US 2006OO13849A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0013849 A1 Strickler et al. (43) Pub. Date: Jan. 19, 2006

(54) MEDICAL DEVICES CONTAINING Publication Classification RADIATION RESISTANT BLOCK COPOLYMER (51) Int. Cl. A6IF I3/00 (2006.01) (76) Inventors: Frederick H. Strickler, Natick, MA (52) U.S. Cl...... 424/422 (US); Robert E. Richard, Wrentham, MA (US) (57) ABSTRACT The present invention relates generally to radiation-resistant Correspondence Address: medical devices which contain polymer regions for release MAYER, FORTKORT & WILLIAMS, PC of therapeutic agents. The present invention also relates to 251 NORTHAVENUE WEST radiation-resistant block copolymer materials for use in 2ND FLOOR connection with insertable or implantable medical devices. WESTFIELD, NJ 07090 (US) The radiation-sterilized medical device comprise (a) a release region and (b) at least one therapeutic agent and the (21) Appl. No.: 10/894,400 release region comprises a radiation resistant copolymer that includes (i) a low Thydrocarbon polymer block and (ii) one (22) Filed: Jul. 19, 2004 or more high T. polymer blocks. Patent Application Publication Jan. 19, 2006 Sheet 1 of 9 US 2006/0013849 A1

H H C n -n}\}(forC - neH NcH CH - H. H. CH 2 HO

CHs 1 CH 1 |

Br CH

FIG 1 Patent Application Publication Jan. 19, 2006 Sheet 2 of 9 US 2006/0013849 A1 - Hine) h n iserH - in H n FS) (H2 H CuBrf ligand th: H - - ch1 CH / -" Y. Y.

CH HC Bf Chi PS

FIG 2 Patent Application Publication Jan. 19, 2006 Sheet 3 of 9 US 2006/0013849 A1

Bf B

d

CH CH C y c1 c 2 CH CH h C

FIG 3 Patent Application Publication Jan. 19, 2006 Sheet 4 of 9 US 2006/0013849 A1

HO CH

r Br

d O y Cu(l)Brf ligand

CH Chs l N c O ch CH CH O Patent Application Publication Jan. 19, 2006 Sheet 5 of 9 US 2006/0013849 A1

Br

O y" Cu(Br figand

CHy H

ch c -- N H, y 2- O o

FIGS Patent Application Publication Jan. 19, 2006 Sheet 6 of 9 US 2006/0013849 A1

-- (CH3)CBrCOBr O N SiMe

O HC Br O~---- y SEMe

FG 6 Patent Application Publication Jan. 19, 2006 Sheet 7 of 9 US 2006/0013849 A1

FIG 7 Patent Application Publication Jan. 19, 2006 Sheet 8 of 9 US 2006/0013849 A1

FIG 8 Patent Application Publication Jan. 19, 2006 Sheet 9 of 9 US 2006/0013849 A1

PrO OH CHSiCHCHSiH,c t X Y

C C

PrO R X Y 4. Hydrolysis/Deprotection

HO R X Y 4

styrene (CH3)2CBrCOBr PS - Polystyrene Block PrO - protected hydroxyl group PS R R - silicone coupling agent X Y 4

FIG 9 US 2006/OO13849 A1 Jan. 19, 2006

MEDICAL DEVICES CONTAINING RADATION (and body) temperature. Polystyrene, on the other hand, has RESISTANT BLOCK COPOLYMER a much higher T and is thus hard at these temperatures. Polystyrene is also thermoplastic in nature, opening up a FIELD OF THE INVENTION wide range of processing capabilities. Depending upon the relative amounts of polystyrene and polyisobutylene, the 0001. The present invention relates generally to radia resulting copolymer can be formulated to have a range of tion-resistant medical devices which contain polymer hardness, for example, from as Soft as about Shore 10A to as regions for release of therapeutic agents. The present inven hard as about Shore 10OD. tion also relates to radiation-resistant block copolymer mate rials for use in connection with insertable or implantable 0007 Whether the system comprises a SIBS copolymer medical devices. or other biocompatible polymers, these materials, once incorporated into a finished medical device, typically BACKGROUND OF THE INVENTION undergo a Sterilization proceSS. Two prevalent Sterilization processes are exposure to ethylene oxide (EtO) and irradia 0002) Numerous polymer-based medical devices have tion by, for example, gamma or electron beam radiation. For been developed for the delivery of therapeutic agents to the Several decades, Sterilization using ethylene oxide has been body. In accordance with Some typical delivery Strategies, a the method of choice for Sterilizing medical devices Such as therapeutic agent is provided within a polymeric carrier catheters, mechanical heart Valves, Sutures, adhesive ban layer and/or beneath a polymeric barrier layer that is asso dages, tracheostomy tubes, and So on. The primary advan ciated with a medical device. Once the medical device is tages associated with the use of EtO Sterilization are the low placed at the desired location within a patient, the therapeu processing temperature and the wide range of compatible tic agent is released from the medical device at a rate that is materials. However, the toxicity of the gas, its potential dependent upon the nature of the polymeric carrier and/or carcinogenicity, and concerns over residuals in the product barrier layer. and the manufacturing environment have Subjected EtO use 0003. Materials which are suitable for use in making to ever increasing regulatory Scrutiny and control and con implantable or insertable medical devices typically exhibit tinues to escalate the cost of EtO Sterilization. In addition, one or more of the qualities of exceptional biocompatibility, EtO is highly reactive and may interact with or otherwise extrudability, elasticity, moldability, good fiber forming adversely affect various therapeutic agents present in a properties, tensile strength, durability, and the like. More medical device. over, the physical and chemical characteristics of the device 0008 Radiation sterilization, whether by gamma rays, materials can play an important role in determining the final X-rays, accelerated electrons, or other means, is a widely release rate of the therapeutic agent. used alternative method for Sterilizing medical devices. 0004. As a specific example, block copolymers of poly Products to be Sterilized are typically exposed to gamma isobutylene and polystyrene, for example, polystyrene-poly rays from a Co-60 or a Cs-137 source or to machine isobutylene-polystyrene triblock copolymers (SIBS copoly accelerated electrons until the desired dose is received. No mers), which are described in U.S. Pat. No. 6,545,097 to toxic agents are involved, and products may be released for Pinchuk et al., which is hereby incorporated by reference in Sale on the basis of documentation that the desired dose is its entirety, have proven valuable as release polymers in delivered. For the Sterilization of polymeric medical devices, implantable or insertable drug-releasing medical devices. AS a typical radiation dose of about 1.0-5.0 Mrad (10-50 kGy) described in Pinchuk et al., the release profile characteristics or higher, is employed. of therapeutic agents Such as paclitaxel from SIBS copoly 0009 Radiation sterilization, however, may modify mer Systems demonstrate that these copolymers are effective many important physical and chemical properties of poly drug delivery Systems for providing therapeutic agents to meric materials. Such as the molecular weight, chain length, Sites in Vivo. entanglement, polydispersity, branching, pendant function 0005 These copolymers are particularly useful for medi ality, and chain termination. These changes in the properties cal device applications because of their excellent Strength, may impact, for instance, the drug-eluting properties of the biostability and biocompatibility, particularly within the polymers and impair the performance of a polymer for a vasculature. For example, SIBS copolymers exhibit high Specific use. For example, from a product use Standpoint, tensile Strength, which frequently ranges from 2,000 to mechanical properties are important characteristics that may 4,000 psi or more, and resist cracking and other forms of be adversely affected by irradiation of polymers. These degradation under typical in Vivo conditions. Biocompat properties include tensile Strength, elastic modulus, impact ibility, including vascular compatibility, of these materials Strength, Shear Strength, and elongation. has been demonstrated by their tendency to provoke mini 0010 For example, when polymers are exposed to radia mal adverse tissue reactions (e.g., as measured by reduced tion, two basic reactions may occur: (1) chain Scission (i.e., macrophage activity). In addition, these polymers are gen a random rupturing of bonds) of polymer molecules and (2) erally hemocompatible as demonstrated by their ability to croSS-linking of polymer molecules. Crosslinking generally minimize thrombotic occlusion of Small vessels when results in the formation of larger, three-dimensional polymer applied as a coating on coronary Stents. Structures. Chain Scission, on the other hand, generally 0006. In addition, these polymers possess many interest results in a decrease in the molecular weight of the polymer ing physical and chemical properties Sought after in medical molecules. Although both of these reactions commonly devices, due to the combination of the polyisobutylene and occur as polymeric materials are Subjected to ionizing polystyrene blockS. Polyisobutylene has a low glass transi radiation, one reaction frequently predominates within a tion temperature (T) and is Soft and elastomeric at room Specific polymer. As a result of chain Scission, Very-low US 2006/OO13849 A1 Jan. 19, 2006 molecular-weight fragments, gas evolution, and unsaturated tion-sterilized medical device comprising (a) a release bonds may appear. Cross-linking generally results in an region and (b) a therapeutic agent. The release region initial increase in tensile Strength, while impact Strength comprises a radiation resistant copolymer that further com decreases and the polymer becomes more brittle with prises (i) a low Thydrocarbon polymer block and (ii) a high increased dose. T. polymer block. 0.011 For polymers with carbon-carbon backbones, it has 0016. The present invention is advantageous in that a been observed that croSS-linking generally will occur if the medical device can be provided, which is resistant to the carbons have one or more hydrogen atoms attached, whereas damaging effects of radiation Sterilization. chain-Scission generally occurs at tetra-Substituted carbons. Polymers containing aromatic molecules are generally more 0017 Another advantage of the present invention is that resistant to radiation degradation than are aliphatic poly implantable or insertable medical devices can be provided, mers; this is true whether or not the aromatic group is which result in controlled release of a therapeutic agent. directly in the chain backbone or not. Thus, both polysty 0018 Yet another advantage of the present invention is renes, with a pendant aromatic group, and polyimides, with that biostable, radiation-resistant polymeric materials are an aromatic group directly in the polymer backbone, are provided which avoid the limitations of standard synthesis relatively resistant to high doses (>4000 kGy). On the other methods for preparing polyisobutylene Via a living cationic hand, homopolymers and copolymers containing polyisobu polymerization process. tylene Such as a SIBS copolymer are generally more SuS ceptible to radiation effects and may undergo chain Scission 0019. These and other embodiments and advantages of during irradiation, especially at the radiation levels typically the present invention will become immediately apparent to used for medical device Sterilization (e.g., about 2.5 Mrad). those of ordinary skill in the art upon review of the Detailed A Summary of the effects of radiation on polymer properties, Description and claims to follow. Such as loSS of elongation, for a number of common ther moplastics and thermosets is provided in “Polymer Materi BRIEF DESCRIPTION OF THE DRAWINGS als Selection for Radiation-Sterilized Products” by Karl J. 0020 FIG. 1 schematically illustrates the synthesis of an Hemmerich, Medical Device & Diagnostic Industry Maga EPDM macroinitiator by the reaction of an EPDM molecule zine, February 2000, pp. 78-89, the entire contents of which having a hydroxyl end functional group with 2-bromo are hereby incorporated by reference. isobutyryl bromide to form an EPDM with a bromoester end 0012 Radiation issues are particularly pronounced in functional group (EPDM macroinitiator). medical devices having thin polymer coatings. This is espe cially true where a radiation Sensitive polymer Such as a 0021 FIG. 2 schematically illustrates the synthesis of a SIBS copolymer is provided in the form of a thin coating on block copolymer having a comb architecture and which the Surface of an expandable medical device Such as a Stent comprises poly(EPDM)-graft-polystyrene by the polymer or balloon. For example, radiation can lead to an unaccept ization reaction of the EPDM macroinitiator with styrene able increase in the surface tack of the SIBS copolymer, monomer under Standard controlled/living radical polymer which can in turn cause defects in the polymer when it is ization conditions. expanded (e.g., in situations where it is in the form of a 0022 FIGS. 3, 4, and 5 schematically illustrate the coating on the Surface of an expandable Stent or balloon). synthesis of three triblock copolymers for the medical 0013 Additionally, SIBS copolymers present special devices of the present invention comprising polystyrene Synthesis challenges. Currently, SIBS copolymers are Syn endblocks and polyolefin midblocks using commercially thesized by a living cationic polymerization process, a available telechelic polyolefins. complex process that requires Stringent reaction conditions 0023 FIG. 6 schematically illustrates the synthesis of a and low temperatures. Ionic (cationic and anionic) polymer macroinitiator from a hybrid organic/inorganic SiMe poly izations typically require reaction conditions free of mois olefinic molecule having a hydroxyl functional group by ture, oxygen, as well as impurities. To date, only a limited reacting the molecule with 2-bromo-isobutyryl bromide to number of monomers have been polymerized by a living form a C-bromoester end group on the end of the poly cationic polymerization process, thus restricting the ability olefinic molecule. to vary the chemical composition of polymers and copoly merS produced by this process. Further, the experimental 0024 FIG. 7 schematically illustrates the structure of the rigor generally involved in ionic polymerizations is often too tri-functional macroinitiator of FIG. 6 from which a three costly for industrial use and free radical routes are preferred. arm Star copolymer can be propagated. 0.014 Hence, it would be advantageous to provide poly 0025 FIG. 8 illustrates an exemplary three-arm star mers that have various properties that are analogous to those copolymer comprising a tri-functional core (e.g., SiMe core of SIBS copolymers (e.g., drug release characteristics and indicated by solid inner lines) with a low T. hydrocarbon biostability/biocompatibility) but which also exhibit inner chain (e.g., polyolefin indicated by the wavy Seg improved immunity to radiation-based changes in polymer ments) each connected to a high T. copolymer Outer chain properties and are easier to Synthesize using a wider array of (e.g., polystyrene indicated by the Solid outer Segments). monomer materials. 0026 FIG. 9 illustrates an exemplary multi-arm block copolymer produced using a Silicone chloride coupling SUMMARY OF THE INVENTION agent. Specifically, a four-arm Star polyolefin copolymer 0.015 These and other challenges of the prior art are comprising two Silicone atoms at the core with hydroxy addressed by the present invention which provides a radia functional end groups is Schematically illustrated. US 2006/OO13849 A1 Jan. 19, 2006

