.US5,827,904; Lidgren et al.US6,448,315 ). Mori et al. Also noted that irradiation did not reduce the oxidation resistance of antioxidant polyethylene. Researchers (McKellop et al. WO01 / 80778; Schaffner et al. EP0995450; Hahn D. US5,827,904; see Lidgren et al., US6,448,315) describes mixing polyethylene powder with an antioxidant and then solidifying the antioxidant-powder mix to obtain oxidation resistant polyethylene. It was. When resin powder, flakes or particles are mixed with vitamin E and then solidified, the polymer material turns yellow (see, eg, US6,448,315). In addition, the addition of antioxidants to UHMWPE prior to irradiation may interfere with UHMWPE cross-linking during irradiation. However, cross-linking is necessary to increase the abrasion resistance of the polymer. Therefore, it would be preferable to dope the medical implant or polymer member thereof in its solidified solid form, eg, in raw materials, machined products or molded products, with antioxidants. However, this has not been possible in the past.
Abstract of the invention
The present invention generally relates to a method for producing an oxidation resistant medical device composed of one or more polymeric substances. More specifically, the present invention relates to a method for producing an antioxidant-doped medical device containing cross-linked polyethylene, for example, cross-linked ultra-high molecular weight polyethylene (UHMWPE), and substances used therein. More specifically, the present invention relates to a method for producing an antioxidant-doped non-oxidizing medical device containing a residual radical-containing cross-linked polyethylene, for example, irradiated ultra-high molecular weight polyethylene (UHMWPE), and a substance used therein.
On the one hand, the present invention provides a method for producing a crosslinked polymeric material, comprising: a) preparing a solidified crosslinked polymeric material irradiated with ionizing radiation; and b) doping the solidified crosslinked polymeric material by diffusion with an antioxidant. provide.
On the other side, the present invention a) prepares a solidified crosslinked polymer material irradiated with ionizing radiation; b) doped the solidified crosslinked polymer material by diffusion with an antioxidant; and c) below the melting point of the solidified crosslinked polymer material. Provided is a method for producing a crosslinked polymer material, which comprises a step of heating the solidified crosslinked polymer material to the temperature of.
On the other hand, in the present invention, the crosslinked polymer material is immersed in a solution of about 50% by weight of antioxidant in an alcohol such as ethanol, and the crosslinked polymer material is CO.<sub>2</sub>Provided is a method for producing a crosslinked polymer substance which is diffused with an antioxidant in a supercritical fluid such as.
On the other hand, the present invention a) puts the solidified crosslinked polymeric material into a pressurizing chamber; b) in the chamber with an antioxidant, in neat form (about 100%), or with an antioxidant and alcohol, eg ethanol 50. % A method of producing a crosslinked polymeric material comprising the steps of filling with a solution such as a mixture; and c) pressurizing the chamber to enhance the diffusion of the antioxidant into the solidified crosslinked polymeric material.
On the other side, the present invention a) dope the solidified polymer material by diffusion with an antioxidant; b) irradiate the solidified polymer material with ionizing radiation to form the solidified crosslinked polymer material; and c) the solidified crosslinked polymer. Provided is a method for producing a crosslinked polymeric material, comprising the steps of annealing the solidified crosslinked polymeric material at a temperature lower or higher than the melting point of the material.
According to the other aspect, the present invention a) solidifies the polymer material; b) irradiates the polymer material with ionizing radiation to form a solidified crosslinked polymer material; c) diffuses the solidified crosslinked polymer material with an antioxidant. To provide a method for producing a crosslinked polymer material, which comprises steps of doping; and d) heating the solidified crosslinked polymer material at a temperature below the melting point of the solidified crosslinked polymer material.
On the other hand, the present invention a) prepares a polymeric substance; b) solidifies the polymeric substance; c) irradiates the solidified polymeric substance with ionizing radiation to form a solidified crosslinked polymeric substance; d) a solidified crosslinked polymer. Of medical implants, which consist of machining a substance to form a medical implant; and e) doping the medical implant with an antioxidant by diffusion to form an antioxidant-doped cross-linked medical implant. Provide a manufacturing method.
On the other side, the present invention a) prepares a solidified polymer material; b) irradiates the solidified polymer material with ionizing radiation to form a solidified crosslinked polymer material; c) machines the solidified crosslinked polymer material. Provided is a method for producing a medical implant, which comprises forming a medical implant; and d) precipitating the medical implant with an antioxidant to form an antioxidant-doped crosslinked medical implant.
On the other side, the present invention a) irradiates the solidified polymeric material with ionizing radiation to form a crosslinked polymeric material; b) machines the solidified crosslinked polymeric material to form a medical implant; and c). Provided is a method for producing a medical implant containing an antioxidant-doped crosslinked polymer substance, which comprises doping the medical implant with an antioxidant by diffusion.
On the other hand, the present invention a) machined a solidified polymer material to form a medical implant; b) diffused the medical implant with an antioxidant; and c) irradiated the medical implant. The present invention provides a method for producing a medical implant containing an antioxidant-doped cross-linked polymer substance, which comprises forming a medical implant containing the cross-linked polymer substance.
On the other side, the present invention a) irradiates the polymeric material with ionizing radiation to form a crosslinked polymeric material; and b) doped the crosslinked polymeric material by diffusion with an antioxidant so that the crosslinked polymeric material is solidified and crosslinked. Provided is a method for producing a medical implant containing a polymer substance, which comprises being annealed at a temperature lower than or higher than the melting point of the polymer substance.
On the other side, the present invention a) compress-molds a polymeric material into other pieces to form an interlocked hybrid material; b) irradiates the linked hybrid material with ionizing radiation to crosslink the linked hybrid. Provided is a method for making a medical implant containing a crosslinked polymeric material, comprising forming the material; and c) doping the crosslinked linked hybrid material by diffusion with an antioxidant.
On the other side, the present invention a) compresses the polymeric material into other pieces to form interface and linking hybrids; b) diffusing the linking hybrids with antioxidants; and c) linking. Provided is a method for producing a medical implant containing a crosslinked polymer substance, which comprises irradiating the hybrid substance with ionizing radiation to form a crosslinked linked hybrid substance.
On the other hand, the present invention a) directly compresses the polymer material to form a medical implant; b) irradiates the medical implant to crosslink the polymer material; c) sterilizes the irradiated medical implant. Diffusion-doped with oxidant; d) Irradiated antioxidant-doped medical implant packaged; and e) Packaged irradiation antioxidant-doped medical implant sterilized by ionizing radiation or gas sterilization and cross-linked sterile Provided is a method for producing a sterile medical implant containing a crosslinked polymer substance, which comprises forming a medical implant.
On the other side, the present invention a) machined a solidified polymer material to form a medical implant; b) irradiated the medical implant to form a medical implant containing a crosslinked polymer material; c. ) Diffusion-doped medical implants with antioxidants; d) Packaged irradiated antioxidant-doped medical implants; and e) Sterilized and cross-linked medical implants by ionizing radiation or gas sterilization. Provided is a method for producing a sterile medical implant containing an antioxidant-doped crosslinked polymer substance, which comprises forming a sterile medical implant.
On the other side, the present invention a) dope the polymeric material by diffusion with an antioxidant; b) compress-mold the polymeric material into other pieces to form interface and linking hybrid material; and c) linking hybrid. Provided is a method for producing a medical implant containing a crosslinked polymer substance, which comprises irradiating the substance with ionizing radiation to form a crosslinked linked hybrid substance.
On the other side, the present invention a) directly compresses polymer material to form medical implants; b) irradiates medical implants with ionizing radiation to form solidified crosslinked medical implants; and c. ) Provided is a method for producing a medical implant containing a crosslinked polymer substance, which comprises doping a solidified crosslinked medical implant with an antioxidant by diffusion.
On the other side, the present invention a) machined solidified polymer material to form a medical implant; b) irradiated the medical implant to form a medical implant containing a crosslinked polymer material; and c) Provided is a method for producing a medical implant containing an antioxidant-doped crosslinked polymer substance, which comprises doping the medical implant with an antioxidant by diffusion.
On the other hand, the present invention a) directly compresses polymer material to form medical implants; b) diffusing medical implants with antioxidants; c) packaging medical implants; And d) Provided is a method for producing a medical implant containing a crosslinked polymer substance, which comprises irradiating a packaged medical implant with ionizing radiation to form a solidified crosslinked sterile medical implant.
On the other hand, the present invention a) machined solidified polymer material to form medical implants; b) diffused the medical implants with antioxidants; c) packaged medical implants; And d) Provided is a method for producing a medical implant containing a crosslinked polymer substance, which comprises irradiating a packaged medical implant with ionizing radiation to form a solidified crosslinked sterile medical implant.
On the other side, the present invention is to a) place the solidified crosslinked polymer material into a pressure chamber; b) fill the chamber with an antioxidant; and c) enhance the diffusion of the antioxidant into the solidified crosslinked polymer material. Provided is a method for producing a crosslinked polymer substance, which comprises a step of pressurizing a room.
On the other side, the present invention a) irradiates off-the-shelf medical instruments made of solidified polymeric material with ionizing radiation to form solidified crosslinked polymeric material; and b) dope the solidified crosslinked polymeric material by diffusion with an antioxidant. The present invention provides a method for producing a medical device containing a crosslinked polymer substance, which comprises forming an antioxidant-doped solidified crosslinked polymer substance.
On the other side, the invention is a) dope of the packaged material by diffusion with an antioxidant; b) insert the medical device into the packaged material; c) seal and package the packaged material containing the medical device. Forming medical devices; and d) Oxidation resistance when exposed to sterilized or cross-linked doses of ionized radiation, consisting of ionizing or gas sterilizing the packaged medical device. Provide a method for manufacturing a package for a medical device.
On the other side, the present invention a) dozes the packaging material with an antioxidant by diffusion; b) inserts the pharmaceutical compound into the packaging material; c) seals and packages the packaging material containing the pharmaceutical compound. Forming pharmaceutical compounds; and d) Oxidation resistance when exposed to sterilized or cross-linked doses of ionizing radiation consisting of ionizing or gas sterilizing the packaged pharmaceutical compounds. Provided is a method for producing a package for a pharmaceutical compound.
On the other side, in the present invention, the implant is a tibial joint liner, a shoulder joint fossa, a patellar member, a finger joint member, an ankle joint member, an elbow joint member, a wrist joint member, an ankle joint member, a Bipolar type artificial hip joint. Tibial knee inserts, tibial knee inserts with reinforced metal and polyethylene posts, intervertebral discs, heart valves, joints, stents and artificial blood vessels, where the polymer material is polymer resin powder, polymer flakes, polymer particles, etc. or a mixture thereof. Provided is a method for producing a medical implant containing a crosslinked polymer substance.
