BACKGROUND OF THE INVENTION

[0002] Drug-eluting implantable medical devices have become popular in recent times for their ability to perform their primary function (such as structural support) and their ability to medically treat the area in which they are implanted.

[0003] For example, drug-eluting stents have been used to prevent restenosis in coronary arteries. Drug-eluting stents may administer therapeutic agents such as anti-inflammatory compounds that block local invasion/activation of monocytes, thus preventing the secretion of growth factors that may trigger VSMC proliferation and migration. Other potentially anti- restenotic compounds include antiproliferative agents, such as chemotherapeutics, which include rapamycin and paclitaxel. Other classes of drugs such as anti-thrombotics, antioxidants, platelet aggregation inhibitors and cytostatic agents have also been suggested for anti-restenotic use.

[0004] Drug-eluting medical stents may be coated with a polymeric material which, in turn, is impregnated with a drug or a combination of drugs. Once the stent is implanted at a target location, the drug is released from the polymer for treatment of the local tissues. The drug is released by a process of diffusion through the polymer layer for biostable polymers, and/or as the polymer material degrades for biodegradable polymers.

[0005] Controlling the rate of elution of a drug from the drug impregnated polymeric material is generally based on the properties of the polymer material. However, at the conclusion of the elution process, the remaining polymer material in some instances has been linked to an adverse reaction with the vessel, possibly causing a small but dangerous clot to form. Further, drug impregnated polymer coatings on exposed surfaces of medical devices may flake off or otherwise be damaged, during deliver}' ^' , thereby preventing the drag from reaching the target site. Still further, drug impregnated polymer coatings are limited in the quantity of the drag to be delivered by the amount of a drug that the polymer coating can carry and the size of the medical devices. Controlling the rate of elution using polymer coatings is also difficult, [0006] Stents made from a hollow-tubular wire filled with therapeutic agents have been proposed. However, forming a hollow-wire stent by bending a hollow-wire into a stent form may cause kinking, cracking, or other undesirable properties in the finished, stent. Accordingly, co-pending U.S. Application No. 12/500,359, filed July 9, 2009, incorporated by reference herein in its entirety, describes methods for forming a hollow-wire stent by forming a core wire, bending the core wire into the selected stent shape, and. then removing the sacrificial or inner member of the core wire. Provisional application no. 61/244,049, filed September 20, 2009, incorporated by reference herein in its entirety, describes additional methods for forming a hollow-wire stent. Further, filling a hollow-wire stent may be problematic due to the small size and tortuous bends in the stent structure. Provisional application no. 61/244,050, filed September 20, 2009, incorporated by reference herein in its entirety, describes methods for filling a hollow-wire stent.

[0007] Accordingly, drug-eluting stents are needed that utilize the advantages of a hollow- wire stent, such as the ability to delivery increased quantities of the therapeutic substance and improved control of the elution rate of the therapeutic substance, while reducing potential manufacturing difficulties of a hollow-wire stent.

BRIEF SUMMARY OF THE INVENTION

[0008] A stent includes a plurality of cylindrical elements joined along a common longitudinal axis to form a tube. The cylindrical elements include struts joined by crowns. Hollow, drug-eluting elements are disposed between adjacent cylindrical elements and connect adjacent cylindrical elements to each other. A therapeutic substance fills the lumen of the drug-eluting elements, and. openings in the walls of the drug-eluting elements allow elution of therapeutic substance from the lumen for treatment of a vessel

[0009] in a method of forming a stent, a plurality of cylindrical elements are formed, wherein each cylindrical element includes a plurality of struts connected together by a series of crowns. A plurality of hollow drug-eluting elements are formed, with the drug-eluting elements including at least one opening through a wall thereof. A lumen of the drug-eluting elements is filled with a therapeutic substance, and the drug-eluting elements are connected between the plurality of cylindrical elements such that ends of each drug-eluting element are connected, to adjacent cylindrical elements such that the cylindrical elements are connected together and aligned generally along a common longitudinal axis to form the stent. The step of filling the drug-eluting elements with a therapeutic substance may take place before or after connecting the drug-eluting elements to the cylindrical elements. BRIEF DESCRIPTION OF DRAWINGS