DETAILED DESCRIPTION OF THE in the ankle, knee, and hand areas, tacks for ligament INVENTION attachment and meniscal repair, rods and pins for fracture fixation, Screws and plates for craniomaxillofacial repair; 0027. The present invention relates to radiation-resistant dental devices Such as void fillers following tooth extraction copolymers that are useful for the delivery of a therapeutic and guided-tissue-regeneration membrane films following agent in connection with an intravascular or intervascular periodontal Surgery; and tissue engineering Scaffolds for medical device. cartilage, bone, Skin and other in Vivo tissue regeneration. 0028. According to an aspect of the present invention, a 0033. The medical devices of the present invention radiation-sterilized medical device is provided, which include medical devices that are used for either Systemic includes: (a) a release region and (b) one or more therapeutic treatment or for the localized treatment of any mammalian agents. The release region further includes at least one tissue or organ. Non-limiting examples are tumors, organs radiation-resistant copolymer that contains (i) one or more including the heart, coronary and peripheral vascular System low T. hydrocarbon polymer blocks and (ii) one or more (referred to overall as “the vasculature'), lungs, trachea, high T. polymer blocks. esophagus, brain, liver, kidney, bladder, urethra and ureters, 0029 Release regions for use in accordance with the eye, intestines, Stomach, pancreas, Vagina, uterus, OVary, and present invention include carrier regions and barrier regions. prostate, Skeletal muscle, Smooth muscle, breast, dermal By "carrier region' is meant a release region which further tissue, cartilage; and bone. comprises a therapeutic agent and from which the therapeu 0034 Specific examples of medical devices for use in tic agent is released. For example, in Some embodiments, a conjunction with the present invention include vascular carrier region is disposed over all or a portion of a medical Stents, which deliver therapeutic agent into the vasculature device Substrate. In other embodiments, a carrier region for the treatment of restenosis. In these embodiments, the constitutes the entirety of the medical device. release region is typically provided over all or a portion of 0.030. By “barrier region' is meant a region which is a Stent Substrate, and is typically in the form of a carrier layer disposed between a Source of therapeutic agent and a Site of (in which case therapeutic agent is disposed within the intended release, and which controls the rate at which release layer) or a barrier layer (in which case the release therapeutic agent is released. For example, in Some embodi layer is disposed over a therapeutic-agent containing ments, the medical device is provided with a barrier region region). that Surrounds a Source of therapeutic agent. In other 0035. As used herein, “treatment” refers to the prevention embodiments, a barrier region is disposed over a Source of of a disease or condition, the reduction or elimination of therapeutic agent, which is in turn disposed over all or a Symptoms associated with a disease or condition, or the portion of a medical device Substrate. Substantial or complete elimination of a disease or condition. 0.031 Hence, in various embodiments, release regions for Preferred Subjects are mammalian Subjects and more pref use in accordance with the present invention are in the form erably human Subjects. of a release layers, which cover all or a part of a medical 0036 By “radiation sterilized' is meant that the medical device Substrate. AS used herein a "layer of a given material device has been exposed to a quantity of radiation that is is a region of that material whose thickness is Small com effective to kill pathogens associated with the medical pared to both its length and width. AS used herein a layer device. The radiation that is used to sterilize the medical need not be planar or conformal (for example, taking on the devices of the present invention is typically ionizing radia contours of an underlying Substrate). Layers can be discon tion, Such as gamma radiation, X-ray radiation, or electron tinuous (e.g., patterned). Terms Such as “film,”“layer” and beam radiation. For example, Sterilizing radiation doses for "coating may be used interchangeably herein. medical devices typically ranges between 100,000 rads and 0.032 Medical devices for use in conjunction with the 100 Mrad. This includes, for example, 100,000 rads, 500, present invention include essentially any medical device for 000 rads, 1,000,000 rads (1 Mrad), 2.5 Mrad, 5 Mrad, 7.5 which controlled release of a therapeutic agent is desired. Mrad, 10 Mirad, 20 Mirad, 50 Mirad and 100 Mirad, as well as Examples of medical devices include implantable or insert ranges between any two of these doses, for example, 100, able medical devices, for example, catheters (e.g., renal or 000 rad to 1 Mrad, 500,000 rad to 20 Mirad, and so forth, vascular catheters such as balloon catheters), guide wires, with 1 Mrad to 10 Mrad being a particularly beneficial balloons, filters (e.g., Vena cava filters), Stents (including range. coronary vascular Stents, cerebral, urethral, ureteral, biliary, 0037. By “radiation stable copolymer” is meant that, at tracheal, gastrointestinal and esophageal Stents), Stent grafts, typical radiation Sterilization doses employed as discussed cerebral aneurysm filter coils (including Guglilmi detach above (e.g., 1 Mrad to 10 Mrad), the copolymer does not able coils and metal coils), vascular grafts, myocardial undergo changes in either molecular weight (e.g., Mw, Mn, plugs, patches, pacemakers and pacemaker leads, heart via either crosslinking or chain Scission) or morphology that valves, biopsy devices, and any coated Substrate (which can Significantly change a functional property of a device or comprise, for example, glass, metal, polymer, ceramic and coating (e.g., drug delivery properties or mechanical prop combinations thereof) that is implanted or inserted into the erties Such as elongation modulus) that negatively impacts body and from which therapeutic agent is released. its performance for its intended application. Examples of medical devices further include patches for delivery of therapeutic agent to intact skin and broken skin 0038. As used herein, polymers are molecules containing (including wounds); Sutures, Suture anchors, anastomosis one or more chains, which contain multiple copies of one or clipS and rings, tissue Staples and ligating clips at Surgical more constitutional units. An example of a common polymer Sites, orthopedic fixation devices Such as interference Screws is polystyrene US 2006/OO13849 A1 Jan. 19, 2006