On the other side, the present invention is a medical device in which the implant includes a balloon catheter, suture, tube and intravenous tube, and the polymer substance is a polymer resin powder, polymer flakes, polymer particles, etc. or a mixture thereof. , Provide a method for manufacturing a medical implant including a non-permanent implant containing a crosslinked polymer substance. Polymer balloons such as those described herein, eg, Polyester Block Copolyamide Polymers (PeBAX).<sup>R</sup>), Nylon and polyethylene terephthalate (PET) balloons are doped with Vitamin E and irradiated before, during or after doping.
On the other side, the present invention provides a method for producing a package for a medical device, which is oxidation resistant when the package is subjected to ionizing radiation sterilization or gas sterilization. Packages include barrier materials such as blow molded blister packs, heat shrinkable packages, heat sealed packages and the like or mixtures thereof.
On the other hand, the present invention comprises a) a solidified polymer material doped by diffusion with an antioxidant; and b) a crosslinked polymer material formed by irradiating the polymer material with ionizing radiation to form a solidified crosslinked polymer material. Provided is a method for manufacturing a medical implant containing.
On the one hand, to obtain sterile crosslinked medical implants, antioxidant-doped medical implants are packaged and sterilized by ionizing radiation or gas sterilization.
On the other hand, the polymeric material of the present invention is a polymeric resin powder, polymeric flakes, polymeric particles, etc. or a mixture thereof, the irradiation of which is carried out in an atmosphere containing about 1% to about 22% oxygen and a radiation dose. Is about 25kGy ~ about 1000kGy.
On the other hand, the polymeric material of the present invention is a polymeric resin powder, polymer flakes, polymer particles and the like or a mixture thereof, wherein the polymeric material contains gases such as nitrogen, argon, helium, neon and the like or combinations thereof. It is irradiated after solidification in an inert atmosphere, and the radiation dose is about 25 kGy to about 1000 kGy.
On the other hand, the polymeric material of the present invention is a solidified polymeric material, the solidification being carried out by compression molding in order to form a slab into which the medical device is machined.
On the other hand, the polymeric material of the present invention is a solidified polymeric material, the solidification being carried out by direct compression molding to form the final medical device.
On the other side, the polymeric material of the present invention is a solidified polymeric material, the solidification being carried out by compression molding into other pieces in order to form an interface and linked hybrid material.
On the other side, the present invention a) compress-molds a polymeric material into other pieces to form an interface and linked hybrid material; b) irradiates the linked hybrid material with ionizing radiation to obtain a crosslinked linked hybrid material. Provided are a method of making a medical implant containing a crosslinked polymeric material, comprising forming; and c) crosslinking and doping the crosslinked hybrid material with an antioxidant by diffusion.
According to one aspect, the invention consists of compressing a polymeric material into a metal or non-metallic piece, eg, another piece such as a metal, ceramic or polymer, to form an interface and a linked hybrid material, the interface of which Provided is a method for producing a medical implant containing a crosslinked polymer substance, which is a metal-polymer or a metal-ceramic interface.
Yet on the other side, the present invention a) compresses the polymer material into other pieces to form an interface and linked hybrid material; b) the linked hybrid material is an antioxidant, eg α such as Vitamin E. -Providing a method for the manufacture of a medical implant containing a crosslinked polymer material, comprising diffusing with tocopherol; and c) irradiating the linked hybrid material with ionizing radiation to form a crosslinked linked hybrid material.
Another aspect of the invention is that a) the polymer material is compression molded to form a medical implant; b) the medical implant is irradiated to crosslink the polymer material; c) the irradiated medical implant is an antioxidant. Diffusion and dope in; d) Package the irradiated antioxidant-doped medical implant; and e) Sterilize the packaged irradiation antioxidant-doped medical implant by ionizing radiation or gas sterilization and crosslink sterile. Provided is a method for producing a medical implant containing a crosslinked polymer substance, which comprises forming a medical implant.
On the other side, the invention a) machined solidified polymer material to form medical implants; b) irradiated medical implants to crosslink the polymer material; c) irradiated medical implants. Diffusion doped with antioxidants; d) Packaged irradiated antioxidant-doped medical implants; and e) Disinfect packaged irradiated antioxidant-doped medical implants by ionizing radiation or gas sterilization Provided is a method for producing a medical implant containing a crosslinked polymer substance, which comprises forming a crosslinked sterile medical implant.
According to the other side, the present invention a) compress-molds the polymeric material into other pieces to form interface and linking hybrids; b) diffuses the linking hybrids with antioxidants; and c). Provided is a method for producing a medical implant containing a crosslinked polymer substance, which comprises irradiating a linked hybrid substance with ionizing radiation to form a crosslinked linked hybrid substance.
On the other side, the present invention a) directly compresses polymer material to form medical implants; b) irradiates medical implants with ionizing radiation to form solidified crosslinked medical implants; and c. ) Provided is a method for producing a medical implant containing a crosslinked polymer substance, which comprises doping a solidified crosslinked medical implant with an antioxidant by diffusion.
On the other side, the present invention a) machined solidified polymer material to form medical implants; b) medical implants by irradiation with ionizing radiation to form solidified crosslinked medical implants; and c) Provided is a method for producing a medical implant containing a crosslinked polymer substance, which comprises doping a solidified crosslinked medical implant with an antioxidant by diffusion.
On the other hand, the present invention a) prepares a polymeric substance; b) solidifies the polymeric substance; c) dopeds the solidified polymeric substance by diffusion with an antioxidant; d) ionizes the antioxidant doped polymeric substance. A method for producing a medical implant, comprising irradiating with radiation to form an antioxidant-doped cross-linked polymer material; and e) machining the cross-linked polymer material to form an antioxidant-doped cross-linked medical implant. I will provide a.
On the other hand, the present invention a) prepares a solidified polymer material; b) doped the solidified polymer material with an antioxidant by diffusion; c) irradiates the antioxidant-doped polymer material with an ionizing radiation to prevent it. Provided is a method for producing a medical implant, comprising forming an oxidant-doped cross-linked polymer material; and d) machining the cross-linked polymer material to form an antioxidant-doped cross-linked medical implant.
On the other hand, the present invention a) prepares a polymeric material; b) solidifies the polymeric material; c) dipped the solidified polymeric material by diffusion with an antioxidant; d) machined the antioxidant doped polymeric material. For medical use, which comprises processing to form an antioxidant-doped polymer substance; and e) irradiating the antioxidant-doped cross-linked polymer substance with ionizing radiation to form an antioxidant-doped cross-linked medical implant. Provided is a method for manufacturing an implant.
On the other hand, the present invention a) prepares a solidified polymer material; b) dipped the solidified polymer material by diffusion with an antioxidant; c) machined the antioxidant doped polymer material to make an antioxidant. Provided is a method for producing a medical implant, which comprises forming a doped polymer substance; and d) irradiating the antioxidant-doped cross-linked polymer substance with ionizing radiation to form an antioxidant-doped cross-linked medical implant. ..
On the other hand, the present invention a) directly compresses polymer material to form medical implants; b) diffusing medical implants with antioxidants; c) packaging medical implants; And d) Provided is a method for producing a medical implant containing a crosslinked polymer substance, which comprises irradiating a packaged medical implant with ionizing radiation to form a solidified crosslinked sterile medical implant.
On the other hand, the present invention a) prepares a polymer substance; b) solidifies the polymer substance; c) processes the solidified polymer substance to form a medical implant; d) antioxidants the medical implant. Diffusion with an agent to form an antioxidant-doped medical implant; e) packaging the medical implant; and f) irradiating the packaged medical implant with ionizing radiation to the antioxidant-doped Provided is a method for manufacturing a medical implant, which comprises forming a cross-linked sterile medical implant.
On the other side, the invention a) prepares a solidified polymer material; b) machines the solidified polymer material to form a medical implant; c) diffuses the medical implant with an antioxidant. To form an antioxidant-doped medical implant; d) package the medical implant; and e) irradiate the packaged medical implant with ionizing radiation to obtain an antioxidant-doped cross-sterile medical implant. Provided is a method for manufacturing a medical implant, which comprises forming.
On the other hand, the present invention a) prepares a polymeric material; b) solidifies the polymeric material; c) dipped the solidified polymeric material by diffusion with an antioxidant to form an antioxidant-doped polymer material. ; d) Machining the antioxidant-doped polymer material to form a medical implant; e) Packaging the medical implant; and f) Irradiating the packaged medical implant with ionizing radiation, Provided is a method for manufacturing a medical implant, which comprises forming an antioxidant-doped cross-linked sterile medical implant.
On the other side, the present invention a) prepares a solidified polymer material; b) doped the solidified polymer material with an antioxidant by diffusion to form an antioxidant-doped polymer material; c) an antioxidant. Machined dope polymer material to form medical implants; d) package medical implants; and e) irradiate packaged medical implants with ionizing radiation to sterilize antioxidant-doped crosslinks. Provided is a method for manufacturing a medical implant, which comprises forming a medical implant.
On the other side, the present invention a) irradiates a solidified polymer material to form a crosslinked polymer material; b) machines the solidified crosslinked polymer material to form a medical implant; c) a medical implant. Diffusion-doped with antioxidant; d) Packaged irradiated antioxidant-doped medical implant; and e) Sterilized packaged medical implant by ionizing radiation or gas sterilization for cross-linked sterile medical use Provided is a method for producing a sterile medical implant containing an antioxidant-doped crosslinked polymer material, which comprises forming an implant.
On the other hand, the present invention a) doss the polymer material with an antioxidant; b) solidifies the antioxidant-doped polymer material; c) machines the solidified antioxidant-doped polymer material to antibacterial. Form an oxidant-doped medical implant; d) Irradiate the medical implant to form a medical implant containing an antioxidant-doped cross-linked polymer substance; e) Package the antioxidant-doped cross-linked medical implant ; And f) Manufacture of sterile medical implants containing anti-oxidant-doped cross-linked polymer material consisting of sterilizing packaged medical implants by ionizing radiation or gas sterilization to form cross-linked sterile medical implants. Provide a method.
On the other side, the present invention a) doss a polymer material with an antioxidant; b) solidifies an antioxidant-doped polymer material; c) irradiates the solidified polymer material with an antioxidant-doped cross-linked polymer material. D) Machine the solidified crosslinked polymer material to form a medical implant containing the antioxidant-doped cross-linked polymer material; e) Package the antioxidant-doped cross-linked medical implant; and f) Provided is a method for producing a sterile medical implant containing an antioxidant-doped crosslinked polymer substance, which comprises sterilizing a packaged medical implant by ionizing radiation or gas sterilization to form a crosslinked sterile medical implant. ..