[0010] The foregoing and other features and advantages of the invention will be apparent from the following description of the invention as illustrated in the accompanying drawings. The accompanying drawings, which are incorporated herein and form a part of the specification, further serve to explain the principles of the invention and to enable a person skilled in the pertinent art to make and use the invention. The drawings are not to scale.

[0011] FIG. 1 is a schematic illustration of an exemplary stent in accordance with an embodiment hereof.

[0012] FIG. 2 is a close-up view of a portion of the stent of FIG. 1.

[0013] FIG. 3 is a cross-section taken along line 3-3 of FIG. 2.

[0014] FIG. 4 is a cross-section taken along line 404 of FIG. 2.

[0015] FIGS. 5 is a perspective view of a cylindrical element of the stent of FIG. 1.

[0016] FIG. 6 is a schematic illustration of a portion of a vessel with a stent disposed therem.

[0017] FIG. 7 is a longitudinal cross-section of an embodiment of drug-eluting element.

[0018] FIG. 8 is a perspective view of an embodiment of a drug-eluting element.

[0019] FIG. 9 is a longitudinal cross-section of an embodiment of a drug-eluting element.

[0020] FIG. 10 is a longitudinal cross-section of an embodiment of a drug-eluting element.

[0021] FIG. 1 1 is a longitudinal cross-section of an embodiment of a drug-eluting element.

[0022] FIGS. 12-18 show schematic illustrations of portions of stents including drug-eluting elements disposed between cylindrical elements.

[0023] FIG. 19 illustra tes an embodiment of a method of forming a stent.

[0024] FIG. 20 illustrates an embodiment of a method of forming a stent.

[0025] FIG, 21 illustrates an embodiment of a method of filling a stent with a therapeutic substance.

DETAILED DESCRIPTION OF THE INVENTION

[0026] Specific embodiments of the present invention are now described with reference to the figures, where like reference numbers indicate identical or functionally similar elements.

[0027] An embodiment of a stent 100 disclosed herein is shown in FIG. 1. In particular, stent 100 includes a plurality of cylindrical elements or bands 102 joined along a common longitudinal axis to form a tube. In the embodiment shown, there are eight cylindrical elements 102a-l 02h joined together to form stent 100, but as would be apparent to those of ordinary skill in the art, more or less cylindrical elements 102 can be used. Each cylindrical

[0028] FIG, 2 illustrates a close-up of a crown 108a of a first cylindrical element 102a, a drug-eluting element 1 10, and a crown 1066 of a second cylindrical element 1026 adjacent the first cylindrical element. As shown in FIG. 2, drug-eluting element 1 10 includes at least one opening 112 for eluting a drag contained within drug-eluting element 110. As shown in the cross-sectional views of FIGS. 3 and 4, wire 101 of cylindrical elements 102 is a solid wire (FIG. 3) and drug-eluting element 1 10 is a hollow wire (FIG. 4). Those of ordinary skill in the art would understand that wire 101 need not be solid, however, wire 101 forming cylindrical elements 102 is not drug- filled. Wire 101 may be formed from, for example and not by way of limitation, stainless steel, cobalt-chromium alloys (such as F-562 cobalt- chromium alloy), cobalt-nickel-chromium-molybdenum alloys (such as MP35N and

MP20N), nickel-titanium alloys (such as Nitinol), magnesium, cobalt-chromium-tungsten- nickel alloys (such as L605), combinations thereof, or other suitable materials known to those of ordinary skill in the art. Drug-eluting element 1 10 is a hollow tube having a relatively thin wall 114 and a lumen 1 16. Lumen 1 16 is filled with a therapeutic substance 120. Wall 1 14 of dmg-eluting element 110 may be made of the materials listed above for wire 101, or any other suitable materials known to those of ordinary skill in the art,