mers of the present invention will typically have one or more glass transition temperatures below ambient temperature and one or more glass transition temperatures above ambient -the-h- temperature. This typically results in the formation of rub bery and hard phases within the release region at ambient temperatures. 0044) A “hydrocarbon polymer block” is a block con taining repeating hydrocarbon units (i.e., repeating units where n is an integer, typically an integer of 10 or more, containing carbon and hydrogen atoms only). The hydro more typically on the order of 10's, 100's, 1000's or even carbon polymer block may be present in the copolymer, for more, in which the constitutional units in the chain corre example, as a midblock or as an endblock. It may be spond to Styrene monomers: provided in a variety of configurations, including cyclic, linear and branched configurations. Branched configurations include Star-shaped configurations (e.g., configurations in which three or more chains emanate from a Single branch point), comb configurations (e.g., configurations having a main chain and a plurality of Side chains) and dendritic configurations (e.g., arborescent and hyperbranched poly mers). The chain or chains forming the hydrocarbon poly merblock(s) may contain, for example, (a) a repeating Series of hydrocarbon units of a single type, or (b) a Series of (i.e., they originate from, or have the appearance of origi hydrocarbon units of two or more types, for instance, nating from, the polymerization of Styrene monomers in this arranged in a repeating (e.g., alternating), random, Statistical case, the addition polymerization of Styrene monomers). AS or gradient distribution. used herein, copolymers are polymers that contain at least two dissimilar constitutional units. 0045. A “telechelic' polymer as used herein is a polymer 0.039 AS used herein, a polymer “block” is a grouping of that contains at least two functional groups per molecule, 10 or more constitutional units, commonly 20 or more, 50 or one at each terminus of the polymer. The functional groups more, 100 or more, 200 or more, 500 or more, or even 1000 on the termini of the polymer can be the same (such as two or more units. A “chain” is a linear (unbranched) grouping hydroxyl groups) or different (Such as one hydroxyl group of 10 or more constitutional units (i.e., a linear block). and one amino group). The preparation of telechelic poly 0040. As noted above, the medical devices of the present merS is taught in the prior art. For example, the preparation invention are radiation-sterilized and include one or more of telechelic star polymers is described in U.S. Pat. No. radiation resistant copolymers containing (a) one or more 5,919,870, assigned to FMC Corporation, the entire contents low T. hydrocarbon polymer blocks and (b) one or more of which are hereby incorporated by reference. high T. polymer blocks. 0046. As will be appreciated by one of skill in the art, the 0041) A “low T. polymer block” is a polymer block that block copolymers described herein, including those displays one or more glass transition temperatures (T,), as described in the preceding paragraphs, may be recovered measured by any of a number of techniques including from the reaction mixtures by any of the usual techniques, differential Scanning calorimetry (DSC), dynamic mechani including but not limited to, evaporation of Solvent, precipi cal analysis (DMA), or dielectric analysis (DEA), that is below ambient temperature, more typically below 25 C., tation with a non-Solvent Such as an alcohol or alcohol/ below 0° C., below -25 C., or even below -50° C. acetone mixture, followed by drying, and So forth. In addi “Ambient temperature” is typically 25 C-45 C., more tion, purification of the copolymer can be performed by typically body temperature (e.g., 35 C.-40°C.). As a result Sequential extraction in aqueous media, both with and with of their low glass transition temperature, low T. polymer out the presence of various alcohols, ethers and ketones. blocks are typically elastomeric at ambient temperature. 0047 Specific examples of hydrocarbon polymer blocks Homopolymers of Some low T. polymer blocks, such as from which the low T. hydrocarbon polymer blocks can be linear or branched silicone (e.g. polydimethylsiloxane), are Selected include blocks which contain polymers of alkenes, Viscous liquids or millable gums at room temperature and including polymers of olefins (i.e., hydrocarbon monomers become elastomeric upon covalent cross-linking. containing a single >C=C- double bond), polymers of 0042 Conversely, an elevated or “high T. polymer dienes (i.e., hydrocarbon monomers containing two >C=C- block” is a polymer block that displays one or more glass double bonds), also called diolefins, or polymers of both transition temperatures, as measured by any of a number of techniques including differential Scanning calorimetry, olefins and dienes, are provided below. dynamic mechanical analysis, or thermomechanical analy 0048) For example, the low T. hydrocarbon polymer sis, which is above ambient temperature, more typically block can comprise an EPDM (ethylene-propylene-diene more typically above 50° C., above 60° C., above 70° C., monomer) copolymer block, which contain units formed above 80° C., above 90° C. or even above from two olefins (ethylene and propylene) and one or more 0043 Hence, due to the presence of one or more low T. dienes (e.g., vinyl norbornene or ethylidene norbornene), blocks and one or more high T. polymer blocks, the copoly which are illustrated in turn in the following structure: US 2006/OO13849 A1 Jan. 19, 2006

-continued -circuitten-ryu-ttCH HCN-CH VCH/ (d) CH CH-CH

0049 Commercially prepared EPDM copolymer blocks include VistalonTM polymers available from Exxon-Mobil. The synthesis of EPDM copolymers is well-known in the art, including preparation via Ziegler-Natta polymerization O H, using homogeneous catalyst compositions based on Vana dium, titanium, Zirconium, and metallocenes. Details of the preparation of EPDM copolymers are given in U.S. Pat. No. 6,486,278, assigned to ExxonMobil Chemical Patents Inc., the entire contents of which are hereby incorporated by reference. Synthesis typically involves contacting ethylene, one or more olefin monomers, and one or more cyclic diolefin monomers, with a catalyst composition prepared from a catalyst activator and a catalyst, by a Solution polymerization process. (g) 0050. In addition to propylene and ethylene, a wide range of olefins are Suitable for use in the preparation of the EPDM, including for example, C to Co C-olefins Such as 1-butene, 1-pentene, 1-hexene, 1-octene, and 1-decene, con and Strained-ring cyclic monoolefins Such as cyclobutene, cyclo pentene, norbornene, alkyl Substituted norbornene, and alk (h) enyl-Substituted norbornene. 0051. The diene monomers, or diolefin components of the EPDM copolymer can be a mixture of one or more cyclic diolefins having from about 6 to about 15 carbon atoms, including 1) single ring alicyclic dienes Such as 1,3-cyclo pentadiene, 2) multi-ring alicyclic fused and bridged ring 0053) The low T. hydrocarbon polymer block may also dienes Such as tetrahydroindene, dicyclopentadiene, be formed from conjugated diene monomers, including but cycloalkenyl and cycloalkylidene norbornenes Such as not limited to, 1,3-butadiene, 2,3-dimethyl-1,3butadiene, 5-methylene-2-norbornene, 5-ethylidene-2-norbornene, 2-methyl-1,3-butadiene (isoprene), 3-ethenyl-1,6-heptadi 5-isopropylidene-2-norbornene, 5-(4-cyclopentenyl)-2-nor ene, 5-ethyl-1,3,5-heptatriene, 5-methyl-1,3-cycloheptadi bornene, 5-cyclohexylidene-2-norbornene, 5-Vinyl-2-cy ene, 2,3-dimethyl-1,3-butadiene, 1,4-diphenyl-1,3-butadi clododecene, and 3) cycloalkenyl-Substituted alkenes, Such ene, cyclopentadiene, cyclohexadiene, cycloheptadiene, as allyl cyclohexene, Vinyl cyclooctene, allyl cyclohexene, cyclooctadiene, anthracene, chloroprene and the like. The Vinyl cyclooctene, allyl cyclodecene, and Vinyl invention also includes hydrogenated forms of polymer cyclododecene. blocks formed from these monomers. 0052] As a further example, the low T. hydrocarbon 0054) Like the low T. hydrocarbon polymer blocks polymer block can comprise the following polydiene and described above, the high T. polymer blocks may be present polyolefin blocks, as well as variants Such as hydrogenated in the copolymers, for example, as midblocks or as end forms of Same: blocks. The high T. polymer blocks may be provided in a variety of configurations, including cyclic, linear and branched configurations. Branched configurations include Star-shaped configurations (e.g., configurations in which three or more chains emanate from a single branch point), comb configurations (e.g., configurations having a main chain and a plurality of branching side chains) and dendritic configurations (e.g., arborescent and hyperbranched poly HO OH, mers). The high T. polymer blocks may contain, for example, a repeating Series of units of a single type, a Series of units of two or more types in a repeating (e.g., alternat ing), random, statistical or gradient distribution, and So forth. US 2006/OO13849 A1 Jan. 19, 2006