On the other hand, the present invention a) dope the polymeric material by diffusion with an antioxidant; b) irradiate the antioxidant-doped polymer material with ionizing radiation to provide a crosslinked antioxidant-doped polymer material. Formed; and c) A method for making a medical implant containing a crosslinked polymeric material, comprising compressing the crosslinked antioxidant-doped polymer material into other pieces to form a crosslinked linked hybrid material. provide.
On the other side, the present invention a) irradiates the solidified polymer material with ionizing radiation to form a solidified crosslinked polymer material; b) directly compresses the polymer material to form a solidified crosslinked medical implant; and c) Provided is a method for producing a medical implant containing a crosslinked polymer substance, which comprises doping a solidified crosslinked medical implant with an antioxidant by diffusion.
On the other hand, the present invention a) dominates a polymeric material with an antioxidant; b) solidifies an antioxidant-doped polymer material; c) machines a solidified antioxidant-doped polymer material to provide anti-oxidant properties. Contains antioxidant-doped cross-linked polymer material, which comprises forming an antioxidant-doped medical implant; and d) irradiating the medical implant to form a medical implant containing an antioxidant-doped cross-linked polymer material. Provided is a method for manufacturing a medical implant.
On the other hand, the present invention a) doss a polymer material with an antioxidant; b) solidifies an antioxidant-doped polymer material; c) irradiates the solidified polymer material with an antioxidant-doped cross-linked polymer material. And d) A medical implant containing an antioxidant-doped cross-linked polymer material, which comprises machining the solidified cross-linked polymer material to form a medical implant containing the antioxidant-doped cross-linked polymer material. Providing a manufacturing method for.
On the other side, the present invention a) dominates off-the-shelf medical devices containing solidified polymer substances by diffusion with antioxidants to form anti-oxidant-doped polymer substances; and b) ionizing radiation on medical devices. Provided is a method for producing a non-permanent medical device containing a crosslinked polymer substance, which comprises irradiating with a crosslinked polymer substance to form a crosslinked polymer substance.
On the other side, the present invention provides a non-oxidizing crosslinked polymeric material containing detectable residual radicals.
On the other hand, the present invention provides non-oxidizing cross-linked medical implants, including permanent and non-permanent medical devices, containing detectable residual radicals.
On the other hand, the present invention a) prepares a polymer substance; b) solidifies the polymer substance; c) processes the solidified polymer substance to form a medical implant; d) ionizes the medical implant. To form a cross-linked medical implant by irradiating with; and e) Manufacture of a medical implant consisting of diffusing the medical implant with an antioxidant to form an antioxidant-doped cross-linked medical implant. Provide a method.
On the other side, the present invention a) prepares a solidified polymer material; b) machines the solidified polymer material to form a medical implant; c) irradiates the medical implant with ionizing radiation to prevent it. A method for producing a medical implant, which comprises forming an oxidant-doped cross-linked medical implant; and d) doping the medical implant with an antioxidant by diffusion to form an antioxidant-doped cross-linked medical implant. provide.
On the other hand, the present invention a) prepares a polymer substance; b) solidifies the polymer substance; c) processes the solidified polymer substance to form a medical implant; d) antioxidants the medical implant. Diffusion with agents to form antioxidant-doped medical implants; e) Medical implants consisting of irradiating medical implants with ionizing radiation to form antioxidant-doped cross-linked medical implants. Providing a manufacturing method for.
On the other side, the present invention a) prepares a solidified polymer material; b) machines the solidified polymer material to form a medical implant; c) diffuses the medical implant with an antioxidant. Provided is a method for manufacturing a medical implant, which comprises forming an antioxidant-doped medical implant; and d) irradiating the medical implant with ionizing radiation to form an antioxidant-doped cross-linked medical implant. To do.
On the other hand, the present invention a) prepares a polymeric substance; b) solidifies the polymeric substance; c) irradiates the polymeric substance with ionizing radiation to form a crosslinked polymeric substance; d) antioxidants the polymeric substance. Manufacture of medical implants comprising diffusing with an agent to form an antioxidant-doped cross-linked polymer material; and e) machining the polymer material to form an antioxidant-doped cross-linked medical implant. Provide a method.
On the other side, the present invention a) prepares a solidified polymer material; b) irradiates the polymer material with ionizing radiation to form a crosslinked polymer material; c) doped the polymer material with an antioxidant by diffusion. The present invention provides a method for producing a medical implant, which comprises forming an antioxidant-doped cross-linked polymer substance; and d) machining the polymer substance to form an antioxidant-doped cross-linked medical implant.
Another aspect of the invention is that a) the polymer material is prepared; b) the polymer material is compression molded to form a medical implant; c) the medical implant containing the interface or ligation hybrid material is antioxidant. Diffusion with an agent to form an antioxidant-doped medical implant; d) package the medical implant; and e) irradiate the packaged medical implant with ionizing radiation to form an antioxidant-doped medical implant. Provided is a method for manufacturing a medical implant, which comprises forming a cross-linked sterile medical implant. On the other side, the polymeric material is compression molded into other pieces or medical implants to form an interfacial or articulated hybrid material.
Another aspect of the invention is that a) the compression molded polymer material that forms the medical implant is prepared; b) the medical implant containing the interface or ligation hybrid material is dope by diffusion with an antioxidant to provide anti-treatment. Forming oxidant-doped medical implants; c) Packaging medical implants; and d) Irradiating packaged medical implants with ionizing radiation to form antioxidant-doped cross-linked sterile medical implants. Provided is a method for manufacturing a medical implant consisting of. On the other side, the polymeric material is compression molded into other pieces or medical implants to form an interfacial or articulated hybrid material.
Another aspect of the invention provides a method of increasing the homogeneity of an antioxidant in a doped polymer material by annealing the doped polymer material below the melting point of the doped polymer material.
Another aspect of the invention provides a method of increasing the uniformity of an antioxidant in a doped polymer material by annealing the doped polymer material above the melting point of the doped polymer material.
Figure 1 shows the penetration depth of vitamin E diffusion into UHMWPE at room temperature, 100 ° C, 120 ° C and 130 ° C.
Figure 2 shows the oxidation index as a function of the depth to one of the representative aged cubes of the number test group (TCRT group, RT1 group, RT16 group, TC100C16 group, 100C1 group, TC100C1 group and 100C16 group). It shows the characteristics. All cubes were made from irradiated polyethylene, four of which were doped with vitamin E under various conditions. The heat control cube was not treated with vitamin E. Vitamin E-doped cubes show less oxidation on the surface and inside of the sample than the corresponding heat control.
FIG. 3 shows the diffusion properties of vitamin E into unirradiated UHMWPE doped at 130 ° C for 96 hours as a function of the subsequent annealing time at 130 ° C.
Figure 4 outlines an example of the order in which UHMWPE is processed and doped at various stages.
Figure 5 outlines an example of the order in which UHMWPE is processed and doped at various stages.
Detailed description of the invention
The present invention provides a method of manufacturing an oxidation resistant crosslinked medical implant comprising a medical device, including permanent and non-permanent devices, and a package made of a polymeric material such as polyethylene. The present invention relates to a method of doping a solidified polyethylene such as UHMWPE before, during or after cross-linking the solidified polyethylene.
In one aspect of the invention, the doping of solidified polyethylene is carried out by diffusion of antioxidants, such as α-tocopherols such as vitamin E. According to one aspect of the invention, the diffusion of antioxidants is facilitated by increasing temperature and / or pressure.
According to another aspect of the invention, antioxidants are applied in pure form, for example as pure Vitamin E, or in various forms, including those dissolved in a solvent.
According to another aspect of the invention, the diffusion rate of the antioxidant into polyethylene is increased by increasing the concentration of the antioxidant solution, eg vitamin E solution.
According to another aspect of the invention, the diffusivity of antioxidants in polyethylene is determined by supercritical fluids such as supercritical CO.<sub>2</sub>(Ie, its temperature is higher than the supercritical temperature, the temperature is 31.3 ° C, the pressure is higher than the supercritical pressure, the pressure is 73.8 bar) and is increased by swelling the solidified polyethylene.
Generally, in the case of vitamin E as an antioxidant, for example, when a resin powder, flakes, particles or a mixture thereof are mixed with vitamin E and then solidified, the color of the polymeric substance changes to yellow. According to the present invention, post-solidification doping avoids exposure of vitamin E to high solidification temperatures and pressures and prevents discoloration of polymeric materials. The present invention can also reduce the thermal effect on antioxidants. Thermal action may reduce the effectiveness of antioxidants in protecting the polymeric material from oxidation.
Doping in the solidified state also forms an antioxidant gradient in the solidified polymeric material. Oxidation of polymeric materials in medical devices can dope a surface layer of a certain thickness, which is a durability issue. This can be done by simply immersing or immersing the final instrument, eg, the final medical implant, in, for example, pure Vitamin E or a solution of Vitamin E at a predetermined temperature for a predetermined time.
According to the methods described herein, antioxidants, such as vitamin E, are doped into the polymeric material before, during, or after irradiation (see, eg, FIGS. 4 and 5).
It may occur that the doped antioxidant leaches from the polymeric material used to make medical implants or medical devices during pre-use storage or in vivo use. For permanent medical devices, the in vivo period can be as long as the patient's remaining life, ranging from implantation of the device to death of the patient, for example 1 to 120 years. If leaching of the antioxidant is a problem, irradiation of the medical implant or medical device, or a portion thereof, may be performed after doping with the antioxidant. It ensures that the antioxidant is cross-linked to the host polymer by covalent bonding, thus preventing the loss of antioxidant from the medical implant or instrument.
According to another aspect of the invention, a polymeric substance such as a resin powder, flakes, particles or a mixture thereof is mixed with an antioxidant and then the mixture is solidified. The solidified antioxidant-doped polymer material can be machined for use as a member of medical implants or as a medical device.
According to another aspect of the invention, solidified polymeric materials such as solidified resin powders, molded sheets, blown films, tubes, balloons, flakes, particles or mixtures thereof form antioxidants such as α-tocopherols. Vitamin E to be taken, doped by diffusion. A solidified polymer substance, such as solidified UHMWPE, is immersed in a solution of 100% Vitamin E or alcohol, such as α-tocopherol in ethanol or isopropanol. Approximately 50% by weight of α-tocopherol solution in ethanol is CO<sub>2</sub>It is used to diffuse into UHMWPE while in contact with a supercritical fluid such as. Balloons, such as PeBAX<sup>R</sup>, Nylon and PET balloons are doped with Vitamin E and irradiated before, during or after doping.
The present invention presents medical devices made of highly cross-linked polyethylene containing metal pieces, such as Bipolar hip prostheses, tibial knee inserts with reinforced metal and polyethylene posts, intervertebral disc systems, and implants with surfaces that cannot be easily sterilized by gas sterilization. Also involved in the next processing step to make.
