MXPA98006471A - Structure of endoprotesis covered with polim - Google Patents

Abstract

The present invention relates to a method for coating an endoprosthesis, characterized in that it comprises the steps of: providing a stent having a generally cylindrical shape, the stent having an inner surface and an outer surface, securely placing a mandrel within the stent, to define a space of substantially constant thickness between the mandrel and the inner surface of the stent, contact the mandrel-containing stent with a polymer in the fluid state, allow the polymer to transform to a substantially non-fluid state, and remove the stent chuck

Description

STRUCTURE OF ENDOPROTESIS REVERSED WITH POLYMER BACKGROUND OF THE INVENTION This invention relates generally to grafts • expandable intraluminal vessels, commonly referred to as stents, and more particularly refers to the coating of metal stents with polymeric materials capable of transporting and releasing therapeutic agents. Stents are implanted within vessels in an effort to maintain their opening, by preventing crushing and / or preventing restenosis. Implantation of a stent is typically achieved by mounting the stent in the expandable portion of a balloon catheter, maneuvering the catheter through the vasculature to place the stent at the desired site within the body lumen, and inflating the balloon to expand the stent. Stents for coupling with the wall of the lumen. The stent automatically latches into its expanded configuration allowing the balloon to deflate and the catheter to be removed to complete the implant procedure. It is often convenient to provide localized pharmacological treatment of a vessel at the site supported by the stent and it has been found convenient to use the stent as a delivery vehicle for that purpose. However, due to the mechanical strength required to adequately support vessel walls, stents typically must be constructed of metallic materials that are not capable of transporting and releasing drugs. Various polymers, on the other hand, are quite capable of transporting and releasing drugs, but in general they do not have the necessary mechanical strength. A previously designed solution to this dilemma has been to coat the metal structure of a stent with polymeric material, in order to provide a stent that is capable of both supporting adequate mechanical loads and delivering drugs. Various approaches have previously been employed to join polymers to metal stents, including immersion, spraying and forming processes. However, these methods have failed to provide an economically viable method for applying a very uniform polymer coating on the stent surfaces or the ability to economically apply different thicknesses or different polymers in different areas on the same stent. The prior art has been unable to overcome these disadvantages and a new approach is required to efficiently and economically apply a polymeric material to a metal stent with a high degree of accuracy.