0055) Specific examples of high T. polymer blocks from 0060 Specific acrylic monomers include (a) acrylic acid which high T. polymer blocks can be selected include (T 105° C), its anhydride and salt forms, such as potassium homopolymer and copolymer blocks formed from (or hav acrylate (T, 194° C) and sodium acrylate (T. 230° C); (b) ing the appearance of being formed from) the following: certain acrylic acid esters such as tert-butyl acrylate (T. various vinyl aromatic monomers, other vinyl monomers, 43-107° C) (T, 193° C), hexyl acrylate (T. 57° C) and other aromatic monomers, methacrylic monomers, and isobornyl acrylate (T 94° C); (c) acrylic acid amides such acrylic monomers. Numerous specific examples are listed as acrylamide (T 165° C), N-isopropylacrylamide (T. below. The T values are published values for homopoly 85-130° C) and N,N dimethylacrylamide (T, 89° C); and mers of the listed monomeric unit. (d) other acrylic-acid derivatives including acrylonitrile (T. 0056 Vinyl aromatic monomers are monomers having 125° C). aromatic and Vinyl moieties, including unsubstituted mono 0061. In some particularly beneficial embodiments, the mers, Vinyl-Substituted monomers and ring-Substituted block copolymers for use in the present invention have one monomers. Several Specific vinyl aromatic monomers fol of the following general structures: BAB or ABA (triblock), low: (a) unsubstituted vinyl aromatics, such as atactic sty B(AB)n or A(BA)n (alternating block), or X(AB)n or rene (T, 100° C), isotactic styrene (T, 100° C) and 2-vinyl X(BA)n (including diblock, triblock, and other radial block naphthalene (T. 151° C), (b) vinyl substituted aromatics copolymers), where A is a low T. block and B is a high T. Such as methyl Styrene, (c) ring-Substituted vinyl aromatics block, n is a positive whole number and X is a Starting Seed including (i) ring-alkylated vinyl aromatics Such as 3-me molecule. Where the block copolymer is of the formula thylstyrene (T 97° C), 4-methylstyrene (T 97° C), 2,4- X-AB)n or X(BA)n and where n=1, the resulting structure is dimethylstyrene (T112° C), 2,5-dimethylstyrene (T 143° frequently called a diblock, where n=2, the Structure is called C.), 3,5-dimethylstyrene (T 104° C), 2,4,6-trimethylsty a triblock (it is common to disregard the presence of Small rene (T. 162° C), and 4-tert-butylstyrene (T, 127° C), (ii) entities Such as the Seed molecule X in describing Such ring-alkoxylated vinyl aromatics, Such as 4-methoxystyrene polymers), and where n=3 or greater, these structures are (T 113° C) and 4-ethoxystyrene (T, 86° C), (iii) ring commonly referred to as Star-shaped block copolymers. halogenated vinyl aromatics Such as 2-chlorostyrene (T. 119° C), 3-chlorostyrene (T 90° C), 4-chlorostyrene (T. 0062 One preferred group of block copolymers has (a) a 110° C), 2,6-dichlorostyrene (T. 167° C), 4-bromostyrene hydrocarbon polymer midblock or main chain, including the (T,118° C) and 4-fluorostyrene (T 95° C) and (iv) ester examples listed above, and (b) one or more high T, end substituted vinyl aromatics such as 4-acetoxystyrene (T. blocks or side chains, which can be for example blocks of 116° C). polystyrene or poly(alkyl methacrylate). 0057. Other specific vinyl monomers include: (a) vinyl 0063. The release regions of the present invention option alcohol (T. 85° C); (b) vinyl esters such as vinyl benzoate ally include a Supplemental polymer in addition to the (T, 71° C), vinyl 4-tert-butylbenzoate (T, 101° C), vinyl above-described copolymers. A variety of polymers are cyclohexanoate (T, 76° C), vinyl pivalate (T, 86° C), vinyl available for use as Supplemental polymers in the release trifluoroacetate (T. 46° C), vinyl butyral (T. 49° C), (c) regions of the present invention. For example, the Supple vinyl amines such as 2-vinyl pyridine (T 104° C), 4-vinyl mental polymer may be a homopolymer or a copolymer pyridine (T 142° C), and vinyl carbazole (T. 227° C), (d) (including alternating, random, Statistical, gradient and vinyl halides such as vinyl chloride (T, 81° C) and vinyl block copolymers), may be cyclic, linear or branched (e.g., fluoride (T. 40° C); (e) alkyl vinyl ethers such as tert-butyl polymers have star, comb or dendritic architecture), may be vinyl ether (T. 88° C) and cyclohexyl vinyl ether (T. 81 natural or Synthetic, and may be thermoplastic or thermo C.), and (f) other vinyl compounds Such as 1-vinyl-2- Setting. Supplemental polymers for the practice of the inven tion may be selected, for example, from the following: pyrrolidone (T. 54° C) and vinyl ferrocene (T, 189° C). polycarboxylic acid polymers and copolymers including 0.058 Specific aromatic monomers, other than vinyl aro polyacrylic acids, acetal polymers and copolymers, acrylate matics, include: acenaphthalene (T214° C) and indene (T. and methacrylate polymers and copolymers (e.g., n-butyl 85° C). methacrylate); cellulosic polymers and copolymers, includ 0059 Specific methacrylic monomers include (a) meth ing cellulose acetates, cellulose nitrates, cellulose propi acrylic acid (T. 228° C), (b) methacrylic acid salts such as onates, cellulose acetate butyrates, cellophanes, rayons, sodium methacrylate (T. 310° C), (c) methacrylic acid rayon triacetates, and cellulose etherS Such as carboxym anhydride (T. 159° C), (d) methacrylic acid esters (meth ethyl celluloses and hydroxyalkyl celluloses, polyoxymeth acrylates) including (i) alkyl methacrylates Such as atactic ylene polymers and copolymers, polyimide polymers and methyl methacrylate (T 105-120° C), syndiotactic methyl copolymerS Such as polyether block imides, polyamidim methacrylate (T. 115° C), ethyl methacrylate (T. 65° C), ides, polyesterimides, and polyetherimides, polysulfone isopropyl methacrylate (T. 81° C), isobutyl methacrylate polymers and copolymers including polyarylsulfones and (T. 53° C), t-butyl methacrylate (T,118° C) and cyclohexyl polyetherSulfones, polyamide polymers and copolymers methacrylate (T92 C.), (ii) aromatic methacrylates Such as including nylon 6,6, nylon 12, polycaprolactams and poly phenyl methacrylate (T 110° C) and including aromatic acrylamides, resins including alkyd resins, phenolic resins, alkyl methacrylates Such as benzyl methacrylate (T54 C.), urea resins, melamine resins, epoxy resins, allyl resins and (iii) hydroxyalkyl methacrylates Such as 2-hydroxyethyl epoxide resins, polycarbonates, polyacrylonitriles, polyvi methacrylate (T. 57° C) and 2-hydroxypropyl methacrylate nylpyrrolidones (cross-linked and otherwise); polymers and (T, 76° C), (iv) additional methacrylates including copolymers of vinyl monomers including polyvinyl alco isobornyl methacrylate (T 110° C) and trimethylsilyl meth hols, polyvinyl halides Such as polyvinyl chlorides, ethyl acrylate (T. 68° C), and (e) other methacrylic-acid deriva ene-Vinylacetate copolymers (EVA), polyvinylidene chlo tives including methacrylonitrile (T 120° C.). rides, polyvinyl etherS Such as polyvinyl methyl ethers, Vinyl US 2006/OO13849 A1 Jan. 19, 2006 aromatic polymers and copolymerS Such as polystyrenes, layer onto a pre-existing Stent. As yet another example, a Styrene-maleic anhydride copolymers, Vinyl aromatic-hy coating can be co-extruded along with an underlying Stent drocarbon copolymers including Styrene-butadiene copoly body. mers, Styrene-ethylene-butylene copolymers (e.g., a poly 0066. If the therapeutic agent is stable at processing Styrene-polyethylene/butylene-polystyrene (SEBS) temperatures, then it can be combined with the copolymer copolymer, available as Kraton E G Series polymers), Sty prior to thermoplastic processing, producing a therapeutic rene-isoprene copolymers (e.g., polystyrene-polyisoprene agent containing carrier region. If not, then a carrier region polystyrene), acrylonitrile-styrene copolymers, acryloni can nonetheless be formed by Subsequent introduction of trile-butadiene-styrene copolymers, Styrene-butadiene therapeutic agent, for example, as discussed below. copolymers and styrene-isobutylene copolymers (e.g., poly isobutylene-polystyrene block copolymers such as SIBS), 0067 Polymeric release regions can also be formed using polyvinylketones, polyvinylcarbazoles, and polyvinyl esters Solvent-based techniques in which copolymer (and Supple Such as polyvinyl acetates, polybenzimidazoles, ionomers, mental polymer, if any) is first dissolved or dispersed in a polyalkyl oxide polymers and copolymers including poly Solvent and the resulting mixture is Subsequently used to ethylene oxides (PEO); polyesters including polyethylene form the polymeric release region. terephthalates and aliphatic polyesterS Such as polymers and 0068. Where solvent-based techniques are used, the sol copolymers of lactide (which includes lactic acid as well as vent System that is Selected will contain one or more Solvent d-l- and meso lactide), epsilon-caprolactone, glycolide Species. The Solvent System preferably is a good Solvent for (including glycolic acid), hydroxybutyrate, hydroxyvalerate, the copolymer and, where included, for the Supplemental para-dioxanone, trimethylene carbonate (and its alkyl polymer and therapeutic agent as well. The particular Sol derivatives), 1,4-dioxepan-2-one, 1,5-dioxepan-2-one, and vent species that make up the Solvent System may also be 6,6-dimethyl-1,4-dioxan-2-one (a copolymer of polylactic Selected based on other characteristics including drying rate acid and polycaprolactone is one specific example); poly and Surface tension. ether polymers and copolymers including polyarylethers Such as polyphenylene ethers, polyether ketones, polyether 0069 Preferred solvent-based techniques include, but are ether ketones, polyphenylene Sulfides, polyisocyanates, not limited to, Solvent casting techniques, Spin coating polyolefin polymers and copolymers, including polyalky techniques, web coating techniques, Solvent Spraying tech lenes Such as polypropylenes, polyethylenes (low and high niques, dipping techniques, techniques involving coating Via density, low and high molecular weight), polybutylenes mechanical Suspension including air Suspension, ink jet (Such as polybut-1-ene and polyisobutylene), polyolefin techniques, electroStatic techniques, and combinations of elastomers (e.g., Santoprene), ethylene propylene diene these processes. monomer (EPDM) rubbers, poly-4-methyl-pen-1-enes, eth 0070. In many embodiments, a mixture containing sol ylene-alpha-olefin