According to one aspect of the invention, the polyethylene member of the medical implant is in close contact with other materials such as metal mesh or back, non-metal mesh or back, tibial tray, patella tray or ostomy shell, where Polyethylenes such as resin powders, flakes and particles are compression molded directly onto these opposite surfaces. For example, polyethylene tibial inserts are manufactured by compression molding of polyethylene resin powder into tibial trays, metal meshes or backs, or non-metal meshes or backs. In the latter case, the mesh is shaped to act as a anchoring interface with bone, either through bone growth or the use of adhesives such as polymethylmethacrylate (PMMA) bone cement. These forms take various forms, including acetabular liners, tibial trays for full or single-partitioned knee implants, patella trays and glenoid members, ankles, elbows or finger members. Another aspect of the invention relates to the mechanical connection of molded polyethylene with other pieces that form part of the implant, such as metal or non-metal pieces.
The interfacial geometrical form is important in that polyethylene takes a geometrical form as its solidified form. Polyethylene has a remarkable'shape memory'due to its very high molecular weight, which results in high density physical entanglement. After solidification, plastic deformation causes a permanent shape change to reach a preferred high entropy shape when melted. The restoration of the original solidified shape is due to the'shape memory'acquired when the polyethylene was solidified.
Recovery of polymeric material when annealed to remove residual radicals is also a problem for medical devices with a high degree of orientation. Balloon catheters can often have polymer chains aligned in the intended axial and radial directions. Balloon catheters made of polyethylene are more effective when used with stents by improving the abrasion resistance resulting from cross-linking. In addition, the use of drug-coated catheters and stents interferes with the use of ethylene oxide sterilization in some cases; therefore ionizing radiation must be used and balloon catheters must be protected from the harmful effects of radical oxidation. It doesn't become. Annealing of these materials near the melting transition temperature results in bulk chain motion followed by a loss of dimensional tolerance in each part. Irradiation by diffusing a solution of α-tocopherol in 100% vitamin E or alcohol, such as ethanol or isopropanol, into a medical device such as a balloon catheter before, during or after exposure to ionizing radiation for cross-linking or sterilization. The problems associated with postoxidation are avoided without the need for heat treatment. Balloons, such as PeBAX, as described here<sup>R</sup>, Nylon and PET balloons are doped with Vitamin E and irradiated before, during or after doping.
In another aspect of the invention, after compression molding of polyethylene onto the counterface by mechanical connection, the hybrid member uses ionizing radiation to reach the desired dose level, eg, about 25 kGy to about 1000 kGy, preferably about 25 kGy to about. Irradiation is performed at 150 kGy, more preferably about 50 kGy to about 100 kGy. On the other side of the invention, since the irradiation step produces residual radicals, a melting step is later incorporated to remove the residual radicals. The polyethylene is solidified into the shape of the interface and retains the polymer'shape memory', so that the polyethylene does not separate from the wall surface.
In another aspect of the invention, the instrument is immersed in a non-oxidizing medium such as an inert gas or inert fluid, which is irradiated to remove crystalline material and rebind / remove residual radicals. Provided is a method of cross-linking polyethylene to make a polyethylene-based medical device, which is heated above the melting point of polyethylene, eg, UHMWPE (about 137 ° C). There is no significant separation between the polyethylene and the wall surface as the shape memory of the compression molded polymer is retained at the mechanically connected interface and the memory is strengthened at the cross-linking step.
On the other side of the invention, after the radical removal step described above, the interface between the metal and the polymer becomes sterile due to the high radiation dose levels used in the irradiation. If substantial oxidation is induced on the outer surface of the polyethylene during the radical removal step or irradiation step, the instrument surface may be further machined to remove the oxidized surface layer. On the other hand, in the present invention, in the case of post-melting machining of implants, the melting step is performed in the presence of an inert gas.
Another aspect of the invention provides a method of sterilizing a fabrication instrument, wherein the instrument is further sterilized with ethylene oxide, gas plasma or other gas if the interface is sterile but the rest of the member is not.
On the other hand, the present invention comprises irradiated antioxidants, including compression molded implants or instruments, wherein the implant or instrument is sterilized by ionizing radiation or gas sterilization to obtain a sterile crosslinked medical implant or medical device. Discloses the packaging of doped medical implants or medical devices.
<u style="single">Definition</u>:: Antioxidants refer to those known in the industry such as: (see, eg, WO01 / 80778, US6,448,315). α- and δ-tocopherols; propyl gallate, octyl or dodecyl; lactic acid, citric acid, tartaric acid and salts thereof; orthophosphate, tocopherol acetate. Vitamin E is preferred.
"Supercritical fluids" are those known in the industry, such as supercritical propane, acetylene, carbon dioxide (CO).<sub>2</sub>). In this regard, the critical temperature is the temperature at which the gas cannot be liquefied by pressure alone when it is higher than that. Below that, the pressure at which a substance can exist as a gas in equilibrium with a liquid at a critical temperature is the critical pressure. The supercritical fluid state usually means that the fluid is attached to a temperature and pressure at which a supercritical fluid, and thus a mixture of supercritical fluids, is obtained, and the temperature is higher than the supercritical temperature, and the temperature is higher than the supercritical temperature. CO<sub>2</sub>In the case of 31.3 ° C, the pressure is higher than the supercritical pressure, and the pressure is CO.<sub>2</sub>In the case of, it is 73.8 bar. More specifically, the supercritical state refers to the state of a mixture under high temperature and pressure, for example, the state of an antioxidant-containing UHMWPE, from which a supercritical fluid mixture is formed and CO.<sub>2</sub>When evaporated, antioxidant-doped UHMWPE is obtained (see, eg, US6448315 and WO02 / 26464).
The term "compression molding" as used herein refers to what is generally known in the art, especially with respect to high temperature molded polymer materials, which are in all physical states, including powdered forms. It can be compressed and machined into slab-shaped or shaped medical implants such as tibial inserts, acetabular liners, acetabular liners, patellas or single-partition inserts.
The term "direct compression molding" as used herein refers to what is commonly known in the art, especially when polyethylene-based appliances, such as polyethylene, are in any physical condition, including in powder form. With respect to moldings applicable to solid supports, such as medical implants compressed into metal surfaces with metal bags, metal meshes or grooves, notches or notches. Compression molding involves a variety of conditions, including resin powders, flakes and particles, for making members of medical implants such as tibial inserts, acetabular liners, glenoid liners, patellas or single-partition inserts. Also includes high temperature compression molding of polyethylene.
The term "mechanical connection" is commonly used with polyethylene, which is manufactured by a variety of methods, including compression molding, heating and irradiation, to form a connection interface and provide a'shape memory'of the connecting polyethylene. Regarding connection with the wall surface. A member of an instrument having such a connecting interface can be referred to as a "hybrid substance". Medical implants with such hybrid materials have a substantially sterile interface.
The term "substantially sterile" refers to an object whose interface is medically sterile enough to be medically acceptable, i.e. an object that does not cause infection or does not require repair, such as a hybrid material or medical treatment with an interface or interface. Regarding the condition of the implant.
A "metal mesh" refers to a porous metal surface of various pore diameters, eg 0.1-3 mm. The pore surface is sintered in several different ways, eg, sintering metal powder with a binder that is later removed to leave the pore surface; sintering short metal fibers 0.1-3 mm in diameter; or continuously opening. It is obtained by sintering metal meshes of different sizes on top of each other so as to have a pore structure.
"Bone cement" refers to what is known in the art as an adhesive used to bond medical devices to bone. Bone cement is typically made from polymethylmethacrylate (PMMA).
"High temperature compression molding" relates to compression molding of polyethylene in various forms, such as resin powder, flakes or particles, which impart new geometrical forms under pressure heating. During high temperature (higher than the melting point of polyethylene) compression molding, polyethylene is heated above its melting point, placed in a mold of the desired shape and pressurized, and cooled under pressure to maintain the desired shape.
"Shape memory" refers to what is known in the art as a property of polyethylene, such as UHMWPE, that reaches a preferred high entropy shape when melted. The preferred high entropy shape is obtained when the resin powder is solidified by compression molding.
The phrase "substantially undetectable residual radicals" refers to the state of the polyethylene member in which radicals have been removed sufficiently to avoid oxidative degradation, which can be assessed by electron spin resonance (ESR). The phrase "detectable residual radicals" refers to the lowest or higher levels of radicals that can be detected by ESR. The lowest level of radicals that can be detected by the latest equipment is about 10<sup>14</sup>Spin / g, so the term "detectable" is 10 in ESR<sup>14</sup>Regarding the detection limit of spin / g.
The term "about" or "approximately" for many values and ranges, as will be apparent to those skilled in the art from the disclosures contained herein, has, for example, the desired degree of cross-linking and / or the desired lack of radicals. , A value or range close to the stated value or range as can be carried out by the present invention. This is, at least in part, due to the diversity of polymer structures. Therefore, these terms include values other than those due to systematic errors.
<u style="single">Polymer material</u>: Ultra High Molecular Weight Polyethylene (UHMWPE) refers to a linear non-branched chain of ethylene having a molecular weight of about 500,000 or more, preferably about 1,000,000 or more, more preferably about 2,000,000 or more. In many cases, the molecular weight can reach about 8,000,000 or more. The initial average molecular weight means the average molecular weight of the UHMWPE starting material before irradiation. See US Patent 5,879,400, PCT / US99 / 16070 filed on July 16, 1999 and PCT / US97 / 02220 issued on February 11, 1997.
The products and processes of the present invention apply to various types of polymeric substances, such as high density polyethylene, low density polyethylene, linear low density polyethylene, ultra high molecular weight polyethylene (UHMWPE) or mixtures thereof. .. Polymeric materials also fall under various forms, such as resin powders, flakes, particles, powders or mixtures thereof, or solidified forms of polyethylene obtained from them, as used herein.
<u style="single">Crosslinked polymer material</u>: Polymeric materials, such as UHMWPE, are crosslinked by a variety of approaches, including those that use cross-linking agents (eg, peroxides and / or silanes) and / or irradiation. Irradiation is the preferred approach for cross-linking. Crosslinked UHMWPE is also obtained in accordance with the disclosures of US Patent 5,879,400, US Patent 6,641,617 and PCT / US97 / 02220.
<u style="single">Solidified polymer material</u>: Solidified polymeric materials are machined from solid, solidified rod materials, materials obtained from the various forms described herein, such as resin powders, flakes, particles or mixtures thereof, which can be solidified. With respect to solid or semi-solid polymeric substances. The solidified polymeric material may take the form of slabs, blocks, solid bar materials, machined parts, films, tubes, balloons, preforms, implants or final medical devices.