[0029] Because drug-eluting elements 110 are not primarily responsible for radial support of stent 100, the wall of the drug-eluting element may be thinner than a hollow tube used for radial support. For example, and not by way of limitation, an outer diameter of drug-eluting element 100 may be in the range of 0.002 inch to 0,004 inch. The thickness of wall 1 14 maybe in the range of 0.0005 inch to 0.001 inch. In an embodiment, stmts 104 may be approximately .01 inch to .06 inch in length and drug-eluting elements 110 may also be approximately .01 inch to .06 inch in length. As shown in FIGS. 3 and 4, both wire 101 of cylindrical elements 102 and drug-el uting elements 110 are round in cross-section. However, those of ordinary skill in the art would recognize that other shapes are equally acceptable, such as oval, elliptical, half-round or D-shaped„ rectangular, etc.

[0030] Drug-eluting elements 110 are connected to cylindrical elements 102 by fusion, welding, soldering, adhesive, or other mechanical or chemical connections known to those skilled in the art. As shown in FIG. 1, the quantity of drug-eluting elements 1 10 between adjacent cylindrical elements 102 may vary from stent to stent, or within a stent itself. For example, more drug-eluting elements 110 may be disposed between cylindrical elements 102 near the ends of stent 100 and less between the cylindrical elements 102 near the middle of stent 100, or vice versa. Such variation permits a variable drug-elution profile along the length of stent 100. Further, instead of or in addition to varying the amount of drug-eluting elements 1 10, the size, therapeutic substance, or size or quantity of openings 1 12 may be varied from stent to stent or within a stent. Different sized drug-eluting elements 1 10, in diameter or length, permit different amounts of a therapeutic substance 120 disposed within lumen 116. Different sized openings 112 permit variable elution rates, as larger holes generally provide faster elution. Similarly, different quantities of openings 1 12 in drug- eluting elements 110 provide variable elution rates and profiles. Openings 112 may be, for example and not by way of limitation, lQ-30um in diameter.

[0031] Further, because the drug-eluting elements 1 10 are individual, different drug- eluting elements may include different therapeutic substances. Further, it would be understood by those of ordinary skill in the art that some elements between cylindrical elements 102 may be solid wire, for example and not by way of limitation, if such elements are not needed for drug-elution but may be needed for other reasons, such as scaffolding.

[0032] FIG. 6 illustrates schematically a cross-section of a portion of a stent 100 disposed in a vessel 130. In this example, some drug-eluting elements 1 10 between adjacent cylindrical elements 102 are shown. Further, openings 1 12 in alternating drug-eluting elements 1 10 face different sides of the stent. As shown in FIG. 6, starting from. 12:00 on a clock and progressing clockwise, the first and third drug-eluting elements 1 10 have holes 1 12 facing outwardly or the ab luminal side of the stent, while the second and fourth drug-eluting elements have openings 1 12 facing inwardly or the luminal side of the stent. Using such a configuration, a first therapeutic substance, such as an anti-proliferative drag, could be used to fill the drug-eluting elements 110 with outwardly facing openings 1 12, and. a second, therapeutic substance different than the first therapeutic substance, such as an anti-coagulant drug, could, be used to fill the drug-eluting elements 110 having inwardly facing openings 1 12. It would be appreciated by those of ordinary skill in the art that the first therapeutic substance and the second therapeutic substance need not necessarily be different. Thus, the same drug may be e luted from drug-eluting elements 110 with outwardly facing openings 112 and drug-eluting elements with inwardly facing openings 1 12. As would be further understood by those of ordinary skill in the art, individual drug-elutmg elements 1 10 can have elution openings 1 12 only on an outwardly facing or abluminal surface of stent 100 (as shown in FIG. 9), only on the inwardly facing or luminal surface of stent 100 (as shown in FIG. 10), both surfaces (as shown in FIG. 7), or may be pro vided anywhere along the circumference of the drug-eluting element 1 10 (as shown in FIG. 8).