copolymers, ethylene-methyl methacry vent, copolymer and Supplemental polymer, if any, is late copolymers and ethylene-Vinyl acetate copolymers, applied to a Substrate to form a release region. For example, fluorinated polymers and copolymers, including polytet the Substrate can be all or a portion of an implantable or rafluoroethylenes (PTFE), poly(tetrafluoroethylene-co insertable medical device, Such as a Stent, to which a release hexafluoropropene) (FEP), modified ethylene-tetrafluoroet layer is applied. On the other hand, the Substrate can also be, hylene copolymers (ETFE), and polyvinylidene fluorides for example, a template from which the polymeric release (PVDF); silicone polymers and copolymers; polyurethanes; region is removed after Solvent elimination. Such template p-xylylene polymers; polyiminocarbonates, copoly(ether based techniques are particularly appropriate for forming esters) Such as polyethylene oxide-polylactic acid copoly Simple objects Such as sheets, tubes, cylinders and So forth, mers, polyphosphazines, polyalkylene oxalates, polyoxaa mides and polyoxaesters (including those containing amines which can be easily removed from a template Substrate. and/or amido groups); polyorthoesters, biopolymers, Such as 0071. In other techniques, for example, fiber forming polypeptides, proteins, polysaccharides and fatty acids (and techniques, the polymeric release region is formed without esters thereof), including fibrin, fibrinogen, collagen, elastin, the aid of a Substrate or template. chitosan, gelatin, Starch, glycosaminoglycans Such as hyalu ronic acid; as well as blends and copolymers of the above. 0072. Where appropriate, techniques such as those listed above can be repeated or combined to build up a release 0064. Numerous techniques are available for forming the layer to a desired thickness. The thickness of the release polymeric release regions of the present invention. For layer can be varied in other ways as well. For example, in example, where the Selected copolymer (and Supplemental one preferred process, Solvent Spraying, coating thickness polymer, if any) has thermoplastic characteristics, a variety can be increased by modification of coating process param of Standard thermoplastic processing techniques can be used eters, including increasing Spray flow rate, Slowing the to form the polymeric release region, including compression movement between the Substrate to be coated and the Spray molding, injection molding, blow molding, Spinning, nozzle, providing repeated passes and So forth. Vacuum forming and calendaring, as well as extrusion into sheets, fibers, rods, tubes and other croSS-Sectional profiles 0073 Where a carrier region is formed (as opposed to, for of various lengths. example, a barrier region), a therapeutic agent can be dissolved or dispersed in the polymer/solvent mixture if 0065. Using these and other techniques, entire devices or desired, and hence co-established with the carrier region. In portions thereof can be made. For example, an entire Stent other embodiments, on the other hand, the therapeutic agent can be extruded using the above techniques. AS another can be dissolved or dispersed within a Solvent, and the example, a coating can be provided by extruding a coating resulting Solution contacted with a polymer region that is US 2006/OO13849 A1 Jan. 19, 2006 previously formed using, for example, one or more of the and tick antiplatelet peptides, (f) vascular cell growth pro application techniques described above (e.g., dipping, spray moterS Such as growth factors, transcriptional activators, and ing, etc.). translational promoters, (g) Vascular cell growth inhibitors Such as growth factor inhibitors, growth factor receptor 0.074 Barrier layers, on the other hand, are formed over antagonists, transcriptional repressors, translational repres a therapeutic-agent-containing region, for example, using Sors, replication inhibitors, inhibitory antibodies, antibodies Solvent-based techniques Such as those discussed above in directed against growth factors, bifunctional molecules con which the copolymer and Supplemental polymer, if any, are Sisting of a growth factor and a cytotoxin, bifunctional first dissolved or dispersed in a Solvent, and the resulting molecules consisting of an antibody and a cytotoxin; (h) mixture is subsequently used to form the barrier layer. The protein kinase and tyrosine kinase inhibitors (e.g., tyr barrier layer Serves, for example, as a boundary layer to phostins, genistein, quinoxalines); (ii) prostacyclin analogs, retard diffusion of the therapeutic agent, for example, acting (i) cholesterol-lowering agents; (k) angiopoietins; (1) anti to prevent a burst phenomenon whereby much of the thera microbial agents Such as triclosan, cephalosporins, ami peutic agent is released immediately upon exposure of the noglycosides and nitrofurantoin; (m) cytotoxic agents, cyto device or a portion of the device to the implant or insertion Static agents and cell proliferation affectors, (n) vasodilating Site. agents; (O) agents that interfere with endogenous vasoactive 0075. In some embodiments, the therapeutic-agent-con mechanisms; (p) inhibitors of leukocyte recruitment, Such as taining region beneath the barrier region will comprise one monoclonal antibodies; (q) cytokines; (r) hormones; and (s) or more polymerS Such as those described elsewhere herein. inhibitors of HSP90 protein (i.e., Heat Shock Protein, which (In these embodiments, the polymeric composition of the is a molecular chaperone or housekeeping protein and is barrier region may, or may not be the same as the polymeric needed for the stability and function of other client proteins/ composition of the underlying therapeutic-agent-containing Signal transduction proteins responsible for growth and region.) AS Such, the therapeutic-agent-containing region Survival of cells) including geldanamycin. can also be established using Solvent-based techniques (e.g., dipping, spraying, etc.) Such as those discussed above. In 0079 Preferred non-genetic therapeutic agents include other embodiments, the therapeutic-agent-containing region paclitaxel, Sirolimus, everolimus, tacrolimus, Epo D, dex beneath the barrier layer is established without an associated amethasone, estradiol, halofuginone, ciloStazole, geldana polymer. In this case, the therapeutic agent can Simply be mycin, ABT-578 (Abbott Laboratories), trapidil, liprostin, dissolved or dispersed in a Solvent or liquid, and the result Actinomycin D, Resten-NG, Ap-17, abciximab, clopidogrel ing Solution/dispersion can be contacted with a Substrate and Ridogrel, among others. again using, for instance, one or more of the above-de 0080 Exemplary genetic therapeutic agents for use in Scribed application techniques. connection with the present invention include anti-Sense DNA and RNA as well as DNA coding for the various 0.076 Where the release region is formed using a solvent proteins (as well as the proteins themselves): (a) anti-Sense based technique, it is preferably dried after application to RNA, (b) tRNA or rRNA to replace defective or deficient remove the Solvents. The release region typically further endogenous molecules, (c) angiogenic and other factors conforms to any underlying Surface during the drying pro including growth factorS Such as acidic and basic fibroblast CCSS. growth factors, vascular endothelial growth factor, endothe 0.077 “Therapeutic agents,”“pharmaceutically active lial mitogenic growth factors, epidermal growth factor, agents,”“pharmaceutically active materials,"drugs,” and transforming growth factor C. and B, platelet-derived endot other related terms may be used interchangeably herein and helial growth factor, platelet-derived growth factor, tumor include genetic therapeutic agents, non-genetic therapeutic necrosis factor C, hepatocyte growth factor and insulin-like agents and cells. Therapeutic agents may be used Singly or growth factor, (d) cell cycle inhibitors including CD inhibi in combination. Therapeutic agents may be used singly or in tors, and (e) thymidine kinase (“TK') and other agents combination. Therapeutic agents may be, for example, non useful for interfering with cell proliferation. Also of interest ionic or they may be anionic and/or cationic in nature. is DNA encoding for the family of bone morphogenic 0078 Exemplary non-genetic therapeutic agents for use proteins (“BMP's"), including BMP-2, BMP-3, BMP-4, in connection with the present invention include: (a) anti BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, thrombotic agents Such as heparin, heparin derivatives, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, urokinase, and PPack (dextrophenylalanine proline arginine and BMP-16. Currently preferred BMP's are any of BMP-2, chloromethylketone); (b) anti-inflammatory agents Such as BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These dimeric dexamethasone, prednisolone, corticosterone, budeSonide, proteins can be provided as homodimers, heterodimers, or estrogen, SulfaSalazine and mesalamine; (c) antineoplastic/ combinations thereof, alone or together with other mol antiproliferative/anti-miotic agents Such as paclitaxel, ecules. Alternatively, or in addition, molecules capable of 5-fluorouracil, cisplatin, Vinblastine, Vincristine, inducing an upstream or downstream effect of a BMP can be epothilones, endostatin, angiostatin, angiopeptin, mono provided. Such molecules include any of the "hedgehog” clonal antibodies capable of blocking Smooth muscle cell proteins, or the DNA's encoding them. proliferation, and thymidine kinase inhibitors; (d) anesthetic 0081 Vectors for delivery of genetic therapeutic agents agents such as lidocaine, bupivacaine and ropivacaine; (e) include Viral vectorS Such as adenoviruses, gutted adenovi anti-coagulants Such as D-Phe-Pro-Arg chloromethyl ruses, adeno-associated virus, retroviruses, alpha virus ketone, an RGD peptide-containing compound, heparin, (Semliki Forest, Sindbis, etc.), lentiviruses, herpes simplex hirudin, antithrombin compounds, platelet receptor antago virus, replication competent viruses (e.g., ONYX-015) and nists, anti-thrombin antibodies, anti-platelet receptor anti hybrid vectors, and non-viral vectorS Such as artificial chro bodies, aspirin, prostaglandin inhibitors, platelet inhibitors mosomes and mini-chromosomes, plasmid DNA vectors US 2006/OO13849 A1 Jan. 19, 2006