The term "non-permanent device" refers to what is known in the art as a device for implantation into the body over a period of up to several months. Some non-permanent devices stay in the body for seconds to minutes, others are implanted for days, weeks or months. Non-permanent instruments include, for example, catheters, tubes, intravenous tubes and sutures.
As used herein, the term "pharmaceutical compound" refers to a drug in the form of a powder, suspension, emulsion, particle, film, cake or molded article. The drug may exist independently or may be formulated as a component of a medical device.
The term "pressurizing chamber" refers to a container or chamber in which the internal pressure is raised above atmospheric pressure.
The term "package" refers to a container in which a medical device is placed and / or transported. Packages include various types of substances, including bags, blister packs, heat shrinkable packages, boxes, ampoules, bottles, tubes, trays, etc. or combinations thereof. Each member may be shipped in several individual types of packages, for example the members may be placed in a bag, then in a tray, then in a box. It may be sterilized and transported throughout the assembly. Packaging materials include, but are not limited to, parchment paper, multilayer polyethylene, nylon 6, polyethylene terephthalate (PET), polyvinyl chloride-vinyl acetate copolymer film, polypropylene, polystyrene and ethylene-vinyl acetate (EVA) copolymers.
The term "sealing" refers to the process of isolating a room or package from the outside atmosphere by closing the opening of the room or package. Sealing can be done by a variety of means, including heating (eg, heat sealing), the use of adhesives, crimping, cold forming, stapling or pressurization.
The term "blister pack" refers to a package consisting of a rigid plastic bowl with a lid that can be peeled off or pierced to remove the packaged contents. The lid is often made of aluminum, or a gas permeable membrane such as Tyvek. Blister packs are often blow molded, and in the process the plastic is heated above its deformation temperature, when the pressurized gas shapes the plastic into the required shape.
The term "heat shrinkable package" refers to a plastic film, bag or tube with a high degree of orientation. Upon heating, the alignment chain shrinks and the package shrinks, often sticking snugly around the medical device.
The term "intervertebral disc system" refers to an artificial plate that separates the spine by the spinal column. The system may be composed of one type of material or may be a cross-linked UHMWPE with a composite structure, eg, a metal end.
The term "balloon catheter" refers to what is known in the art as an instrument used to dilate the lumen of a blood vessel or analog. Balloon catheters are thin-walled polymer instruments, usually with inflatable tips, used to dilate occluded arteries, stents, or measure blood pressure. Commonly used polymer balloons include, for example, polyether block copolyamide polymers (PeBAX).<sup>R</sup>), Nylon and polyethylene terephthalate (PET) balloons. Commonly used polymeric materials used in balloons and catheters include, for example, copolymers of polyether and polyamide (eg, PeBAX).<sup>R</sup>), Polyamides, polyesters (eg PET), and ethylene vinyl alcohol (EVA) used in the fabrication of catheters.
Medical Instrument Tubes: Materials used in medical instrument tubes, including intravenous tubes, include polyvinyl chloride (PVC), polyurethane, polyolefins and blends or alloys such as thermoplastic elastomers, polyamide / imide, polyester, polycarbonate or various. There are various fluoropolymers.
The term "stent" refers to what is known in the art as a metal or polymer cage-like device used to dilate an internal lumen such as a blood vessel. Stents are usually introduced into the body in a collapsed state and expanded by a balloon catheter where desired in the body where they remain.
The "melting transition temperature" refers to the lowest temperature at which all crystalline parts of a substance disappear.
<u style="single">interface</u>: In the present invention, the term "interface" refers to an arrangement in which a member contacts another piece (eg, a metal or non-metal member) to form an interface between the polymer and the metal or other polymeric material. It is defined as the gap in the medical device that is formed when the implant is taken. For example, polymer-polymer or polymer-metal interfaces are present in orthopedic joints and artificial bone parts, such as medical prostheses such as artificial hips, knees, elbows or ankles.
Medical implants incorporating factory-assembled pieces in close contact with polyethylene form an interface. In most cases, the interface cannot easily come into contact with ethylene oxide gas or gas plasma during the gas sterilization process.
<u style="single">Irradiation</u>: In one aspect of the invention, the type of radiation, preferably ionization, is used. According to another aspect of the invention, doses of ionizing radiation from about 25 kGy to about 1000 kGy are used. Radiation dose is about 25kGy, about 50kGy, about 65kGy, about 75kGy, about 100kGy, about 150kGy, about 200kGy, about 300kGy, about 400kGy, about 500kGy, about 600kGy, about 700kGy, about 800kGy, about 900kGy, about 1000kGy or 1000 It is an integer value above, or around it, or somewhere in between. Preferably, the radiation dose is from about 25 kGy to about 150 kGy or from about 50 kGy to about 100 kGy. These types of radiation, including gamma rays and / or electron beams, kill or inactivate bacteria, viruses or other microorganisms that can contaminate interfacial medical implants to sterilize products. .. Irradiation can be performed in an oxygen-containing air atmosphere, whether electron or gamma ray irradiation, with oxygen concentrations in the atmosphere at least 1%, 2%, 4% or about 22%. Alternatively, it is an integer value around or in the middle. On the other side, the irradiation may be carried out in an inert atmosphere, which contains a gas selected from the group consisting of nitrogen, argon, helium, neon and the like or combinations thereof. Irradiation can be done even in a vacuum.
According to the preferred features of the present invention, irradiation may be performed in a sensitized atmosphere. It consists of a gaseous material that is small enough to diffuse into the polymer and acts as a polyfunctional graft moiety upon irradiation. Examples include substituted or unsubstituted polyunsaturated hydrocarbons; acetylene hydrocarbons such as acetylene; conjugated or unconjugated olefin hydrocarbons such as butadiene and (meth) acrylate monomers, but chlorotrifluoro. Sulfur monochloride containing ethylene (CTFE) or acetylene is particularly preferred. By "gaseous" is meant that the sensitized atmosphere is present in the gas phase above or below its critical temperature at the irradiation temperature.
<u style="single">Metal piece</u>: According to the present invention, the piece forming the interface with the polymer substance is, for example, a metal. Metal pieces that are functionally related to polyethylene are, for example, made of cobalt-chromium alloys, stainless steel, titanium, titanium alloys or nickel-cobalt alloys, according to the invention.
<u style="single">Non-metal piece</u>: According to the present invention, the piece forming the interface with the polymer substance is, for example, a non-metal. The non-metal piece, which has a functional relationship with polyethylene, is made of, for example, a ceramic material according to the present invention.
<u style="single">Inert atmosphere</u>: The term "inert atmosphere" refers to an environment having less than 1% oxygen, more preferably an oxidant condition such that crosslinks are formed with radicals in the polymeric material without oxidation during the sterilization process. An inert atmosphere can oxidize medical devices containing polymeric substances such as UHMWPE.<sub>2</sub>Is used to avoid. Inert atmosphere conditions such as nitrogen, argon, helium or neon are used to sterilize polymer medical implants with ionizing radiation.
Inert atmosphere conditions such as nitrogen, argon, helium, neon or vacuum are also used to sterilize polymer-metal and / or polymer-polymer interfaces with ionizing radiation in medical implants.
The Inactive atmosphere condition also relates to an inert gas, an inert fluid or an inert liquid medium, such as nitrogen gas or silicon oil.
<u style="single">Anaerobic environment</u>: Anoxic environment refers to an environment containing 21 to 22% or less oxygen, preferably 2% or less oxygen, and a gas, such as nitrogen. Oxygen concentrations in anoxic environments are at least 1%, 2%, 4%, 8%, 10%, 12%, 14%, 16%, 18%, 20%, or about 22% or less, or around or It may be an integer value in the middle.
<u style="single">vacuum</u>: The term vacuum refers to an environment that does not have enough gas to form crosslinks with radicals in the polymeric material without oxidation during the sterilization process. Vacuum can oxidize medical devices containing polymeric substances such as UHMWPE.<sub>2</sub>Is used to avoid. Vacuum conditions can be used to sterilize polymer medical implants with ionizing radiation.
Vacuum conditions can be created using a commercially available vacuum pump. Vacuum conditions can also be used when sterilizing polymer-metal and / or polymer-polymer interfaces with ionizing radiation in medical implants.
<u style="single">Residual radicals</u>: Residual radicals refer to radicals generated when a polymer is exposed to ionizing radiation such as gamma rays or e-beams. Some of the radicals recombine with each other to form crosslinks, but some are trapped in the crystalline part. The captured radicals are also known as residual radicals.
According to one aspect of the invention, residual radical levels in the polymer generated by ionizing radiation (eg, gamma rays or electron beams) are preferably examined using electron spin resonance and treated appropriately to reduce radicals.
<u style="single">Sterilization</u>: One aspect of the invention discloses a sterilization process for medical implants containing polymeric substances such as crosslinked UHMWPE. The process consists of sterilizing medical implants, for example at dose levels of 25-70 kGy, by ionization sterilization with gamma rays or electron beams, or by gas sterilization with ethylene oxide or gas plasma.
Another aspect of the invention also discloses a sterilization process for medical implants containing polymeric substances such as crosslinked UHMWPE. The process consists of sterilizing medical implants by ionizing with gamma rays or electron beams, for example at dose levels of 25-200 kGy. The sterilization dose level is higher than the standard level used for irradiation. This is to crosslink or further crosslink the medical implant during sterilization.
On the other hand, the present invention sterilizes the interface with ionizing radiation and heats the medium above the melting point of the irradiated UHMWPE (about 137 ° C) to remove the crystalline part and rebond / remove residual radicals; Contact with other pieces, including polymeric materials solidified by compression molding into other pieces to form interfacial and articulated hybrid materials, consisting of sterilizing medical implants with gas, such as ethylene oxide or gas plasma. Discloses the sterilization process of medical implants containing polymeric substances such as crosslinked UHMWPE.
<u style="single">heating</u>: One aspect of the present invention discloses a process of increasing the uniformity of an antioxidant after doping a polymer member of a medical implant during the manufacturing process by heating for a time corresponding to the melting point of the polymeric substance. For example, the preferred temperature is about 137 ° C or less. In another aspect of the invention, the oxygen concentration is at least 1%, 2%, 4% or about 22%, or an integer value around or in between, in the air, in an oxygen-containing atmosphere. The heating steps used are disclosed. On the other side, the present invention discloses a heating step performed while the implant is in contact with the inert atmosphere, the inert atmosphere being selected from the group consisting of nitrogen, argon, helium, neon, etc. or a combination thereof. Contains the gas to be produced. On the other hand, the present invention discloses a heating step performed in contact with a non-oxidizing medium, such as an inert fluid medium, in contact with the implant, which contains about 1% or less oxygen. On the other hand, the present invention discloses a heating step performed while the implant is present in vacuum.