[0033] In another embodiment shown in FIG. 7, a drug-eluting element 110 includes a divider or barrier 118 dividing lumen 116 into two sections. Barrier 118 extends longitudinally such that a lumen 1 16 is disposed on the abluminal side of drug-eluting element 1 10 and a second lumen 1 16' is disposed on the lumen side of drug-eluting element 110. A first therapeutic substance 120 is disposed in lumen 1 16 and a second therapeutic substance 120' is disposed in lumen 116'. Openings 1 12 on the abluminal or outwardly facing surface of drug-eluting element 110 allow first therapeutic substance 120 to elute from lumen 116 and openings 112' on the luminal or inwardly facing surface allow second therapeutic substance 120' to elute from lumen 116'. For example, and not by way of limitation, an antiproliferative drug may be disposed in lumen 1 16 and an anti-coagulant drug may be disposed in lumen 1 16'. Those of ordinary skill in the art would recognize the benefits of other drag combinations in such an embodiment.

[0034] FIGS. 12-18 show various embodiments of how drug-eluting elements 110 may be placed between cylindrical elements 102 of a stent. In FIGS. 12-1 8, only two cylindrical elements 102a, 1026 of a stent are shown for convenience, but one of ordinary skill in the art would recognize that the embodiments shown can be used between any two cylindrical elements 102 of a stent with any number of cylindrical elements, and that different embodiments can be used for the same stent and may be combined.. Further, the portions of wire cylindrical elements 102 and drug-eluting elements 110 shown in dashed lines indicate that these portions are behind the solid lines as the stent is tubular.

[0035] In FIG. 12, the cylindrical elements 102a, 1026 are offset such that crowns 108a of the first cylindrical element 102a align longitudinally with crowns 1066 of the second cylindrical element 1026. The drug-eluting elements 1 10 are connected to crowns 108a of [0036] In FIG. 13, the cylindrical elements 102a, 1026 are aligned such that crowns 108a of the first cylindrical element 102a align longitudinally with crowns 1086 of the second cylindrical element 1026. The drug-eluting elements 1 10 are connected between crowns 108a of the first cylindrical elements 102a and crowns 108a of the second cylindrical element 102,6 in what is generally referred to in the art as a peak-to-valley connection.

[0037] In FIG. 14, the cylindrical elements 102α, 1020 are offset as in FIG. 12 such that crowns 108a of the first cylindrical element 102a align longitudinally with crowns 1066 of the second cylindrical element 1026 and crowns 106a of the first cylindrical element 102a align with crowns 108/? of the second cylindrical element 1026. The drug-eluting elements 110 of the embodiment of FIG. 14, ho we ver, are connected between crowns 106a of the first cylindrical element 102a and crowns 1086 of the second cylindrical element 1026 in what is generally referred to in the art as a valley-to-valley connection.

[0038] In FIG. 15, the drug-eluting elements 1 10 are connected between a strut 104a of the first cylindrical element 102a and a strut 1046 of the second cylindrical element 1026 in what is generally referred to in the art as a strut-to-strut connection. In FIG, 16 the drug- eluting elements 110 are connected between a crown 108a of the first cylindrical element 102a and a strut 1046 of the second cylindrical element 1026 in what can be referred to as a peak-to-strut connection. In FIG. 17 the drug-eluting elements 1 10 are connected between a crown 106a of the first cylindrical element 102a and a stmt 1046 of the second, cylindrical element 1026 in what can be referred to as a valley-to-stmt connection.

