Dendritic and star-shaped contrast agents for medical devices and bioabsorbable radiopaque bulk material and method for producing same

Abstract

In accordance with the present invention, a high intensity radiopaque contrast agent is disclosed. The agent may be coated on or incorporated within bulk material which may then be subsequently utilized to fabricate a radiopaque medical device. Primary effects through chemistry include higher radiopaque concentrations per unit weight of the radiopaque element or agent. Secondary effects include selective placement of the radiopaque elements which may further enhance the radiopacity of the device with reduced requirements of the radiopaque agent. Such a radiopaque contrast agent may be produced in various forms such as a dendrimer and / or incorporated as the end groups of polymeric chain. In addition one can incorporate biological and / or pharmaceutical agents in combination with the present invention.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This Application claims priority under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 60 / 662,957 filed on Mar. 18, 2005.FIELD OF THE INVENTION [0002] The present invention relates to intravascular devices used in medical treatment and procedures. More specifically, the present invention relates to a new class of organic high intensity X-ray contrast agents suitable for enhancing the imaging of medical devices, particularly polymeric medical devices and polymeric coatings being fabricated from a polymer with the contrast agent dispersed within, conjugated at one or both ends of the polymers, as well as the method of manufacture of such materials and devices. DISCUSSION OF THE RELATED ART [0003] Recently, transluminal prostheses have been widely used in the medical arts for implantation in blood vessels, biliary ducts, or other similar organs of living body. These prostheses are commonly known as stents and are used to maint...

AI Technical Summary

Benefits of technology

[0017] The high intensity X-ray contrast agent in accordance with the present invention overcomes the disadvantages and shortcomings of what is currently available and satisfies the unmet needs of imaging medical devices, particularly non-metallic medical devices by maximizing the intensity of the x-ray contrast agent both through primary and secondary effects. Primary effects include incorporating the radiopaque element and maximizing the content of this element in the contrast agent through chemistry, while secondary effects include optimizing the location of the radiopaque element within the polymer. Essentially by selectively maximizing and incorporating the iodine content within and dispersed throughout the polymer one can tune the radiopacity of polymeric materials to levels previously not available. Moreover, the creation and optimization of this contrast agent allows for improved processing characteristics when combined with polymeric materials and as such may further reduce manufacturing costs while providing a polymeric material with improved high intensity radiopacity with a satisfactory degradation profile.

[0019] In an exemplary embodiment of the present invention, the contrast agent may contain a multiplicity of iodine atoms or bromine atoms or a combination of both in a single molecule in order to enhance the x-ray image produced by dispersing the agent throughout the material that either the device will be fabricated from or applied as a coating to the device. In accordance with the present invention, the contrast agent can be constructed from any core of dendrimer containing free functional groups such as amine, hydroxyl, sulfhydryl, isocyante, and result in a molecule containing a multiple of three (3) iodine or bromine or a combination of both atoms with each additional conjugation of small iodine or bromine containing building block, such as triiodobenzoic acid or as triiodobenzoic acid chloride. When constructed in this fashion, the contrast agent may be substantially soluble in common organic solvent such as acetone, dimethylacetamide (DMA), dimethylsulfoxide (DMSO), acetone, THF, 1,4-dioxane, DCM etc. and also has substantially good miscibility with common organic polymers such as PLGA, PLA etc. The contrast agent in accordance with the present invention can form a solid solution with a polymer matrix that can then form the basis of a medical device. The contrast agent in accordance with the present invention is substantially biocompatible and can be added to polymer or polymer mixtures, and / or inorganic / organic composite materials to enhance its X-ray image quality.

[0021] In yet another exemplary embodiment of the present invention, selective incorporation of the contrast agent to a polymeric structure can be accomplished in a number of ways. By ensuring placement of the contrast agent in certain areas of the polymer structure and not in other areas, additional secondary improvements in radiopacity can be realized without affecting material and / or mechanical properties. One such example is incorporation of the contrast agent at the proximal and distal ends of the polymer chain. By utilizing methods such as orientrusion, which may provide for a high degree of molecular orientation of the polymer chains within the polymer, one can create a polymeric material with high intensity radiopacity at the select portions of the bulk material which would be significantly more radiopaque than the surrounding areas where the contrast agent was not present. Like wise the selective placement of the contrast agents in the coating material can provide one with secondary benefits similar to those obtained with selective placement of the contrast agents in the bulk material.