In another aspect of the invention, a method of heating the implant to reduce / increase the uniformity of the antioxidant is described. Medical devices containing polymer raw materials such as UHMWPE are typically heated to temperatures below about 137 ° C after the antioxidant doping step. The medical device continues to be heated in the inert medium until the desired homogeneity of the antioxidant is reached.
The terms "below melting point" or "below melting" relate to temperatures below the melting point of polyethylene, such as UHMWPE. The term "below melting point" or "below melting" refers to temperatures below 145 ° C that vary depending on the melting point of polyethylene, such as 145 ° C, 140 ° C or 135 ° C, which is the nature of the polyethylene being treated. For example, it also depends on the molecular weight average and range, batch deviation, and the like. Melting temperature is typically measured using a differential scanning calorimetry (DSC) at a heating rate of 10 ° C / min. The peak melting temperature measured in this way is called the melting point, for example, about 137 ° C for some types of UHMWPE. In order to determine the melting temperature and determine the irradiation and annealing temperatures, it is desirable to perform a melting test on the starting polyethylene material.
The term "annealing" refers to heating a polymer below its peak melting point. Annealing time is at least 1 minute to several weeks. On one side, the annealing time is from about 4 hours to about 48 hours, preferably from 24 to 48 hours, more preferably from about 24 hours. The "annealing temperature" relates to the thermal conditions of annealing according to the present invention.
The term "contact" refers to the physical proximity or contact of a sensitizer so that it can perform its intended function. Preferably, the polyethylene structure or preform is well contacted so that it is immersed in the sensitizer to ensure sufficient contact. Immersion is defined as placing the sample in a particular environment at an appropriate temperature for a sufficient period of time, eg, immersing the sample in a solution of an antioxidant. The environment is heated to temperatures ranging from room temperature to temperatures below the melting point of the substance. The contact time is at least about 1 minute to several weeks, and the period varies depending on the temperature of the environment.
The term "non-oxidizing" refers to the state of a polymeric material having an Oxidation Index (AU) of less than about 0.5 after aging the polymeric material in an air 80 ° C oven for 5 weeks. As such, non-oxidizing crosslinked polymeric materials typically exhibit an oxidation index (AU) of less than about 0.5 after an aging period.
<u style="single">doping</u>: Doping refers to processes well known in the art (see, eg, US Pat. Nos. 6,448,315 and 5,827,904). In this regard, doping usually relates to contacting a polymeric substance with an antioxidant under certain conditions, eg, doping UHMWPE with an antioxidant under supercritical conditions, as described herein.
More specifically, the solidified polymeric material is doped with an antioxidant by immersing the material in a solution of the antioxidant. The antioxidant is thus diffused into the polymer. For example, the substance is 100% immersed in antioxidants. The material may be immersed in an antioxidant solution and a carrier solvent may be used to dilute the antioxidant concentration. To increase the diffusion depth of the antioxidant, the material may be doped over an extended period of time in the presence of high temperature, high pressure and / or supercritical fluids.
The doping process lasts from about 1 hour to several days, preferably from about 1 hour to 24 hours, even more preferably from 1 hour to 16 hours, for polymeric substances, medical implants or instruments to antioxidants such as vitamin E. Consists of immersion. Antioxidants are heated to room temperature or below about 160 ° C and doping is done at room temperature or below about 160 ° C. Preferably, the antioxidant is heated to 100 ° C and doping is done at 100 ° C.
Following the doping step, a heating step may be performed in the air or in an oxygen-free environment to improve the uniformity of the antioxidant in the polymeric material, medical implant or instrument. Heating is carried out at or above the peak melting point.
In another aspect of the invention, medical devices are cleaned prior to packaging and sterilization.
The present invention is further described in the examples below, but these are by no means limiting to the present invention.
Example
Vitamin E: Unless otherwise stated, Vitamin E (Acros)<sup>TM</sup>99% D-α-tocopherol, Fisher Brand) was used in the experiments described here. Vitamin E used is a very pale yellow color and is a viscous fluid at room temperature. Its melting point is 2-3 ° C.
Example 1. Solidification of UHMWPE resin mixed with Vitamin E Vitamin E was dissolved in ethanol to give a solution with a 10% (w / v) vitamin E concentration. The vitamin E-ethanol solution was then dry blended with GUR1050 ultra high molecular weight polyethylene (UHMWPE) resin. Two batches were prepared: one had a vitamin E concentration of 0.1% (w / v) and the other had a vitamin E concentration of 0.3% (w / v). Vitamin E concentration was examined after evaporation of ethanol. Both batches were then solidified on a Carver experimental bench press at a temperature of 230 ° C in air. The 0.1% (w / v) solution turned dark yellow and the 0.3% (w / v) solution turned brown. The discoloration was uniform throughout the solidified UHMWPE block.
The discoloration was thought to be the result of the decomposition of vitamin E when heated in the presence of oxygen.
Example 2. Discoloration of Vitamin E when exposed to heat in air or vacuum Experiments were conducted to determine if vitamin E discoloration was due to aeration at high temperatures and if heating vitamin E under vacuum would avoid discoloration.
A drop of Vitamin E solution as described here was placed on an experimental glass slide. The glass slides were then heated to 180 ° C. in air for 1 hour in an air convection oven. Vitamin E changed its color to dark brown. The discoloration was almost certainly due to the breakdown of vitamin E.
A drop of Vitamin E was placed on a laboratory glass slide. The glass slides were then heated to 180 ° C. under vacuum in a vacuum oven for 1 hour. In contrast to heating in air, Vitamin E showed no noticeable discoloration after heating in vacuum. Therefore, in the absence of air or oxygen, the heat treatment of vitamin E does not exhibit a noticeable discoloration.
Example 3. Solidification of UHMWPE / Vitamin E in anoxic environment Dissolve Vitamin E in ethanol to obtain a solution. The GUR1050 polyethylene resin is degassed under vacuum or placed in an oxygen-free environment to substantially remove dissolved oxygen. The Vitamin E-ethanol solution is then dry-blended with GUR1050 polyethylene resin. Prepare two batches: one is degassed GUR1050 and the other is as-accepted GUR1050 polyethylene resin. The dry blend mixture is then solidified separately on a Carver experimental bench press. Solidification can be performed in an oxygen-free environment to minimize discoloration of the solidified material.
Example 4. Pin-on-disc (POD) wear test of pins treated with 0.1% and 0.3% vitamin E Experiments were conducted to investigate the effect of vitamin E on the cross-linking efficiency of UHMWPE. Vitamin E (α-tocopherol) was mixed and solidified with GUR1050UHMWPE powder in two concentrations, eg 0.1% and 0.3% by weight / volume. The solidification of UHMWPE into the block was performed by compression molding. One additional solidification was performed without vitamin E additives for use as a control. The three solidified blocks were mechanically divided into halves, each half was packaged under vacuum and irradiated with gamma rays (Steris, Northborough, MA) up to 100 kGy.
Cylindrical pins were cut out of the irradiation block with a diameter of 9 mm and a length of 13 mm. Pins were first subjected to accelerated aging at 80 ° C in air for 5 weeks and then tested on a two-way pin-on-disk (POD). The POD test was performed for a total of 2 million cycles, and the wear was weighed every 500,000 cycles. The test was performed at a frequency of 2 Hz in the presence of bovine serum as a lubricant.
The typical wear rate of UHMWPE without radiation history and vitamin E is approximately 8.0 mg / million cycles. The wear rates of the 100 kGy-irradiated vitamin E-added pins were 2.10 ± 0.17 and 5.01 ± 0.76 mg / million cycles for 0.1% and 0.3% vitamin E concentrations, respectively. The reduction in abrasion resistance is less with high vitamin E content.
Increasing the vitamin E content can reduce the radiation-induced long-term oxidative instability of polyethylene. In other words, the resistance of UHMWPE to post-oxidation oxidation can be improved by blending with vitamin E. However, the cross-linking density of UHMWPE obtained at high irradiation doses decreases with increasing concentration of vitamin E content in the mixture.
Example 5. Diffusion of Vitamin E into solidified polyethylene A drop of Vitamin E was placed on the machined surface of GUR1050UHMWPE solidified in air. After 6 hours, Vitamin E droplets were no longer visible on the machined surface, indicating that it had diffused into the polyethylene.
Example 6. Diffusion of Vitamin E in Irradiated Polyethylene Compression molded GUR1050UHMWPE (Perplas, Lancashire, UK) was irradiated with gamma rays at a dose level of 100 kGy. Cylindrical pins (n = 10) with a diameter of 9 mm and a height of 13 mm were machined from the irradiated material. One of the basal surfaces of 5 pins (n = 5) was moistened with vitamin E. The other 5 pins were used as control samples. Group 2 pins were placed in air at room temperature for 16 hours. They were then placed in a convection oven at 80 ° C in air for accelerated aging.
The aged pins were removed from the oven after 5 weeks and examined for the degree of oxidation. First, the pin was cut in half along the axis of the cylinder. One cut surface was then microtome sectioned (150-200 μm) and an infrared spectrum was collected using a BioRad UMA 500 infrared microscope as a function of the distance from the end corresponding to one of the base surfaces of the cylinder. For vitamin E treated pins, oxidation levels were quantified from the basal surface moistened with vitamin E.
Carbonyl vibration (1740 cm) after subtracting the corresponding baseline<sup>-1</sup>) Area 1370 cm<sup>-1</sup>The oxidation index was calculated by standardizing for the methylene oscillation range of.
The application of vitamin E to the surface of irradiated polyethylene substantially reduced the level of oxidation. Therefore, this method can be used, for example, in medical devices containing polymeric substances to improve the long-term oxidative stability of irradiated polyethylene.
Example 7. Diffusion of Vitamin E into polyethylene, then irradiation Compression molding GUR1050UHMWPE (Perplas, Lancashire, UK) was machined into cubes (n = 4) with a side of 19 mm. The surface of the 2 cubes was moistened with Vitamin E and left at room temperature for 16 hours. The remaining 2 cubes were placed without the addition of vitamin E. One cube in each group with and without vitamin E was packaged in an oxygen-free environment (eg, about 2% oxygen), and the remaining 5 cubes in each group were packaged in air. The cubes in each package were irradiated with gamma rays at a dose level of 100 kGy.
The irradiated cubes were removed from the package and placed in an oven at 80 ° C in air for accelerated aging.
The aged cubes were removed from the oven after 5 weeks and examined for the degree of oxidation. First, the cube was cut in half. One of the cut surfaces was then sliced (150-200 μm) with a microtome and an infrared spectrum was collected using a BioRad UMA 500 infrared microscope as a function of distance from one end.
Carbonyl vibration (1740 cm) after subtracting the corresponding baseline<sup>-1</sup>) Area 1370 cm<sup>-1</sup>The oxidation index was calculated by standardizing for the methylene oscillation range of.