(e.g., pCOR), cationic polymers (e.g., polyethyleneimine, Synthetic corticosteroids Such as dexamethasone, predniso polyethyleneimine (PEI)), graft copolymers (e.g., polyether lone, methprednisolone and hydrocortisone, (n) lipoxyge PEI and polyethylene oxide-PEI), neutral polymers such as nase pathway inhibitorS Such as nordihydroguairetic acid polyvinylpyrrolidone (PVP), SPIO17 (SUPRATEK), lipids and caffeic acid, (o) leukotriene receptor antagonists, (p) Such as cationic lipids, liposomes, lipoplexes, nanoparticles, antagonists of E- and P-selectins, (q) inhibitors of VCAM-1 or microparticles, with and without targeting Sequences Such and ICAM-1 interactions, (r) prostaglandins and analogs as the protein transduction domain (PTD). thereof including prostaglandins such as PGE1 and PGI2 0082) Cells for use in connection with the present inven and proStacyclin analogS Such as ciprostene, epoprostenol, tion include cells of human origin (autologous or alloge carbacyclin, iloprost and beraprost, (s) macrophage activa neic), including whole bone marrow, bone marrow derived tion preventers including bisphosphonates, (t) HMG-CoA mono-nuclear cells, progenitor cells (e.g., endothelial pro reductase inhibitorS Such as lovastatin, pravastatin, fluvas genitor cells), Stem cells (e.g., mesenchymal, hematopoietic, tatin, Simvastatin and cerivastatin, (u) fish oils and omega neuronal), pluripotent stem cells, fibroblasts, myoblasts, 3-fatty acids, (v) free-radical ScavengerS/antioxidants Such Satellite cells, pericytes, cardiomyocytes, Skeletal myocytes as probucol, Vitamins C and E, ebSelen, trans-retinoic acid or macrophage, or from an animal, bacterial or fungal Source and SOD mimics, (w) agents affecting various growth (Xenogeneic), which can be genetically engineered, if factors including FGF pathway agents such as bFGF anti desired, to deliver proteins of interest. bodies and chimeric fusion proteins, PDGF receptor antago 0083) Numerous therapeutic agents, not necessarily nists Such as trapidil, IGF pathway agents including Soma exclusive of those listed above, have been identified as tostatin analogS Such as angiopeptin and ocreotide, TGF-B candidates for vascular treatment regimens, for example, as pathway agents such as polyanionic agents (heparin, fucoi agents targeting restenosis. Such agents are useful for the din), decorin, and TGF-f antibodies, EGF pathway agents practice of the present invention and include one or more of Such as EGF antibodies, receptor antagonists and chimeric the following: (a) Ca-channel blockers including benzothi fusion proteins, TNF-C. pathway agents Such as thalidomide aZapines Such as diltiazem and clentiazem, dihydropyridines and analogs thereof, Thromboxane A2 (TXA2) pathway Such as nifedipine, amlodipine and nicardapine, and pheny modulatorS Such as Sulotroban, Vapi.prost, daZOXiben and lalkylamines Such as Verapamil, (b) Serotonin pathway ridogrel, as well as protein tyrosine kinase inhibitorS Such as modulators including: 5-HT antagonists Such as ketanserin tyrphostin, genistein and quinoxaline derivatives, (x) MMP and naftidrofuryl, as well as 5-HT uptake inhibitors such as pathway inhibitorS Such as marimastat, illomastat and met fluoxetine, (c) cyclic nucleotide pathway agents including astat, (y) cell motility inhibitors Such as cytochalasin B, (Z) phosphodiesterase inhibitorS Such as ciloStazole and dipy antiproliferative/antineoplastic agents including antimetabo ridamole, adenylate/Guanylate cyclase Stimulants Such as lites Such as purine analogs (e.g., 6-mercaptopurine or forskolin, as well as adenosine analogs, (d) catecholamine cladribine, which is a chlorinated purine nucleoside analog), modulators including O-antagonists Such as praZOsin and pyrimidine analogs (e.g., cytarabine and 5-fluorouracil) and bunaZosine, B-antagonists Such as propranolol and C/B- methotrexate, nitrogen mustards, alkyl Sulfonates, ethylen antagonists Such as labetalol and carvedilol, (e) endothelin imines, antibiotics (e.g., daunorubicin, doxorubicin), receptor antagonists, (f) nitric oxide donors/releasing mol nitroSoureas, cisplatin, agents affecting microtubule dynam ecules including organic nitrates/nitriteS Such as nitroglyc ics (e.g., vinblastine, Vincristine, coichicine, Epo D, pacli erin, isosorbide dinitrate and amyl nitrite, inorganic nitroSo taxel and epothilone), caspase activators, proteasome inhibi compounds Such as Sodium nitroprusSide, Sydnonimines tors, angiogenesis inhibitors (e.g., endostatin, angiostatin Such as molsidomine and linsidomine, nonoates Such as and Squalamine), rapamycin, cerivastatin, flavopiridol and diazenium diolates and NO adducts of alkanediamines, Suramin, (aa) matrix deposition/organization pathway S-nitroSO compounds including low molecular weight com inhibitorS Such as halofuginone or other quinazolinone pounds (e.g., S-nitroso derivatives of captopril, glutathione derivatives and tranilast, (bb) endothelialization facilitators and N-acetyl penicillamine) and high molecular weight such as VEGF and RGD peptide, and (cc) blood rheology compounds (e.g., S-nitroso derivatives of proteins, peptides, modulatorS Such as pentoxifylline. oligosaccharides, polysaccharides, Synthetic polymerS/oli 0084. Numerous additional therapeutic agents useful for gomers and natural polymerS/oligomers), as well as C-ni the practice of the present invention are also disclosed in troSo-compounds, O-nitroSo-compounds, N-nitroSo-com U.S. Pat. No. 5,733,925 assigned to NeoRX Corporation, the pounds and L-arginine, (g) ACE inhibitors Such as cilaZapril, foSinopril and enalapril, (h) ATII-receptor antagonists Such entire disclosure of which is incorporated by reference. as Saralasin and losartin, (i) platelet adhesion inhibitorS Such 0085. Therapeutic agents also include ablation agents, as albumin and polyethylene oxide, () platelet aggregation sufficient amounts of which will result in necrosis (death) of inhibitors including ciloStazole, aspirin and thienopyridine undesirable tissue, Such as malignant tissue, prostatic tissue, (ticlopidine, clopidogrel) and GP IIb/IIIa inhibitors such as and So forth. Examples include OSmotic-stress-generating abciximab, epitifibatide and tirofiban, (k) coagulation path agents, for example, Salts. Such as Sodium chloride or potas way modulators including heparinoids Such as heparin, low sium chloride, organic Solvents, particularly those Such as molecular weight heparin, dextran Sulfate and B-cyclodex ethanol, which are toxic in high concentrations, while being trin tetradecasulfate, thrombin inhibitorS Such as hirudin, well tolerated at lower concentrations, free-radical generat hirulog, PPACK(D-phe-L-propyl-L-arg-chloromethylke ing agents, for example, hydrogen peroxide, potassium tone) and argatroban, FXa inhibitors Such as antistatin and peroxide or other agents that can form free radicals in tissue; TAP (tick anticoagulant peptide), Vitamin Kinhibitors such basic agents Such as Sodium hydroxide, acidic agents Such as as warfarin, as well as activated protein C, (I) cyclooxyge acetic acid and formic acid; enzymes Such as collagenase, nase pathway inhibitorS Such as aspirin, ibuprofen, flurbi hyaluronidase, pronase, and papain, oxidizing agents, Such profen, indomethacin and Sulfinpyrazone, (m) natural and as Sodium hypochlorite, hydrogen peroxide or potassium US 2006/OO13849 A1 Jan. 19, 2006 peroxide, tissue fixing agents, Such as formaldehyde, acetal 0091. In some aspects, the hydrophilicity of the block dehyde or glutaraldehyde; and naturally occurring coagul copolymer can be increased by forming copolymers with lants, Such as gengpin. one or more hydrophilic monomers, Such as, hydroxyethyl methacrylate or other monomers including those numerous 0.086 A wide range of therapeutic agent loadings can be examples of hydrophilic monomerS Specifically listed above used in connection with the dosage forms of the present for preparation of high T. polymer blocks. In alternative invention, with the pharmaceutically effective amount being embodiments, the hydrophobicity of the resulting copolymer readily determined by those of ordinary skill in the art and is increased by forming copolymers with one or more ultimately depending, for example, upon the condition to be hydrophobic monomers. Any one or more of a number of treated, the nature of the therapeutic agent itself, the tissue hydrophobic monomers can be used, including but not into which the dosage form is introduced, and So forth. limited to methyl methacrylate or other monomers including 0.087 As will be appreciated by one of skill in the art, the those numerous examples of hydrophobic monomerS Spe release profile associated with the release region can be cifically listed above for preparation of high T. polymer modified, for example, by altering the chemical composition blocks. of the release region (e.g., by changing the chemical com 0092 Although one of skill in the art would readily position of the copolymer, by blending one or more Supple discern whether a monomer is predominantly hydrophilic or mentary polymers with the copolymer, etc.) and/or by hydrophobic, various monomers having hydrophilic or changing the physical Structure of the release region or hydrophobic characteristics and which are Suitable for use in Surrounding regions (e.g., by adding a separate barrier layer the present invention and which can be used to modulate the that contains one or more polymers, etc.). hydrophilic and/or hydrophobic character of the materials of 0088 For instance, according to various aspects of the the present invention are exemplified, but not limited, by the present invention, the release profile associated with a following: (1) hydrophobic monomers including the follow release region of the medical device can be modified in a ing: vinyl aromatic monomers, including unsubstituted vinyl number of ways, including, but not limited to, (a) changing aromatics, Vinyl Substituted aromatics, and ring-Substituted the composition of the low T. polymer block(s) and/or high Vinyl aromatics, vinyl esters, vinyl halides, alkyl vinyl T. polymer blocks within the copolymer, thus changing, for ethers, and other vinyl compounds Such as 1-vinyl-2-pyr example, the biostability, hydrophilicity and/or hydropho rolidone and vinyl ferrocene; aromatic monomers other than bicity of the copolymer, (b) changing the molecular weight Vinyl aromatics, including acenaphthalene and indene; of the low T. or high T. polymer blocks and/or other acrylic monomers, including alkyl acrylates, arylalkyl acry polymer blocks, (c) changing the ratio of the low T. polymer lates, alkoxyalkyl acrylates, halo-alkyl acrylates, and cyano block(s) relative to the high T. polymer block(s), (d) chang alkyl acrylates, methacrylic monomers, including meth ing the distribution of the low T. and high T. polymer blocks acrylic acid esters (methacrylates) and other methacrylic (e.g., midblock VS. endblock) within the polymer and/or (e) acid derivatives including methacrylonitrile; acrylic changing the architecture of the copolymer (e.g., a linear monomers, including acrylic acid esters and other acrylic copolymer VS. a branched copolymer), among others. acid derivatives including acrylonitrile, alkyl methacrylates and aminoalkyl methacrylates, alkene-based monomers, 0089. The release profile associated with a release region including ethylene, isotactic propylene, 4-methyl pentene, of the medical device can also be modified by changing the 1-octadecene, and tetrafluoroethylene and other unsaturated number, order, thickness, or position of carrier and barrier hydrocarbon monomers, cyclic ether monomers, ether regions with respect to one another. For example, the release monomers other than acrylates and methacrylates, and other profile can be modified by varying the thickness of the monomers including epsilon-caprolactone; and (2) hydro release region. Moreover, multiple release regions can be philic monomers including the following: vinyl amines, employed to modify the release profile, for example, (a) a alkyl vinyl ethers, and other vinyl compounds, methacrylic barrier layer containing the copolymer of the invention can monomers including methacrylic acid and methacrylic acid be positioned over a carrier layer containing the copolymer Salts, acrylic monomerS Such as acrylic acid, its anhydride of the invention and a therapeutic agent, (b) multiple carrier and Salt forms, and acrylic acid amides, alkyl vinyl ether layers of the invention, either of the same or different monomerS Such as methyl vinyl ether; and cyclic ether content (e.g., different polymer and/or therapeutic agent monomerS Such as ethylene oxide. content) can be stacked on top of one another, either with or 0093. In this connection, in some preferred embodiments, without intervening barrier layers, (c) multiple carrier layers the present invention comprises coatings and medical of the invention of differing compositions can be positioned devices having coatings comprising triblock copolymers laterally with respect to one another, and So forth. In having endblocks that contain one or more hydrophilic addition, where a carrier region is employed, a therapeutic chains, including homopolymer chains of ethylene oxide agent concentration gradient can be established within the (PEO), homopolymer chains of vinylpyrrolidone (PVP), or carrier region to control release of therapeutic agent. copolymer chains comprising a combination thereof, 0090 Hence, in certain embodiments of the present arranged in a repeating (e.g., alternating), random, Statistical invention, the drug release rate of the therapeutic releasing or gradient distributions. In other preferred embodiments, agent is controlled by changing the hydrophilic/hydrophobic the endblocks contain chains comprising one or more hydro ratio of the block copolymer of the present invention Such phobic polymerS Such as homopolymer chains of polym that the overall hydrophilicity of the copolymer is increased ethyl methacrylate (PMMA), homopolymer chains of poly or decreased (or, viewed conversely, the overall hydropho Styrene, and copolymer chains comprising a combination of bicity is increased or decreased). AS will be appreciated by the same, arranged in a repeating (e.g., alternating), random, one of Skill in the art, the ratio may be changed in a number Statistical or gradient distribution. The endblocks can also of ways. employ a combination of both hydrophilic and hydrophobic US 2006/OO13849 A1 Jan. 19, 2006 11 monomers that exhibit desired drug diffusion and release 2-boroisobutyrate and methyl 2-bromopropionate) or benzyl properties. The hydrophilic and/or hydrophobic monomers halides (e.g., 1-phenylethyl bromide and benzyl bromide). A can be Selected from various monomer Species, including wide range of transition-metal complexes, Such as Ru- (e.g., but not limited to those numerous monomerS Specifically Grubbs catalyst), Cu-, and Fe-based systems are employed. listed above for preparation of high T. polymer blocks. For Cu-based Systems, ligands Such as 2,2'-bipyridine and 0094. In certain embodiments, the drug release rate is aliphatic amines are typically employed to control both the controlled by blending hydrophobic or hydrophilic polymers solubility and activity of various ATRP catalysts. A typical in the release layers of the invention with the copolymers ATRP mechanism is illustrated by the following scheme:

Initiation : RX -- Met -- R -- Mett (n+1)X

Alkyl Metal M Halide, Initiator ion R-MX -- Met - R-M" Mett (n+1)X

x M X Propagation | + Methin - R--M.--M" + Met' (n+1}x described herein, thereby increasing the hydrophobicity or 0097. The copolymers of the medical devices of the hydrophilicity, respectively, of the release layers. In one present invention can be Synthesized, for example, by a free exemplary embodiment, the invention provides a blend radical process that comprises: (a) providing a macro comprising a triblock copolymer in accordance with the initiator, the macro-initiator comprising a free radical ter invention, which is blended with a hydrophilic polymer Such minated low T. block and (b) conducting a free radical as 2-hydroxyethyl methacrylate (HEMA), poly(2-vinyl pyri polymerization reaction in the presence of a monomer. dine) (PVP), or a combination of these materials. The 0098. In embodiments where it is desirable to synthesize triblock graft copolymer, in a preferred embodiment, com high T. polymer blocks having a main chain and a plurality prises a midblock of a polyolefin or polydiene Such as of Side chains, the polymerization can proceed in the pres EPDM and end blocks of polystyrene copolymer. ence of (i) a macro-monomer, which comprises the Side 0.095 AS will be appreciated by one of skill in the art, the chain and has a free-radical polymerizable end group and (ii) copolymers of the present invention may be Synthesized a free-radical polymerizable comonomer or a combination according to known methods, including ionic and, in par of comonomers, each containing a polymerizable unsatur ticular, radical polymerization methods Such as azobi ated group. Preferably, the end group is terminally unsatur S(isobutyronitrile)- or peroxide-initiated processes, and con ated and the polymerizable comonomer is an unsaturated trolled/living radical polymerizations Such as metal OOC. catalyzed atom transfer radical polymerization (ATRP), 0099. The polymers of the present invention can also be stable free-radical polymerization (SFRP), nitroxide-medi Synthesized using a difunctional free radical initiator Such as ated processes (NMP), and degenerative transfer (e.g., dimethyl-2,6-heptanedioate, which is used to polymerize, reversible addition-fragmentation chain transfer (RAFT)) for example, acrylate monomers (e.g., ethyl acrylate) to processes. These methods are well-detailed in the literature form a polyacrylate macro-initiator. and are described, for example, in an article by Pyun and Matyjaszewski, Synthesis of Nanocomposite Organic/Inor 0100. A “macro-monomer' as used herein is a macro ganic Hybrid Materials. Using Controlled "Living' Radical molecule, commonly a polymer, which has one reactive Polymerization, Chem. Mater, 13:3436-3448 (2001), the group, often as an end-group, which enables it to act as a contents of which are incorporated by reference in their monomer molecule, contributing only a Single monomeric entirety. unit to a chain of the final macromolecule. Each mac romonomer molecule is attached to the main chain of the 0096. In polymerizations of a monomer (M, in scheme final polymer by reaction of only one monomeric unit in the below) via ATRP, radicals are generated by the redox macromonomer molecule. Homopolymerization or copoly reaction of organic halides Such as alkyl halides (RX, in merization of a macromonomer yields comb or graft poly Scheme below) with transition-metal complexes (Met, in mers. For example, a long-chain vinyl polymer or oligomer Scheme below). Radicals can then propagate but are rapidly (as used herein, an oligomer is a polymer containing from deactivated by the oxidized form of the transition-metal 2-9 constitutional units) that has a polymerizable double catalyst. Initiators typically used are C-haloesters (e.g., ethyl bond at the end of the chain is a macromonomer. US 2006/OO13849 A1 Jan. 19, 2006

0101 Examples of some commonly employed free radi EPDM macroinitiator is used to polymerize styrene accord cal initiator compounds include hydroperoxide, peroxides, ing to published methods for ATRP polymerization. The Such as diacetyl peroxide, di-tert-butyl peroxide, di-benzoyl resulting copolymer comprises a number of polystyrene Side peroxide, and azo compounds, Such as azobis(isobutyroni chains originating from the double bond in the incorporated trile), tertiary butyl perbenzoate, di-cumyl peroxide and norbornene monomer of the EPDM molecule. A represen potassium perSulfate. tation of a resulting block copolymer having a comb archi 0102) Examples of macro-initiators include free radical tecture is shown in FIG. 2. terminated EPDM. In some embodiments, the macro-initia tor is a mono- or di-functional polyolefin compound reacted EXAMPLE 2 to yield a 2-bromoisobutyrate end group. Synthesis of Polyolefin-Based Graft Copolymers 0103 Examples of macro-monomers include polysty 0110) A low T. hydrocarbon polymer block is prepared rene, polyethylene oxide, polyvinylpyrrollidone, polymeth from functionalized polydiene and polyolefin blockS, Such ylmethacrylate, each with a polymerizable end group, for as those which are commercially available with functional example, a group that provides terminal unsaturation, Such ized end groups as polichelic'TM polymers from FMC as alkyl methacrylate-terminated polystyrene. Lithium (Gastonia, N.C.). For example, the following diol 0104 Examples of comonomers include unsaturated and triols of polyolefins are utilized to formulate the poly monomers or a combination of monomers, each containing meric materials and devices of the present invention. a polymerizable unsaturated group, Such as alkyl methacry lates, alkyl acrylates, hydroxyalkyl methacrylates, vinyl esters or Styrene.

EXAMPLE 1.