SUMMARY OF THE INVENTION The present invention provides a method for joining a polymeric material to a metal endoprosthesis - which overcomes the disadvantages of previously employed processes. More particularly, by this method, very precisely controlled polymer thicknesses can be applied to selected surfaces of the stent. The resulting stent has the mechanical strength necessary to adequately support a blood vessel, while being capable of delivering a pre-selected amount of drug or drugs for a desired period of time. Furthermore, the added polymer does not interfere with the deployment of the stent and therefore allows the stent to freely expand. The methods of the present invention require the use of mandrels and / or molds to apply precise amounts of polymer to the surfaces of stents. Furthermore, the advantageous positioning of these implements with respect to the endoprosthesis allows the thickness of the polymer to be varied from surface to surface. In this way it is easily possible to apply a thicker layer of polymer to the side facing the blood of the stent than to the side facing the vessel, or vice versa. Additionally, when employing successive molding operations, different polymers, selected for their different ability to absorb and release different therapeutic agents, can be applied to selected surface of the stent. Alternatively, the polymer can be applied to one side of the endoprosthesis as a preformed liner, while the subsequent molding operation not only serves to coat the opposite surface of the endoprosthesis but also to adhere the pre-formed liner to the endoprosthesis. By implanting a stent with said differentiated surfaces, it is therefore possible to directly expose the vessel wall to a therapeutic agent, while exposing the blood to a different therapeutic agent. Alternatively, it is possible to load polymers with different transport capacities of a particular therapeutic agent in order to supply different concentrations in a desired pattern. The method of the present invention includes a number of alternate embodiments, including the use of various combinations of mandrel configuration and exterior molds. The polymer is applied either by dip coating, pultrusion or injection molding processes. The embodiments of the method of the present invention ensure that very precisely dimensioned coatings result, even after the drying and cooling processes are completed. A final sawing or separation step may be necessary for some stent configurations in order to restore the flexibility and expandability desired to the stent. A laser is used for this purpose, to cut quickly and accurately and / or remove polymer from various locations in the coated stent. These and other features and advantages of the embodiments of the present invention will be apparent from the following detailed description of a preferred embodiment which, when taken in conjunction with the accompanying drawings, illustrates by way of example the principles of the invention. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a cross-sectional view of a mandrel that is placed inside a stent. Figure 2 is a cross-sectional view of a mandrel in position within an endoprosthesis and an enclosed outer mold. Figure 3 is a cross-sectional view of a mandrel inserted in a stent containing pre-formed liner. DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The Figures generally illustrate the techniques employed to apply a polymer to a stent in accordance with the present invention. Any of a variety of stent configurations can be subjected to the coating process described herein, including but not limited to grooved tube or multi-link type designs. The metals with which said endoprostheses are formed can include stainless steels, nickel-titanium (NiTi), and tantalum among others. The polymer or combination of polymers that are applied to the stent are chosen for the ability to transport and release, at a controlled rate, various therapeutic agents such as anti-thrombogenic drugs to antiproliferative agents. The polymeric material of the method of the invention preferably comprises a bio-degradable, bio-absorbable polymer film, which is capable of being charged with