Application of vitamin E to the surface of polyethylene prior to irradiation in an air or anoxic environment substantially reduced oxidation levels. Therefore, this method is used to improve the long-term oxidative stability of polyethylene, which will later irradiate medical devices containing sterilizing and / or crosslinked polymeric substances, such as polymeric substances.
Example 8. Fabrication of highly cross-linked medical devices Tibial knee inserts are machined from compression molded GUR1050UHMWPE. The insert is then immersed in 100% Vitamin E or a solution of Vitamin E. Diffusion of vitamin E into the insert is facilitated by increasing temperature and / or pressure, which can be done in the air or in an inert or anoxic environment. After reaching the desired vitamin E diffusion levels, the insert is packaged in air or in an inert or anoxic environment. The packaged insert is then irradiated to a dose of 100 kGy. Irradiation serves two purposes: (1) crosslink polyethylene to improve wear resistance; and (2) sterilize implants.
In this example, the polyethylene implant may be any polyethylene medical device, including those that interface with other substances such as metals. An example of this is a non-modular metal backed polyethylene member used in total arthroplasty.
Example 9. Diffusion of Vitamin E in polyethylene An experiment was conducted to investigate the diffusion of synthetic vitamin E (DL-α-tocopherol) into UHMWPE. Solidified GUR1050U HMWPE (Perplas, Lancashire, UK) was machined into 2 cm cubes. The cubes were immersed in α-tocopherol for doping (Fisher Scientific, Houston, TX). Doping was performed in an oven under nitrogen purge. The cubes were doped with nitrogen at 0.5-0.6 atm under nitrogen pressure at 25 ° C, 100 ° C, 120 ° C or 130 ° C for 16 hours, first purging the oven with nitrogen, then evacuating, and then nitrogen. Applied by adjusting the amount (in all cases except 25 ° C, performed at atmospheric pressure in the air). After doping, the sample was rinsed with ethanol to remove excess α-tocopherol from the surface of the cube. The degree of α-tocopherol diffusion into polyethylene was quantified by observing with an infrared microscope and measuring the characteristic absorption of α-tocopherol as a function of the depth from the free surface.
The α-tocopherol-doped cubes were mechanically halved and sectioned (approximately 100 μm slices) using LKB Sledge Microtome (Sweden). This section was analyzed using a BioRad UMA 500 infrared microscope (Natick, MA). Infrared spectra were collected with a pore size of 50 × 50 μm as a function of the depth from one end of the cube on the free surface side. Absorbance typically produced by Vitamin E, ie 1226 ~ 1275 cm<sup>-1</sup>The spectrum was analyzed by quantifying the absorbance of the wavenumber. Integrate the area under absorbance, 1850-1985 cm<sup>-1</sup>Standardized for the control absorbance peak of. Each baseline was excluded from the integrals of both Vitamin E Absorbance and Control Absorbance. The standardized value is called the vitamin E index.
Figure 1 shows the diffusive properties of polyethylene cubes doped at four different temperatures (25 ° C, 100 ° C, 120 ° C and 130 ° C). The depth of α-tocopherol diffusion in polyethylene increased with temperature from 400 μm at 25 ° C to 3 mm at 130 ° C under atmospheric pressure.
The diffusion depth and homogeneity of the antioxidant can be varied by varying the doping temperature in this example of Vitamin E.
Example 10. Artificial aging of UHMWPE with and without vitamin E An experiment was conducted to investigate the effect of vitamin E on the thermal oxidative stability of irradiated UHMWPE. Two identical cylindrical pins (9 mm in diameter and 13 mm in height) were machined from UHMWPE blocks irradiated with gamma rays up to 100 kGy. One bottom of the cylindrical pin was coated with natural vitamin E (DL-α-tocopherol) and the other pin was left untreated. Both pins were then subjected to accelerated aging in the oven at 80 ° C for 5 weeks. After aging, the pins were attached to the microtome to make 200 μm flakes perpendicular to both sides of the bottom of the cylinder. Microtome sections (200 μm each) were then analyzed with a BioRad UMA 500 infrared microscope. Infrared spectra were collected as a function of the depth from the end of the microtome section corresponding to the bottom of the vitamin E exposed cylinder. 1680 ~ 1780cm<sup>-1</sup>The spectrum was analyzed by quantifying the carbonyl absorption of the wavenumber. Integrate the area under absorbance, 1330 ~ 1390 cm<sup>-1</sup>Standardized for the area under the control absorbance peak of. Integral of both carbonyl and control absorbances excluded each baseline. The standardized value is called the oxidation index.
The untreated UHMWPE pin sample showed an oxidation index about 6 times higher than that of the vitamin E treated pin.
Example 11. Improved oxidation resistance with vitamin E doping Compression molded GUR1050U HMWPE blocks (Perplas Ltd., Lancashire, UK) (3 inches in diameter) were gamma-irradiated in vacuum to a dose of 111 kGy (Steris Isomedix, Northborough, MA). The irradiation block was machined into a half cube with dimensions of approximately 2 cm x 2 cm x 1 cm.
Four groups of half cubes were immersed in α-tocopherols for doping (α-D, LT, Fischer Scientific, Houston, TX). Half cubes of the RT1 group were soaked at room temperature for 1 hour. Half cubes of the RT16 group were soaked at room temperature for 16 hours. Half cubes in the 100C1 group were soaked at 100 ° C for 1 hour. Half cubes in the 100C16 group were soaked at 100 ° C for 16 hours. There were a total of 3 half-cubes in each group. In addition, 3 groups of thermal controls were made with 3 half cubes in each group. The TCRT group was a semi-cube machined from one of the irradiation blocks. The TC100C1 group was a half-cube heated to 100 ° C for 1 hour in air. The TC100C16 group was a half-cube heated to 100 ° C in air for 16 hours.
The above immersion and heat control half cubes were then cleaned with a dishwasher. Cleaning was performed by a portable Kenmore dishwasher (Sears Inc., Hoffman Estates, IL) in a standard cycle with rinsing and heat drying. During cleaning, all half-cube test samples were placed in a cylindrical inelastic polyethylene mesh 2 inches in diameter and closed at the ends. This ensured that the cleaning fluid was distributed without the sample moving around. Electrasol<sup>TM</sup>(Reckitt Benckiser Inc., Berkshire, UK) was used as a cleaning agent.
After cleaning, the samples were subjected to accelerated aging to examine the effect of tocopherol doping under different conditions on the oxidative stability of irradiated UHMWPE. Accelerated aging was performed by placing the sample in the oven at 80 ° C for 5 weeks in the air.
After aging, the half cube was cut in half and attached to a microtome to make 200 μm flakes perpendicular to one 2 cm × 2 cm surface. Microtome sections (200 μm each) were then analyzed with a BioRad UMA 500 infrared microscope. Infrared spectra were collected as a function of the depth from the end of the microtome section corresponding to the surface immersed in tocopherol and further exposed to air during aging. 1680 ~ 1780cm<sup>-1</sup>The spectrum was analyzed by quantifying the carbonyl absorption of the wavenumber. Integrate the area under absorbance, 1330 ~ 1390 cm<sup>-1</sup>Standardized for the area under the control absorbance peak of. Integral of both carbonyl and control absorbances excluded each baseline. The standardized value is called the oxidation index.
The maximum oxidation value of each microtome section was calculated, and the average of 3 sections from each of the above groups is shown in Table 1. Thermal control on 111 kGy irradiation, cleaning and aged samples with tocopherol-doped UHMWPE at room temperature showed high levels of oxidation. The average maximum oxidation levels of irradiated, tocopherol-doped, cleaned and aged samples over 1 and 16 hours were undoped but lower than each thermal control with a similar thermal history.
These results indicate that cleaning by washing and drying did not remove tocopherols that had diffused into the UHMWPE, and tocopherols protected against oxidation of high-dose irradiated UHMWPEs under strong aging conditions.
<tables num="1"><img id="000002" he="67" wi="160" file="JP5758317B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>
Thermal control (TC100C1 group) for 111 kGy irradiated, cleaned and aged samples with tocopherol-doped UHMWPE at 100 ° C for 1 hour showed higher oxidation levels than the corresponding tocopherol-doped test samples (100C1 group). Similarly, thermal control (TC100C16 group) for 111 kGy irradiated, cleaned and aged samples with tocopherol-doped UHMWPE at 100 ° C for 16 hours showed higher oxidation levels than tocopherol-doped test samples (100C16 group). It was. Thermal control and oxidation levels of the test samples showed no significant difference between the 1 hour and 16 hour immersion times. Oxidation levels for 100 ° C doped samples were lower than those doped at room temperature.
Figure 2 shows the oxidation index properties as a function of the depth to one of the representative aged cubes of each test group (TCRT, RT1, RT16, TC100C16, 100C1, 100C1 and 100C16). Shown.
Example 12: Balloon catheter ionization sterilization The increasing use of drug coatings on balloons and stents has often hampered the use of ethylene oxide sterilization. In addition, improved wear resistance is desired for balloons used to expand metal stents. Immerse the polyethylene balloon in Vitamin E under room temperature pressure for 16 hours. The balloon is then exposed to ionizing radiation at a dose level of 25-100 kGy. Radiation sterilizes the member without affecting the drug and crosslinks the polyethylene to improve wearability. Oxidation due to residual radicals can be minimized by the presence of vitamin E.
Example 13: Improving the oxidation resistance of packaged materials Immerse the polyethylene film package in Vitamin E at room temperature and keep under pressure for 16 hours. The package is then sterilized by ionizing radiation at a dose of 25-40 kGy. The package is protected from oxidative embrittlement, which can affect both the mechanical integrity of the package and its gas barrier properties.
Example 14: UHMWPE irradiation and doping Processed as follows: (1) gamma-irradiated up to 65 kGy, (2) gamma-irradiated up to 100 kGy, and (3) unirradiated GUR1050U HMWPE cubes from three different rod materials (20 mm on a side) ) Was produced by a machine. The cube was doped by immersing it in Vitamin E (DL-α-tocopherol) for 16 hours at room temperature. Two groups of machine-made cubes from 65 kGy on the one hand and 100 kGy on the other were packaged after doping with vitamin E and re-irradiated with gamma rays at dose levels of 25-40 kGy for sterilization. The remaining group of cubes machined from unirradiated material was pre-doped with vitamin E, packaged, and re-irradiated with gamma rays at dose levels 125-140 kGy for cross-linking and sterilization.
Example 15: Irradiation and Vitamin E Doped UHMWPE Pin-on-Disc (POD) Abrasion Before and After Aging The solidified GUR1050U HMWPE rod material was gamma-irradiated at 65 kGy and 100 kGy. Cylindrical pin (9 mm diameter and 13 mm height) samples for POD wear testing were machined from the irradiation rod material. Samples were doped with Vitamin E (α-tocopherol) for 16 hours at room temperature in the air. After doping, the sample was further gamma-sterilized at a dose of 27 kGy. These two groups are referred to as α-T-92 and α-T-127 because they have total radiation doses of 92 kGy and 127 kGy, respectively.