[0039] In FIG. 18, the cylindrical elements 102a, 1026 are offset as in FIG. 12 such that crowns 108a of the first cylindrical element 102a align longitudinally with crowns 1066 of the second cylindrical element 1026. The drug-eluting elements 1 10 in FIG. 18 are curved or bended and are connected to crowns 108a of the first cylindrical element 102a and crowns 1066 of the second cylindrical element 1026 in a peak-to-peak connection. The bends of the drug-eluting elements 110 of FIG. 18 are in the same directing such that the drug-eluting elements 1 10 may nest together when the stent is in a radially compressed configuration for delivery. However, those of ordinary skill in the art would recognize that the bends need not face the same direction. Further, those of ordinary skill in the art would recognize that curved drug-eluting elements may be used in each of the embodiments described in FIGS, [0040] FIG, 19 outlines a method for forming a stent 100 in accordance with an embodiment hereof. In step 300, cylindrical el em exits 102 are formed. In step 302, drug- eluting elements 110 are formed without a therapeutic substance disposed therein. In step 304, openings 1 12 are formed, in wall 114 of dmg-eluting elements 110. Openings 112 may be laser cut, drilled, etched, or otherwise provided in wall 114 of drug-eluting element 1 10. In step 306, lumens 1 16 of drug-eluting elements 1 10 are filled with a therapeutic substance 120. Lumens 116 may be filled, by any method known to those of ordinary skill in the art, for example: (1) solution fill via coupling to end of hollow element; (2) use of an azeotropic solution to evaporate mixture of solvents off, leaving solid drug behind (in this instance, hollow elements would be placed in a sonicating bath of this solvent mixture and drug); (3) a sonicating bath of solvent and drag in a cryochamber that allows for solvent to be sublimated, leaving dry drug behind, and methods described in U.S. Provisional Application No.

61/244,050, filed September 20, 2009, which is incorporated by reference herein in its entirety. Further, because drug-eluting elements 1 10 are filled prior to attachment to cylindrical elements 102, the open ends of lumen 116 may assist in filling the drug-eluting element 1 10. However, the ends may be closed off, as described in more detail herein, and lumen 116 may be filled through openings 112 or other, larger openings made for filling lumen 116. These additional filling openings are closed prior to using the stent. After lumens 1 16 of drug-eluting elements 110 are filled, the drug-eluting elements 1 10 are connected to cylindrical elements 102 in step 308 to form a stent.

[0041] In the method described above, if drug-eluting elements 1 10 are fused or welded to cylindrical elements 102 and the therapeutic substance 120 is sensitive to heat, an insulative material or heat-sink may be disposed at each end of drug-eluting element 1 10. As shown in FIG. 9, plugs 122 may be provided at each end of dmg-eluting element 110. Plugs 122 may be made from a relatively insulative material, such as a polymer or composite ceramic-polymer material. Examples include poiyimide. P IPE, glass reinforced or impregnated PTFE and glass reinforced or impregnated poiyimide. Such an insulative plug 122 insulates therapeutic substance 120 from heat as drug-eluting elements 1 10 are fused or welded to cylindrical elements 102. Plugs 122 may be connected to dmg-eluting elements 110 by fusion, welding, adhesive, compression fit, or other connections known to those of ordinary skill in the art. Alternatively, plugs 122 may be a made of a conductive material whereby the generated heat is quickly dissipated into the surrounding stent or additional heat sink. Examples of conductive materials include cobalt based alloys, steels, gold,, tantalum, platinum-iridium alloys and others. In some embodiments, plugs 122 may be made radiopaque by adding radiopaque material such as barium sulfate, tungsten or tantalum to the polymer or polymer compos te or the material selected may be radiopaque such as tantalum and gold to improve visibility of the implant. Further, plugs 122 may be included even if not needed as an insulator or heat sink, and may be used, simply to seal ends of lumen 1 16 or as a radiopaque marker.