and releasing therapeutic drugs. The polymeric materials, preferably including but not limited to, polycaprolactone (PCL), poly-DL-lactic acid (DL-PLA) and poly-L-lactic acid (L-PLA) or lactide. Other bio-absorbable bio-absorbable polymers such as polyorthoesters, polyiminocarbonates, aliphatic polycarbonates and polyphosphazenes may also be suitable, and other non-degradable polymers capable of transporting and delivering therapeutic drugs may also be suitable. Examples of non-degradable synthetic polymers are those sold under the PARYLENE and PARYLAST trademarks by Advanced Surface Technology, Co. of Billerica, Massachusetts, E.TJ.A. and polyurethane, polyethylene, polyethylene terephthalate, ethylene vinyl acetate, silicone and • polyethylene oxide (PEO). Examples of therapeutic drugs, or agents that can be combined with polymeric materials, include anti-platelets, anti-coagulants, anti-fribines, anti-thrombin and anti-proliferative. Examples of anti-platelets, anti-coagulants, anti-fibrins, and antithrombin include, but are not limited to, sodium heparin, low molecular weight heparin, irudine, argatroban, forscolin, vapiprost, prostacyclin, and prostacyclin analogs. , dextran, D-phe-pro-arg-chloromethyl ketone (synthetic anti thrombin) dipyridamole, platelet membrane receptor antibody Illa / glyco-protein recombinant Ilb irudin ,. thrombin inhibitor (available from Biogen Corp. of Cambridge Massachusetts E.U.A.) and an anti-platelet drug sold under the trademark 7E-3B by Centocor, Inc., of Malvern, Pennsylvania, E.U.A.). Examples of cytostatic and antiproliferative agents include angiopeptin (a somastotine analog available from Ibsen Company of angiotensin converting enzyme inhibitors such as CAPTOPRIL (available from Squibb Pharmaceuticals, Cincinnati, Ohio, USA) CILAZAPRIL available from Hoffmann-La Roche, Inc. from Carleton, Michigan, USA or LISINOPRIL (available from Merck Pharmaceuticals of Kouts, Indiana, USA); calcium channel blockers (such as NIFEDIPINE) Colchicine, - fibroblast growth factor (FGF) antagonists fish oil (omega-3-fatty acid), histamine antagonists, LOVASTATIN, (an inhibitor of HMG-CoA reductase, a cholesterol-lowering drug, also available from Merck Pharmaceuticals (methotrexate, monoclonal antibodies such as PDGF receptors), nitroprusside, fos or ordigesterase inhibitors, prostaglandin inhibitor (available from Glaxo Wellcome, Inc. of Durham, North Carolina, USA) seramin ( a PDGF antagonist), serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist) and nitric oxide Other drugs or therapeutic agents that may be appropriate include alpha-interferon and epithelial cells under genetic engineering, for example While previous therapeutic agents have been employed to prevent or treat restenosis, each is provided in a manner for example and collectively the examples are not intended to be limiting, since other therapeutic drugs can be developed, which are equally applicable for use with the present invention. The treatment of diseases using the above therapeutic agents is known in the art. In addition, the calculation of dosage, dosage rates and appropriate duration of treatment are previously known in the art. Figure 1 illustrates the method of the present invention in its simplest form. The endoprosthesis 12 first slides on a mandrel in the shape of a core pin 14 after which a pin cover 16 is adapted to its distal end. The core pin extends from a proximal section 15 of increased diameter, similar to the outer diameter of the pin cap. As these two pin components advance with each other, the tapered configurations of the corresponding receiving surfaces 18 automatically cause the stent to be centered with respect to the core pin. The interference fit between the core pin and the pin cap ensures that the components are properly assembled and aligned during subsequent handling and processing. The pin is dimensioned precisely to provide the desired spacing 19 between the outer surface of the pin and the inner surface of the stent. This fixation of the stent also serves to minimize the contact area between the stent and the mandrel, which is limited to only two very narrow circles at the opposite edges of the stent.