[0024] The use of compounds in conjunction with the present invention can provide distinct clinical advantages over existing therapies and / or devices. More specifically, compounds that are capable of causing lysis or degradation of the embolic debris can be incorporated into the filtering portion of the present invention. A factor to consider in the selection of such a compound is the origin of the debris be it thrombus, plaque, atheroma, or any other form representing an embolus. As the mesh and or pore size of the filtering aspect of the present invention decreases, more embolic material may become trapped in the filtering mechanism of the present invention, thereby increasing the load on the filtering portion. While small emboli (typically smaller than 100 microns) are not a major concern because of the body's natural ability to enzymatically degrade, digest or lyse the emboli, the embolic load on the filter itself can be overloaded and result in formation of a thrombus if the blood flow is significantly slowed to the point which allows for a thrombus formation. In this situation the incorporation or application of compounds, which can degrade trapped emboli, can be beneficial. Some exemplary suitable compounds may include: Tissue Plasminogen activator (TPA); Streptokinase(SK); Reteplase; Tenecteplase; Urokinase; Lanoteplase; Staphylokinase; and / or Nadroparin(anti-factor Xa). In addition, the filtering portion of the present invention may incorporate an antithrombotic and / or antithrombogenic agent to prevent the formation of a thrombus. Some exemplary compounds may include: Heparin; Fragmin (dalteparin, low MW Heparin); a monoclonal antibody such as ReoPro™ (abciximab, antiplatelet antibodies) Acenocoumarol; Anisindione; Dicumarol; Warfarin; Enoxaparin (Lovenox); Anagrelide (Agrylin); Indomethacin (Indocin); Dipyridamole; Clopidogrel; Aggrenox; and / or Coumadin. Furthermore, an affinity-binding compound may also be incorporated with the filtering aspect of the present invention by itself or in combination with other compounds. Affinity-binding compounds can promote the binding and / or adhesion of embolic material thus facilitating entrapment of embolic material and subsequent removal from the blood stream. Whether incorporated into the strut or membrane by methods such as chemical surface treatments, bombardment, placement into reservoirs, or in the case of polymeric struts and membranes, blended with the material itself, or by application of a coating to the struts and / or membranes with a compound, any identified compound or combination of identified compounds may be used. Furthermore any number of compounds may suggest themselves to one who is skilled in the art and may be utilized in connection with the present invention alone or in combination with other compounds.

[0025] The foregoing exemplary embodiments of the present invention provide a high intensity radiopaque contrast agent which may be used independently, for example as a coating or may be incorporated within a polymeric material to be subsequently fabricated into medical devices in accordance with the present invention. Moreover, the incorporation of drugs and / or agents may be combined with the high intensity contrast agent to realize additional synergistic benefits. As noted above, the incorporation of biological and / or pharmaceutically active agents with the present invention can be utilized for the additional purposes of preventing thrombus formation, promotion of binding, and degradation of thrombus, all of which provide a patient benefit.

Problems solved by technology

However, one concern with such stents is that they are often impractical for use in some vessels such as the carotid artery.

A sufficient force placed on the patient's neck could cause the stent to collapse, resulting in injury to the patient.

They typically do not have the necessary radial strength to effectively hold open a diseased vessel.

In addition, the plurality of wires or fibers used to make such stents could become dangerous if separated from the body of the stent, where they could pierce through the vessel.

Methods of using the shape memory characteristics of these alloys in medical devices intended to be placed within a patient's body present operational difficulties.

For example, with shape memory alloys having a stable martensite temperature below body temperature, it is frequently difficult to maintain the temperature of the medical device containing such an alloy sufficiently below body temperature to prevent the transformation of the martensite phase to the austenite phase when the device was being inserted into a patient's body.

With intravascular devices formed of shape memory alloys having martensite-to-austenite transformation temperatures well above body temperature, the devices can be introduced into a patient's body with little or no problem, but they must be heated to the martensite-to-austenite transformation temperature, which is frequently high enough to cause tissue damage.

However, the prior art has yet to disclose any suitable tube-cut self-expanding stents.

In addition, many of the prior art stents lacked the necessary rigidity,or hoop strength to keep the body vessel open.

In addition, many of the prior art stents have large openings at their expanded diameter.

However, due to the relative position of these materials in the galvanic series versus the position of the base metal of the stent in the galvanic series, there is a certain challenge to overcome; namely, that of galvanic corrosion.

For these types of devices a major challenge exists in how to impart / increase the radiopacity of these devices with out the use of radiopaque markers or coatings.

However addition of barium sulfate in large percentage quantities such as this may affect the integrity of the base material, reducing strength, and adversely affecting other mechanical properties and characteristics.

Furthermore, inorganic contrast agents such as barium sulfate and zirconium oxide do not readily dissolve or do not easily disperse in organic solvents, which are commonly used to dissolve non-degradable and biodegradable polymers.

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