[0042] Alternatively, the ends of drug-eluting element 1 10 may be sealed by other methods. For example, methods described in provisional application no. 61/244,050, filed September 20, 2009. incorporated by reference herein in its entirety, for sealing an end of a wire, may be used to seal ends of drug-eluting element 110. Further, as shown in FIG. 10, the ends of wall 1 14 may be swaged to dose off the ends of drug-eluting element 1 10, as shown at 124. For example, a tube that is longer than drug eluting element 110 may be cut by a curved press that simultaneously presses the walls 1 14 at the location of the cut together, as shown in FIG. 10. This closes off the ends of lumen 1 16 and provides a surface to fuse or otherwise connect drug-eluting elements 1 10 to cylindrical elements 102. In another embodiment, shown in FIG. I I, the ends of drug-eluting element 1 10 are tapered such that the diameter at the ends is smaller than the diameter in the middle portion of drug-eluting element 110. Such tapered drug-eluting elements 110 may assist in improved crimping and reducing the crossing profile of the stent, particularly in the regions where the drug-eluting elements 1 10 are joined to the cylindrical elements 102.

[0043] Another method for forming a stent 100 is outlined, in FIG. 20. In step 400, cylindrical elements 102 are formed. In step 402, drug-eluting elements 1 10 are formed without a therapeutic substance disposed therein. In step 404, openings 112 are formed through the wali(s) 1 14 of drug-eluting elements 1 10. Openings 1 12 may be laser cut, drilled, etched, or otherwise provided, through wall(s) 1 14 of drug-eluting element 1 10. Further, those of ordinary skill in the art would recognize that openings 1 12 may be formed prior to or after connecting drug-eluting elements 1 10 to cylindrical elements 102. In step 406, the drug-eluting elements 110 are connected to the cylindrical elements 102 to form a stent. After the drug-eluting elements 110 are connected to the cylindrical elements, lumens 116 of drug-eluting elements 1 10 are filled with a therapeutic substance 120 in step 408. Lumens 1 16 may be filled by any method known to those of ordinary skill in the art, for example, those listed above in the description of the method of FIG. 19. The method of FIG. 20 fills the lumens 1 16 of drug-eluting elements 1 10 after the drug-eluting elements have been connected to cylindrical elements 102, instead of before as in the method of FIG. 19. [0044] Those of ordinary skill in the art would recognize that in some situations, some of the drug-eluting elements 110 could be filled with a therapeutic substance before being connected to cylindrical elements 102 and others could be filled, with a therapeutic substance after being connected to cylindrical elements 102. For example, and not by way of limitation, if different therapeutic substances are used, drug-eluting elements to be filled with therapeutic substances that are sensitive to heat may be attached to the cylindrical elements prior to being filled, and drug-eluting elements to be filled with therapeutic substances that are not sensitive to heat may be filled prior to being attached to the cylindrical elements.

[0045] FIG. 21 outlines a method for filling a stent with drug-eluting elements 110 connected to cylindrical elements 102. In particular, the method of FIG. 21 may be utilized, for example, after step 406 of FIG. 20. Further, the method of claim 21 is particularly useful when some of the drug-eiuting elements are to be filled with a first therapeutic substance and other of the drug-eluting elements are to be filled with a second therapeutic substance different from the first therapeutic substance. ^' Thus, in step 500, a stent is formed with unfilled drug-eluting elements 110 connected between cylindrical elements 102. In step 502, a first group of unfilled drug-eluting elements are masked, leaving a second group of unfilled drug-eluting elements unmasked. In step 504, the stent is exposed to a first therapeutic substance to fill the unmasked second group of drug-eluting elements with the first therapeutic substance. The mask on the first group of drug-eluting elements prevents them from being filled. The drug-eluting elements may be filled utilizing any method known to those of ordinary skill in the art, including, but not limited to, the methods described above with respect to FIG. 19. In step 506, the mask is removed from first group of unfilled drug- eluting elements and the second group of drug-eiuting elements (now filled) is masked. In step 508, the stent is exposed to a second therapeutic substance to fill the unmasked first group of drug-eluting elements with the second therapeutic substance. The mask on the second, group of drug-eluting elements prevents them from being filled. The drug-eluting elements may be filled, utilizing any method known to those of ordinary skill in the art, including, but not limited to, the methods described, above with respect to FIG. 19. In step 510, the mask is removed from the second group of drug-eluting elements, leaving a stent with the first group of drug-eluting elements filled with the second therapeutic substance and the second group of drug-eluting elements filled with the first therapeutic substance. Those of ordinary skill in the art are familiar with suitable masks and methods of applying and removing such masks. [0046] Stent 100 may be used conventionally in blood vessels of the body to support such a vessel after an angioplasty procedure. It is known that certain drugs eluted from stents may- prevent restenosis or other complications associated with angioplasty or stents. Stent 100 may alternatively be used in other organs or tissues of the body for delivery of drugs to treat tumors, inflammation, erectile dysfunction, nervous conditions, or other conditions that would be apparent to those skilled in the art,