The structure is subsequently immersed in the select polymer while the polymer is in a liquid or molten state. Adjustment of polymer viscosity - it may be necessary in order to ensure free access to the space between the core pin and the endoprosthesis through the slots or spacings of the link. This adjustment can be achieved by thermal or chemical means and is best optimized by empirical methods as is well known in the art. The presence of the pin is strictly limited and thus controls precisely the maximum thickness of the polymer that can be applied to the inner surface of the stent. Furthermore, prolonged or repeated contact with the polymer allows a substantially thicker layer of polymer to be constructed on the exterior of the stent, while the thickness of the inner layer remains constant. Alternatively, subsequent exposure to a second polymer allows the outer side, i.e. of the endoprosthesis vessel, to be coated with a different polymer than that which is connected to the inner surface of the endoprostheses, i.e. the blood side . After the polymer or polymers have all solidified or sufficiently set, the core pin and the pin cap are removed.

As an alternative to the immersion or submersion technique in the endoprosthesis / core pin structure, it is adapted to the exit port of an extruder and the polymer is applied to the endoprosthesis using a pultrusion technique well known in the art. Selecting the appropriate viscosity of the polymer again is critical, not only to ensure perfusion of the polymer through openings in the endoprosthesis and in the space between the endoprosthesis and the core pin, but also to achieve adequate coverage. Figure 2 illustrates a further alternative embodiment of the present invention, wherein an outer mold is employed in addition to the core pin described above. The endoprosthesis 12 is again first mounted with respect to the core pin 14 and the pin cover 16, after which the entire structure fits into an external mold 20. The endoprosthesis is thus held in position to define the precise spacing 19 between the outside of the core pin 16 and the inner surface of the endoprosthesis and between the outer surface of the endoprosthesis and the interior of the external mold 21. Subsequently, polymer is injected either by any number of routes, including through a passage that it extends through the core pin 14 or through the external mold 20. The viscosity of the polymer must be selected to facilitate its flow into the mold and through the stent, to ensure that an uninterrupted coating of the stent is achieved. Conditions that affect the viscosity requirements include, but are not limited to, the anticipated temperatures, cooling rates, molding times, orifice sizes and mold pressure and the particular m from which the stent is formed, etc. The appropriate viscosity is easily chosen by a person skilled in the art using simple empirical techniques. After the polymer has solidified or sufficiently cured, the coated stent and core pin are removed from the mold as a unit and then the core pin and the pin cap are removed from the stent. Successive molding operations with core pins with different sizes or outer molds allow layers of different materials to accumulate on the inner or outer surface of the endoprosthesis. An alternate embodiment avoids the use of the core pin and cap described above, whereby a pre-formed polymer liner is initially inserted into the stent. By sequentially applying polymer in its liquid state to the exterior of the endoprosthesis, the liner remains attached to the applied polymer and in this way the endoprosthesis is completely circumscribed in the polymer. The pre-formed nature of the liner serves to precisely define the thickness of the polymer that will be • applied to the inner surface of the stent. A dip coating process without the use of an exterior mold allows the polymer to collect selectively on the outside of the stent, while the use of an external mold positively limits its external thickness. The polymer from which the liner is pre-formed does not necessarily have to correspond to the polymer that is subsequently applied in fluid form, thus different types of polymer can be applied to the surfaces of the stent. Figure 3 illustrates the preferred method of practicing this modality. The polymer liner 24 which will comprise the inner surface of the finished product, but is applied to a silicon or Teflon support tube 22, either by extrusion or dip coating. The metal stent then slides on the coated tube and then a tapered mandrel 26 is inserted into the tube. The taper 28 of the tapered mandrel facilitates insertion and expands the polymer liner tightly against the inner surface of the stent 12. The exterior of the stent is then coated with polymer, either by immersion or pultrusion without an outer mold, or by casting injection with the use of an external mold. After curing, the tapered mandrel 26 and support tube 22 are removed to provide a fully coated endoprosthesis. Depending on the type of structure of the stent to which the polymer is applied, it may be necessary to remove some of the polymer or at least cut the polymer at selected sites in order to restore the necessary flexibility to the stent. In a multi-joint endoprosthesis or links, for example, the various links must be able to undergo a relative movement during the expansion of the device. The presence of the polymer or at least the presence of a continuous mass of polymer between the links can inhibit relative movement and thus inhibit expansion of the stent during deployment. In order to avoid this inhibition of movement or expansion, it is necessary to remove or at least perforate the polymer at said locations. The preferred method of doing this is with the use of a laser, with which the polymer material can be penetrated quickly and precisely as required. With certain stent configurations, it is advantageous to apply polymer to the stent while the stent is in the expanded state. The stent initially expands, such as by advancing the core pin and the pin cap together, to force the stent high enough-over the tapered surface to achieve its deployment diameter. • Alternatively, an over-sized liner and mandrel can be used. Any of the various alternate embodiments described above can then be used to apply the polymer. For certain stent configurations, the application of the polymer while the stent is in the expanded state results in less "trussing" between the columns and generates greater mechanical stability in the final product. Additionally, the final polymer coating may require little or no laser processing for separation or cleaning, before the stent contracts to its pre-delivery outer diameter or "0. D.". After the stent is coated and trimmed, one or more therapeutic agents can be loaded to desired concentration levels, according to methods that are well known in the art, to make the device ready for implantation. While a particular form of the invention has been illustrated and described, it will also be apparent to those skilled in the art that various modifications may be made without departing from the scope of the invention. Accordingly, the invention is not intended to be limited except by the appended claims.

Claims (21)