Synthesis of EPDM-Based Block Copolymer (b) 0105 1. Synthesis of EPDM Macroinitiator HO OH, and 0106) A low T. hydrocarbon polymer block is prepared from EPDM (ethylene-propylene-diene monomer) copoly

mer blocks (e.g., VistalonTM polymers from Exxon-Mobil), as described above. The EPDM block copolymer comprises ethylene, propylene and a diene termonomer block, in this case, ethylidene norbornene. End-functional groups are formed on the EPDM by hydroboration of the diene mono mers with 9-BBN (9-borabicyclo3.3.1nonane), followed by reaction with hydrogen peroxide. Hydroboration of alk 0111. These materials are used in Separate experiments to enes generally involves attack of the double bond of the yield linear A-B-A triblock copolymers having a low T. ethylidene norbornene monomer by BH to form a 4-mem hydrocarbon midblock and high T. polymer end blocks such bered ring transition State (), as follows: as polystyrene endblockS. A polyolefin copolymer is pre pared by first reacting a di-hydroxy-terminated poly(olefin) with 2-bromo-isobutyryl bromide. This forms a macroini H--BH tiator with two C-bromoester groups. These groups can be H---BH, used to initiate the polymerization of Styrene to form the triblock copolymer via atom transfer radical polymerization techniqueS or other controlled/living radical polymerization H BH methods. FIGS. 3, 4, and 5 schematically illustrate the formulation of three linear polystyrene-polyolefin-polySty CH-C-C-H rene triblock copolymers according to various embodiments of the present invention. These diols and triols, listed above, may also be used to initiate ring opening polymerization of cyclic monomerS Such as lactide, glycolide, caprolactone, or 0107 The addition of peroxide resolves the transition caprolactam to produce triblock polymers. State into the alcohol, providing a hydroxyl end-functional 0112 In addition, a tri-functional polyolefin having a group. The hydroxyl groups are then reacted with 2-bromo hybrid inorganic/organic structure is used to create a three isobutyryl bromide to form the EPDM with bromoester end armed star copolymer of the structure, SiMe-(BA). The functional groups (EPDM macroinitiator), as shown in FIG. tri-functional SiMe-core polyolefin having a hydroxyl func 1. tional group is reacted with 2-bromo-isobutyryl bromide to 0108) 2. Polystyrene-Poly(EPDM)-Polystyrene Block create a macroinitiator having C-bromoester groups, as Copolymer Synthesis schematically illustrated in FIG. 6. 0109 Astyrene-EPDM-styrene based block copolymer is 0113 Generally, there are two methods for generating synthesized using known techniques, to form an EPDM Star shaped polymers. One may either link a given number hydrocarbon backbone with polystyrene side chains. This of linear chains to the same central core fitted with reactive US 2006/OO13849 A1 Jan. 19, 2006 functions ("arm first method) or grow branches from a 6. The device of claim 1, wherein Said copolymer is a multifunctional core that is able to initiate the polymeriza comb copolymer comprising a low Thydrocarbon polymer tion in multiple directions (“core first” method). The tri main chain and a plurality of high T. polymer side chains. functional SiMe-core polyolefin may be produced according 7. The device of claim 1, wherein said hydrocarbon block to previously known methods, such as the “arm first is a polyolefin block. method using commercially available anionic initiators that 8. The device of claim 1, wherein said hydrocarbon block have protected functional groups (FMC Lithium, Gastonia, is a polydiene block. N.C.), and are described in U.S. Pat. No. 6,362.284, which 9. The device of claim 1, wherein said hydrocarbon block is hereby incorporated by reference in its entirety. According is a poly(olefin-co-diene) block. to the “arm first method, a monofunctional hydroxy-pro 10. The device of claim 1, wherein said hydrocarbon tected initiator is used to polymerize typically butadiene or block is a poly(olefin-co-diene) block in which the olefin isoprene with, for example, methyltrichlorosilane as a cou comprises one or both of ethylene and propylene and the pling/linking agent. The living polymer chain ends react diene comprises vinyl norbornene or ethylidene norbornene. with Sillylchloro groups on the methyltrichlorosilane to pro 11. The device of claim 1, wherein said high T. block is duce the three arm Star polymer. The hydroxy functional Selected from the group consisting of a poly (vinyl aromatic) groups are formed by the deprotection (hydrolysis) of the block, a poly(alkyl methacrylate) block and a poly(Vinyl protecting group, as described in U.S. Pat. No. 6,362.284. pyridine) block. 0114. As shown in FIG. 7, the macroinitiator comprises 12. The device of claim 1, wherein said high T. block a tri-functional SiMe core with polyolefinic arms having comprises polystyrene. reactive end groups comprising C-bromoester groups. The 13. The device of claim 1, wherein Said release region is copolymer is formed by polymerizing the macroinitiator a carrier region that comprises Said therapeutic agent. with a styrene comonomer under Standard atomic transfer 14. The device of claim 1, wherein Said release region is radical polymerization conditions. A representative final a barrier region disposed over a therapeutic-agent-contain architecture of a three-arm Star comprising a SiMe tri ing region that comprises Said therapeutic agent. functional core with polyolefin inner chain lengths con 15. The device of claim 1, wherein said release region is nected to polystyrene outer chains, is shown in FIG. 8. in the form of a coating layer that coverS all or a part of Said medical device. 0115) If desired, these hydroxy-protected polyolefin 16. The device of claim 1, wherein said medical device is arms, described above, may be coupled with different sili an implantable or insertable medical device. cone coupling agent other than methyltrichlorosilane to 17. The device of claim 1, wherein said implantable or provide multi-arm block copolymers, as illustrated by FIG. insertable medical device is Selected from a catheter, a guide 9. A variety of Silicone chloride coupling agents is available wire, a balloon, a filter, a Stent, a Stent graft, a vascular graft, through the Gelest Corporation. As shown in FIG. 9, bis a vascular patch and a shunt. (methyldichlorosilyl) ethane may be used as the coupling 18. The device of claim 1, wherein said implantable or agent. The living polymer chain ends react with Sillylchloro insertable medical device is adapted for implantation or groups on the bis(methyldichlorosilyl) ethane to produce a insertion into the coronary vasculature, peripheral vascular four-arm Star polyolefin copolymer with hydroxy functional System, esophagus, trachea, colon, biliary tract, urinary tract, end groups with the copolymer having two Silicone atoms in prostate or brain. the center core. As described in U.S. Pat. No. 6,362.284, the 19. The device of claim 1, wherein said therapeutic agent hydroxy functional groups are formed by the deprotection is Selected from one or more of the group consisting of (hydrolysis) of the protecting group. anti-thrombotic agents, anti-proliferative agents, anti-in 0116. Although various embodiments are specifically flammatory agents, anti-migratory agents, agents affecting illustrated and described herein, it will be appreciated that extracellular matrix production and organization, antine modifications and variations of the present invention are oplastic agents, anti-mitotic agents, anesthetic agents, anti covered by the above teachings and are within the purview coagulants, vascular cell growth promoters, vascular cell of the appended claims without departing from the Spirit and growth inhibitors, cholesterol-lowering agents, vasodilating intended Scope of the invention. agents, and agents that interfere with endogenous vasoactive mechanisms. 20. The device of claim 2, wherein said copolymer is What is claimed is: made by a process that comprises (a) providing a macro 1. A radiation stable medical device comprising (a) a initiator, Said macro-initiator comprising a free radical ter release region and (b) at least one therapeutic agent, said minated low Thydrocarbon block and (b) conducting a free release region comprising a radiation Stable copolymer that radical polymerization reaction in the presence of a macro further comprises (i) a low T. hydrocarbon polymer block monomer comprising Said endblocks each having a free and (ii) one or more high T. polymer blocks. radical polymerizable end group. 2. The device of claim 1, wherein Said copolymer com 21. The device of claim 20, wherein the macro-monomer prises a low T. hydrocarbon polymer midblock and a plu comprises a polystyrene block, a polyethylene oxide block, rality of high T. polymer endblocks. a polyvinylpyrrolidone block, a polyalkylmethacrylate 3. The device of claim 1, wherein Said copolymer is a block, or a combination thereof. triblock copolymer 22. The device of claim 20, wherein the macro-initiator is 4. The device of claim 1, wherein Said copolymer is a Star a free radical terminated polyolefin or polydiene. copolymer. 23. The device of claim 20, wherein the free radical 5. The device of claim 1, wherein said copolymer is a polymerization reaction is further conducted in the presence dendritic copolymer. of one or more hydrophilic monomerS Selected from Vinyl US 2006/OO13849 A1 Jan. 19, 2006

amine monomers, alkyl vinyl ether monomers, methacrylic 24. A method of forming the medical device of claim 1, acid and acid Salt monomers, acrylic acid monomer, acrylic comprising: (a) providing a Solution comprising (i) a Solvent acid amide monomers, alkyl vinyl ether monomers, cyclic System and (ii) said copolymer; and (b) forming said release ether monomers, or one or more hydrophobic monomers region from Said Solution by removing Said Solvent System Selected from Vinyl aromatic monomers, vinyl ester mono from Said Solution. mers, vinyl halide monomers, alkyl vinyl ether monomers, 1-vinyl-2-pyrrollidone monomer, Vinyl ferrocene monomer, 25. The method of claim 24, wherein said Solution further acenaphthalene monomer, indene monomer, alkyl acrylate comprises a therapeutic agent in dissolved or dispersed monomers, arylalkyl acrylate monomers, alkoxyalkyl acry form. late monomers, halo-alkyl acrylate monomers, cyano-alkyl 26. The method of claim 24, wherein said solution is acrylate monomers, alkyl methacrylate monomers, ami applied over a therapeutic-agent-containing region that com noalkyl methacrylate monomers, methacrylonitrile mono prises Said therapeutic agent. mer, acrylonitrile monomer, ethylene monomer, isotactic propylene monomer, 4-methyl pentene monomer, 1-octa 27. The method of claim 24, wherein said release region decene monomer, tetrafluoroethylene monomer, cyclic ether is formed by a technique comprising a spraying process. monomers, ether monomers, and epsilon-caprolactone OOC.