[0047] The therapeutic substance or drag 120 may include, but is not limited to, antineoplastic, antimitotic, antiinflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antiproliferative, antibiotic, antioxidant, and antiallergic substances as well as combinations thereof. Examples of such antineoplastics and/or antimitotics include paclitaxel (e.g., TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g., Taxotere® from Aventis S. A., Frankfurt, Germany), methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g., Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g., Mutaniycin® from Bristol-Myers Squibb Co., Stamford,, Conn.). Examples of such antiplatelets, anticoagulants, antifibrin, and

antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro- arg-chioromethylketone (synthetic antithrombin), dipyridamole, glycoprotein lib/Ilia platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as Angiomax™ (Biogen, Inc., Cambridge, Mass.). Examples of such cytostatic or

antiproliferative agents include ABT-578 (a synthetic analog of rapamycin), rapamycin (sirolimus), zotarolimus, everoiimus, angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g., Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or Hsinopril (e.g., Prinivil® and Prinzide® from Merck & Co., Inc., White-house Station, N.J.), calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3 -fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station, N.J,), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, iriazolopyrimidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents that may be used include nitric oxide, alpha-interferon, genetically engineered epithelial cells, and dexamethasone. In other examples, the therapeutic substance is a radioactive isotope for implantable device usage in radiotherapeutic procedures.

Examples of radioactive isotopes include, but are not limited to, phosphorus (P ³² ), palladium (Pd ^{J Oj} ), cesium (Cs ^{J j J} ), Iridium (P ⁹² ) and iodine ( ²⁵ ). While the preventative and treatment properties of the foregoing therapeutic substances or agents are well-known to those of ordinary skill in the art, the substances or agents are provided by way of example and are not meant to be limiting. Other therapeutic substances are equally applicable for use with the disclosed methods and compositions.

[0048] Further, a carrier may be used with the therapeutic substance or drag. Examples of suitable carriers include, but are not limited to, ethanol, acetone, tetrahydrofuran, dym.ethylsulfoxi.de, a combination thereof, or other suitable carriers known to those skilled, in the art. Still further, a surfactant may be formulated with the drug and. the solvent to aid elution of the drug.

[0049] While various embodiments of the present invention have been described above, it should be understood that they have been presented, by way of illustration and example only, and not limitation. It will be apparent to persons skilled in the relevant art that various changes in form and detail can be made therein without departing from the spirit and scope of the invention. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplar}' embodiments, but should, be defined, only in accordance with the appended claims and their equivalents. It will also be understood that each feature of each embodiment discussed herein, and. of each reference cited herein, can be used, in combination with, the features of any other embodiment. Furthermore, there is no intention to be bound by any expressed or implied theory presented, in the preceding technical field, background, brief summary or the detailed description. All patents and publications discussed herein are incorporated by reference herein in their entirety.