Half of the cylindrical sample was subjected to accelerated aging at 80 ° C in air for 5 weeks. Both unaged and aged samples were subjected to POD wear testing. Pin wear was tested on a custom two-way pin-on-disc wear tester at a frequency of 2 Hz by rubbing the pin against the implant-finished cobalt-chromium wall in a rectangular wear path (Muratoglu et al., Biomaterials, 20). (16): 1463-1470, 1999). The peak contact stress was 6 MPa at the time of the test. Using calf serum as a lubricant, wear was quantified by weight every 500,000 cycles. First, the pins were subjected to a 200,000 cycle POD test to reach a steady state wear rate independent of surface diffusion or roughness. Three pins in each group were then tested for a total of 2 million cycles. The wear rate was calculated as a linear regression of the number of cycles of wear vs. 200,000 to 2 million cycles. The wear rates of the doped and aged cross-linked polyethylene are shown in Table 2.
<tables num="2"><img id="000003" he="46" wi="159" file="JP5758317B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>
The wear resistance of the doped sample was similar before and after aging, indicating that the presence of antioxidants taken in by diffusion protected the irradiated polyethylene from oxidation and thus prevented increased wear after aging. Typically, the wear rate of 100 kGy irradiated UHMWPE is about 1 mg / million cycles (Muratoglu et al., Biomaterials, 20 (16): 1463-1470, 1999). Aging of 105 kGy-irradiated UHMWPE can increase its wear rate by more than 20 mg / cycle (Muratoglu et al., Clinical Orthopedics & Related Research, 417: 253-262, 2003).
Example 16: Oxidation stability of a polyether block copolyamide balloon Polyester Block Copolyamide Polymer (PeBAX)<sup>R</sup>) Balloons are packaged and then sterilized with gamma rays or electron beams. Radical annihilation is essential to ensure a long shelf life (eg, 3 year shelf life), as there is concern about oxidative embrittlement of these materials due to radical generation. Given that the highly aligned polymer chains relax when exposed to high temperatures and contract radially and axially, these materials cannot be heat treated after irradiation.
Immerse the polyether block copolyamide balloon in a solution of Vitamin E or a solvent such as Vitamin E and alcohol. The balloon is packaged and then exposed to a bactericidal dose of 25-70 kGy. The high radiation dose is due to the double bactericidal dose. Sterilization can be done in air or in a hypoxic atmosphere. Vitamin E minimizes the oxidative effects of residual radicals generated during the bactericidal process and also reduces unwanted cross-linking.
Example 17: Oxidative stability of nylon balloon Nylon polymer balloons are packaged and then sterilized with gamma rays or electron beams. Radical annihilation is essential to ensure a 3-year shelf life, as radical formation may cause oxidative embrittlement of these materials. Given that the highly aligned polymer chains relax when exposed to high temperatures and contract radially and axially, these materials cannot be heat treated after irradiation.
Immerse the nylon balloon in a solution of Vitamin E or a solvent such as Vitamin E and alcohol. The balloon is packaged and then exposed to a bactericidal dose of 25-70 kGy. The high radiation dose is due to the double bactericidal dose. Sterilization can be done in air or in a hypoxic atmosphere. Vitamin E minimizes the oxidative effects of residual radicals generated during the bactericidal process and also reduces unwanted cross-linking.
Example 18: Oxidative stability of polyethylene terephthalate balloon Balloons made of polyethylene terephthalate (PET) polymer are packaged and then sterilized with gamma rays or electron beams. Radical annihilation is essential to ensure a long shelf life (eg, 3 year shelf life), as there is concern about oxidative embrittlement of these materials due to radical generation. Given that the highly aligned polymer chains relax when exposed to high temperatures and contract radially and axially, these materials cannot be heat treated after irradiation.
Immerse the PET balloon in a solution of Vitamin E or a solvent such as Vitamin E and alcohol. The balloon is packaged and then exposed to a bactericidal dose of 25-70 kGy. The high radiation dose is due to the double bactericidal dose. Sterilization can be done in air or in a hypoxic atmosphere. Vitamin E minimizes the oxidative effects of residual radicals generated during the bactericidal process and also reduces unwanted cross-linking.
Example 19: Oxidative stability of composite balloons Composite balloons made from a combination of polymers including polyethylene, PET, polyether block copolyamides, polyvinyl acetate and nylon are sterilized with gamma rays or electron beams after packaging. Radical annihilation is essential to ensure a long shelf life (eg, 3 year shelf life), as there is concern about oxidative embrittlement of these materials due to radical generation. Given that the highly aligned polymer chains relax when exposed to high temperatures and contract radially and axially, these materials cannot be heat treated after irradiation.
Immerse these composite balloons in a solution of Vitamin E or a solvent such as Vitamin E and alcohol. The balloon is packaged and then exposed to a bactericidal dose of 25-70 kGy. The high radiation dose is due to the double bactericidal dose. Sterilization can be done in air or in a hypoxic atmosphere. Vitamin E minimizes the oxidative effects of residual radicals generated during the bactericidal process and also reduces unwanted cross-linking.
Example 20: Sterilization of polypropylene medical devices Polypropylene is widely used in the medical industry to make syringes, vials and many other instruments, often by injection molding. Polypropylene is known to exhibit oxidative decomposition when subjected to ionization sterilization with gamma rays or electron beams or gas sterilization with ethylene oxide or gas plasma.
Immerse a polypropylene syringe in a solution of vitamin E or a solvent such as vitamin E and alcohol. Package the syringe and then expose it to a germicidal dose of 25-70 kGy. The high radiation dose is due to the double bactericidal dose. Sterilization can be done in air or in a hypoxic atmosphere. Vitamin E minimizes the oxidative effects of residual radicals generated during the bactericidal process and also reduces unwanted cross-linking.
Example 21: Sterilization of soft PVC tubing Soft polyvinyl chloride (PVC) is used in various medical devices, including tubes. Even if pre-sterilized with ethylene oxide, many manufacturers use gamma rays or electron beams to sterilize. Exposure to ionizing radiation often causes these materials to turn brown and yellow, which is believed to be due to oxidation (Medical Plastics and Biomaterials Magazine, March, 1996, Douglas W. Luther and Leonard A. Linsky). Yellowing is reduced when antioxidants are incorporated into PVC with a mechanical mixer or extruder.
Immerse the PVC tube in a solution of Vitamin E or a solvent such as Vitamin E and alcohol. The tube is packaged and then exposed to a germicidal dose of 25-70 kGy. The high radiation dose is due to the double bactericidal dose. Sterilization can be done in air or in a hypoxic atmosphere. Vitamin E minimizes the oxidizing action of residual radicals generated in the bactericidal process, resulting in color stabilization and improved shelf life of PVC materials.
Example 22: Annealing after doping After doping, annealing can be performed to obtain a more uniform antioxidant distribution. Unirradiated UHMWPE cubes were doped by immersion in undiluted α-tocophenol at 130 ° C. for 96 hours. One cube was machine-divided and attached to a microtome. As described in Example 9, microtome sections were analyzed using an infrared microscope and the Vitamin E index was examined as a function of surface-side depth that was free during doping. After doping, other doped cubes were annealed at 130 ° C for various times. Dope and annealed cubes were also analyzed using an infrared microscope to examine changes in vitamin E index properties as a function of annealing time. Figure 3 shows the diffusive properties examined in the doped and doped and annealed cubes. The unannealed sample had a much higher surface concentration than the inside, but the sample annealed at the same temperature for 100 hours showed nearly uniform properties. Therefore, post-doping annealing can be used to increase the uniformity of antioxidant distribution throughout the host polymer. The temperature and time of annealing can be adjusted by performing a parameter analysis as described herein.
Example 23: UHMWPE machining sequence UHMWPE can be doped with antioxidants at various stages, for example as outlined in Figures 4 and 5.
It should be understood that the description, examples and data show exemplary embodiments, but are for illustration purposes only and are not intended to limit the invention. Various changes and modifications within the invention will be apparent to those skilled in the art from the considerations, disclosures and data contained herein, which are also considered part of the invention.
<figref num="1">FIG. 1 shows the penetration depth of vitamin E diffusion into UHMWPE at room temperature, 100 ° C, 120 ° C and 130 ° C.</figref><figref num="2">Figure 2 shows the oxidation index as a function of the depth to one of the representative aged cubes of the number test group (TCRT group, RT1 group, RT16 group, TC100C16 group, 100C1 group, TC100C1 group and 100C16 group). Shows the characteristics.</figref><figref num="3">FIG. 3 shows the diffusion properties of vitamin E into unirradiated UHMWPE doped at 130 ° C for 96 hours as a function of the subsequent annealing time at 130 ° C.</figref><figref num="4">FIG. 4 outlines an example of the order in which UHMWPE is processed and doped at various stages.</figref><figref num="5">FIG. 5 outlines an example of the order in which UHMWPE is processed and doped at various stages.</figref>
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| Document | Relation | Office |
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| JP11239611A | Cites | Japan |
| WO00049079A1 | Cites | World Intellectual Property Organization (WIPO) |
| JP2000126281A | Cites | Japan |
| Journal of Biomedical Materials Research,1999年,Vol.48,No.4,p474-478 | Non-patent | – |
| 関節外科,1999年,Vol.18,No.12,p1382-1388 | Non-patent | – |
| 日本機械学会中国四国支部総会・講演会講演論文集,2002年,Vol.40th,p31-32,116 | Non-patent | – |
| 日本機械学会年次大会講演論文集,2002年,Vol.2002,No.02-1,p63-64,222 | Non-patent | – |
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- Publication
- 5758317
- Publication, DOCDB
- 5758317
- Publication, EPODOC
- JP5758317B
- Application
- 16768
- Application, DOCDB
- 2012016768
- Application, EPODOC
- JP20120016768
Titles2
- English
- Manufacturing method of oxidation-resistant polymer substance
- Japanese
- 耐酸化性ポリマー物質の製造方法
Classification
- CPC, 16
- A61L27/16
- B29C35/0805
- A61L27/505
- B29C43/003
- C08K5/005
- C08K5/1545
- C08L23/06
- C08L2312/06
- Y10T29/49995
- Y10T29/49
- Y10T428/31855
- A61L29/041
- A61L29/143
- A61L31/048
- A61L31/143
- C08J3/28
- IPC, 9
- A61L27 00
- A61L29 00
- A61L31 00
- A61B
- A61F2 00
- A61F2 958
- A61L27 16
- A61L27 50
- C08K5 34