1. CLAIMS 1. A method for coating a stent, characterized in that it comprises the steps of: providing a stent having a generally cylindrical shape, the stent having an inner surface and an outer surface; securely placing a mandrel within the stent, to define a space of substantially constant thickness between the mandrel and the inner surface of the stent; contact the endoprosthesis containing mandrel with a polymer in the fluid state; allowing the polymer to transform to a substantially non-fluid state; and removing the mandrel from the stent. 2. - The method according to claim 1, characterized in that the endoprosthesis containing mandrel is contacted with the polymer to coat the outer surface of the endoprosthesis with a polymer layer having a thickness that is greater than the thickness of the space between the mandrel and the inner surface of the stent. 3. The method according to claim 2, characterized in that the stent is contacted with the polymer by submerging the stent in a polymer base while the polymer is fluid. 4. - The method according to claim 1, characterized in that the endoprosthesis is contacted with the polymer by a pultrusion technique. 5. - The method according to claim 1, characterized in that it further comprises the step of re-contacting the endoprosthesis containing mandrel with the polymer, while the polymer is in a fluid state after the polymer with which the The endoprosthesis has been previously contacted, transformed into a substantially non-fluid state and prior to removal of the mandrel, whereby the outer and inner surfaces of the endoprosthesis differ in terms of the thickness of the polymer coatings. 6. - The method according to claim 1, characterized in that it further comprises the step of contacting the endoprosthesis with a second polymer, while the second polymer is in a fluid state after the first polymer has been transformed to a substantially not fluid and before removing the mandrel, whereby the outer and inner surfaces of the stent are differentiated in terms of the types of the coated polymers. The method according to claim 1, characterized in that the mandrel comprises a core pin and a pin cover, wherein the pin cover slidably receives the distal end of the core pin and wherein both the core pin and the cover The pins include a conical surface extending to a diameter greater than that of the endoprosthesis, the method further comprising the step of advancing the pin cover on the core pin, whereby the endoprosthesis is coaxially held in position relative to the core pin. . 8. Method for coating an endoprosthesis, characterized in that it comprises the steps of: providing a stent having a generally cylindrical shape, the stent having an inner surface and an outer surface; securely placing a mandrel within the stent, to define a first space of a first substantially constant thickness between the mandrel and the inner surface of the stent; securely placing the mandrel-containing stent within an outer mold, to define a second space of a second substantially constant thickness between the outer mold and the outer surface of the stent; introducing a polymer in a fluid state in the first and second spaces; allowing the polymer to transform to a substantially non-fluid state; and removing the outer mold from around the endoprosthesis and the mandrel from the interior of the endoprosthesis. 9. - The method according to claim 8, characterized in that the first thickness is greater than the second thickness. 10. - The method according to claim 9, characterized in that the second thickness is greater than the first thickness. 11. - The method according to claim 8, characterized in that it further comprises the steps of: removing only the outer mold from around the stent after the polymer has been transformed to a substantially non-fluid state, -place in a safe manner the endoprosthesis containing a mandrel inside a second external mold to define a third space between the outer surface of the coated stent with the first polymer and the second outer mold; and introducing a second polymer in a fluid state into the third space. 12. Method for coating a stent, characterized in that it comprises the steps of: providing a stent having a generally cylindrical shape, the stent having an inner surface and an outer surface; adjusting a pre-formed liner of a first polymer within the stent; contacting the stent with a second polymer in a fluid state, and allowing the second polymer to transform to a substantially non-fluid state. 13. - The method according to claim 12, characterized in that the first and second polymers are equal. 14. - The method according to claim 12, characterized in that the first and second polymer are different. 15. - The method according to claim 12, characterized in that it further comprises the step of inserting a mandrel into the liner of the first adapted polymer within the stent in order to expand the lining of the first polymer against the outer surface of the stent. 16. The method according to claim 15, characterized in that the mandrel has a tapered tip. 17. - The method according to claim 12, characterized in that it further comprises the step of safely placing the endoprosthesis containing liner, inside an outer mold to define a space between the outer surface of the endoprosthesis, the mold has a first constant thickness. 18. The method according to claim 17, wherein the lining of the first polymer has a second constant thickness and wherein the first and second thicknesses are equal. 19. - The method according to claim 17, wherein the polymer cylinder has a second constant thickness and wherein the first and second thicknesses are not equal. 20. The method according to claim 19, characterized in that the first thickness is greater than the second thickness. 21. The method according to claim 19, characterized in that the second thickness is greater than the first thickness.