« PreviousContinue »
(19) United States
(12) Patent Application Publication (io) Pub. No.: US 2006/0036316 Al
Zeltinger et al. (43) Pub. Date: Feb. 16,2006
INHERENTLY RADIOPAQUE BIORESORBABLE
POLYMERS FOR MULTIPLE USES
CROSS-REFERENCE TO RELATED
 This application claims benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 60/601, 526, filed Aug. 13, 2004.
BACKGROUND OF THE INVENTION  1. Field of the Invention
 Preferred embodiments of the present invention relate to inherently radiopaque bioresorbable polymers for use in fabricating medical devices, such as stents. More particularly, the polymeric compositions comprise halogencontaining phenol moieties.
 2. Description of the Related Art
 Medical devices comprised of metal or polymer are used for numerous clinical applications every day. Metal medical devices are generally radiopaque due to the nature of the material whereas polymer medical devices are generally not naturally radiopaque. Hence, there remains a need for additional radiopaque bioresorbable polymeric formulations for use in devices that provide the advantage of radiopacity for a variety of medical procedures. A prime example of such a device includes vascular stents which are described below.
 Vascular stents are used widely in a variety of applications, including, especially, in the treatment of heart disease. It has been reported that in 1998, about 61 million Americans had some form of heart disease, which since about 1990 has been the single leading cause of death in the United States. One type of heart disease, coronary artery disease (CAD), is characterized, at least in part, by the inhibition of blood flow through the arteries that supply blood to the heart muscle due to the buildup of plaque (arteriosclerosis) in the arteries. CAD is suspected to account for 1 out of every 5 deaths that occur in the U.S.A. In 2001, about 1.1 million people had a new or recurrent myocardial infarction (heart attack due to coronary arterial disease). See, for example, Report by the American Heart Association, "Heart and Stroke Statistical Update", 2001, American Heart Association, Dallas, Tex. Currently more than 500,000 Americans are treated annually for blocked coronary arteries. This number is expected to double over the next 10 years in light of the aging population.
 Vascular stents generally comprise a mesh tube, which is inserted into an artery to keep the artery open after it has been stretched with a balloon during the course of an angioplasty procedure. Typically, the vascular stent is mounted on a balloon catheter that is inserted via the femoral artery and pushed to the desired location in the coronary artery. There, the balloon is inflated, thus expanding the stent and pressing it against the vessel wall to lock it in place.
 Most stents are constructed from metal, including, for example, stainless steel or nitinol. While such metal stents possess certain desirable characteristics, such as sufficient radial strength to hold open a subject artery and radio-opacity (allowing an implanted stent to be seen and monitored by X-ray radiography/fluoroscopy), metal stents
also exhibit a number of significant disadvantages. For example, the insertion and expansion of a metal stent in an artery tends to further injure the diseased vessel, potentially leading to the development of intimal hyperplasia and further occlusion of the vessel by the resulting in-growth of smooth muscle cells and matrix proteins through the stent struts. Another disadvantage associated with use of metal stents is that once deployed, they become permanent residents within the vessel walls—long after their usefulness has passed. Indeed, the useful lifespan of a stent is estimated to be in the range of about 6 to 9 months. After this time, the chronic stresses and strains imposed on the vessel architecture by the permanent metal implants are believed to promote in-stent restenosis. Another disadvantage associated with the use of metal stents is that the placement of multiple permanent metal stents within a vessel may be a barrier to subsequent surgical bypass. Further, the deployment of a first metal stent may become a physical hurdle to the later delivery of a second stent at a distal site within the same vessel. In contrast to a metal stent, a bioresorbable stent may not outlive its usefulness within the vessel. Moreover, a bioresorbable stent may be used to deliver a greater dose of a therapeutic, as a drug and/or biological agent could be coated on the stent as well as embedded in the device itself. Further, such a stent could deliver multiple drugs and/or biological agents, at the same time or at various times of its life cycle, to treat specific aspects or events of vascular disease. Additionally, a bioresorbable stent may also allow for repeat treatment of the same approximate region of the blood vessel.
 U.S. Pat. No. 6,475,477 ("the '477 patent") teaches medical devices formed from radiopaque biocompatible polymers with hydrolytically unstable polymer backbones and pendant free carboxylic acid groups that promote polymer degradation and resorption; incorporated herein in its entirety by reference. Not only are many of the disclosed polymers less than ideal for use in stents, the polymers with free carboxylic acid groups are prepared from monomers with benzyl-protected free acid moieties that are selectively removed from the polymer via hydrogenolysis in the presence of a palladium catalyst and hydrogen. While such a method is effective for removing the benzyl protecting groups with little or no cleaving of the polymer backbone, the palladium catalyst used therein is relatively expensive, and traces of palladium are difficult to remove from the polymer product.
 Some of the aforementioned deficiencies of the '477 patent have been addressed in U.S. patent application Ser. No. 11/176,638, filed Jul. 7, 2005, and Ser. No. 10/952, 274, filed Sep. 27, 2004, both of which are incorporated herein by reference in their entireties. However, there remains a need for additional radiopaque bioresorbable polymeric formulations that provide advantageous physicochemical properties adapted for use in fabricating a variety of implantable medical devices.
 Hutmacher D W, Sittinger M, Risbud M V. Scaffold-based tissue engineering: rationale for computeraided design and solid free-form fabrication systems. Trends Biotechnol. 2004 July; 22(7):354-62.
 A1 is selected from the group consisting of
 For purposes of summarizing the invention, certain aspects, advantages and novel features of the invention have been described herein above. Of course, it is to be understood that not necessarily all such advantages may be achieved in accordance with any particular embodiment of the invention. Thus, the invention may be embodied or carried out in a manner that achieves or optimizes one advantage or group of advantages as taught or suggested herein without necessarily achieving other advantages as may be taught or suggested herein.
 An embodiment provides an inherently radiopaque, biocompatible, bioresorbable polymer, wherein the polymer comprises one or more recurring units of the Formula (I):
 X1 and X2 are each independently selected from the group consisting of Br and I;
 yl and y2 are each independently zero or an integer in the range of 1 to 4, with the proviso that the sum of yl and y2 is at least one;
 R1 is
 R5 is selected from the group consisting of H, ... alkyl, and C^C^ heteroalkyl. In a preferred embodiment, X1, X2, yl and y2 are selected so that X1 and X2 are present in an amount that is effective to render the polymer radiopaque.
 In an embodiment of a polymer comprising a recurring unit of the Formula (I), R1 in Formula (I) is:
 wherein R3 is H or a non-crystallizable C1 to C29 hydrocarbon;
 Z1 and Z2 are each independently O or S; and
 m is an integer in the range of 1 to 8.
 In another embodiment of a polymer comprising a recurring unit of the Formula (I), R1 in Formula (I) is:
 R13 and R14 are each independently selected from the group consisting of —CH=CH—, —(CH2)C—, —(CHJ1)—, —CHJ2—CHJ3—, _CH=CH—(CHJ1)—, and —(CH2)C—(CHJ1)—;
 c is zero or an integer in the range of 1 to 8;
 J1, J2 and J3 are each independently selected from the group consisting of H, Br, I, —NH-Q2 and —C(=Z8)-OQ3;
 Q1, Q2 and Q3 are each independently H or a non-crystallizable group comprising from about 1 to about 30 carbons;
 Z7 and Z8 are each independetly O or S;