Patent Publication Number: US-2006020329-A1

Title: Semi-directional drug delivering stents

Description:
RELATED APPLICATION  
      The present application is a continuation in part application of provisional patent application No. 60/574,898, filed on May 26th, 2004. 
    
    
     FIELD OF THE INVENTION  
      The present application is directed to a stent configured to deliver one or more therapeutic agents to an area of interest within a bodily or luminal structure. More specifically, a semi-directional drug delivery stent for selectively delivering one or more therapeutic agents to the area of interest within a bodily or luminal structure is disclosed.  
     BACKGROUND OF THE INVENTION  
      The mammalian circulatory system is comprised of a heart, which acts as a pump, and a system of blood vessels which transports blood to various points in the body. For a variety of reasons, the blood vessels and luminal structures associated with the circulatory system may develop a variety of vascular disabilities or dysfunctions. For example, one common vascular dysfunction, commonly known as an aneurysm, is the abnormal widening of the blood vessel. Typically, aneurysms are formed as a result of the weakening of the wall of a blood vessel and subsequent ballooning of the weakened vessel wall. In contrast, stenosis is the narrowing of a lumen or an opening that occurs in organs, vessels, or other luminal structures within the body, thereby impeding or otherwise restricting the flow of blood therethrough. A number of physiological complications have been associated with vascular disabilities or dysfunctions, such as ischemia cardiomyopathy, angina pectoris, and myocardial infarction. In response, several procedures have been developed for treating vascular disabilities or dysfunctions.  
      One common method used to treat vascular dysfunctions requires the implantation of mechanical support devices, commonly referred to as “stents.” Stents act as radially expandable mechanical scaffolds providing support to the incompetent vascular region. In addition, the stent may be coated with one or more therapeutic agents thereby providing a drug-eluding device capable of delivering a therapeutic agent to an area of interest, such as a luminal wall, within a vascular structure. One or more grafts may be positioned on the stent to augment the supportive effects of the stent or to enhance the therapeutic effects of the stent. While stents and stent-graft devices have proven successful in treating a number of vascular dysfunctions, a number of shortcomings have been identified. For example, the targeted delivery of therapeutic agents to areas of interest within luminal structures has proven problematic. More specifically, current drug-eluding stents or stent-graft devices lack the capability to directionally deliver therapeutic agents to an area of repair. As a result, the drug or other therapeutic agent positioned on or otherwise applied to a stent are indiscriminately dispensed into the luminal vessel and bloodstream of a patient. As a general rule, the amount of therapeutic agent loaded on a stent is minute and does not reach systemic, toxic, or physiological concentrations. Consequently, drug delivery stent designers have focused on controlling release of the drug such that localized therapeutic levels are reached and have largely ignored limiting systemic exposure. However, restricting the diffusion of chemotherapeutics into systemic circulation becomes increasingly more important as more cytotoxic agents are used and/or larger drug-eluding vascular prosthetics are employed.  
      In light of the foregoing, there is an ongoing need for stents and stent-graft devices capable of directionally delivering one or more therapeutic agents to an area within a vascular structure thus minimizing systemic exposure and maximizing local therapeutic effect.  
     BRIEF SUMMARY OF THE INVENTION  
      A semi-directional drug delivery stent for selectively delivering one or more therapeutic agents to an area of interest within a bodily or luminal structure is disclosed.  
      In one embodiment, a semi-direction drug delivery stent includes a generally cylindrical body defining at least one internal passage positioned longitudinally therein, a non-permeable material applied to the cylindrical body, and at least one therapeutic agent applied to the at least one of the cylindrical body and the non-permeable material. The non-permeable material is configured to act as a diffusion barrier. In one embodiment, the non-permeable material prevents the therapeutic agent from diffusing into the internal passage formed in the stent, thereby effectively preventing the systemic administration of the therapeutic agent through the bloodstream and while delivering the therapeutic agent to tissue positioned proximate to the stent.  
      In another embodiment, a device for implantation in within a luminal body is disclosed and includes a cylindrical body defining an internal passage formed longitudinally therein, a non-permeable material applied to an outside surface of the cylindrical body, and at least one therapeutic agent applied to the non-permeable material.  
      A method of making a stent is also disclosed and includes providing a cylindrical body defining a longitudinal internal passage, applying a non-permeable material to an outside surface of the cylindrical body, and applying at least one therapeutic agent to the non-permeable material.  
      In another embodiment, a method for directionally delivering therapeutic agents to a targeted site within a luminal body is disclosed and includes providing a stent defining a longitudinal internal passage and having a non-permeable material applied to an outside surface of the stent, the non-permeable material having at least one therapeutic agent applied thereto, positioning the stent within a luminal body, eluding the therapeutic agent from the non-permeable material into a wall of the luminal body, and restricting the therapeutic agent from eluding into the internal passage of the stent with the non-permeable material. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
      Various embodiments of a semi-directional drug delivery stent will be explained in more detail by way of the accompanying drawings, wherein components having similar but not necessarily the same or identical features, may have the same reference numeral, and wherein:  
       FIG. 1  shows a perspective view of an embodiment of a radially expandable stent;  
       FIG. 2  shows a perspective view of an embodiment of a semi-directional drug delivery stent having a non-permeable graft positioned thereon;  
       FIG. 2A  shows a perspective view of an embodiment of the semi-directional drug delivery stent wherein the non-permeable graft positioned thereon includes one or more surface irregularities formed thereon;  
       FIG. 3  shows a cross sectional view of an embodiment of a semi-directional drug delivery stent as viewed along lines  4 A- 4 A of  FIG. 2 ;  
       FIG. 4  shows a cross sectional view of an embodiment of a semi-directional drug delivery stent as viewed along lines  4 B- 4 B of  FIG. 2 ;  
       FIG. 5  shows a cross sectional view of another embodiment of a semi-directional drug delivery stent as might be viewed along lines  4 A- 4 A of  FIG. 2  in a stent graft similar to the embodiment shown in  FIG. 2 ,  
       FIG. 6  shows a cross sectional view of an embodiment of a semi-directional drug delivery stent implanted within a luminal structure;  
       FIG. 7  shows a perspective view of an embodiment of a semi-directional drug delivery stent having a non-permeable graft with a sealing layer positioned thereon; and  
       FIG. 8  shows a perspective view of an embodiment of the semi-directional drug delivery stent wherein the stent includes a distal portion having a diameter greater than the diameter of a medial portion. 
    
    
     DETAILED DESCRIPTION  
       FIG. 1  shows an embodiment of a radially expandable stent configured to be inserted into a luminal structure. As shown, the stent  5  comprises a cylindrical body  7  having an internal surface  9  defining an internal passage  11 , and an outer surface  13 . The internal passage  11  is coaxially positioned along the longitudinal axis L of the stent  5 . In the illustrated embodiment, the stent  5  is comprised of a first cylindrical body member  7 A coupled to a second cylindrical body member  7 B, thereby forming a modular radially expandable stent. In another embodiment, any number of cylindrical body members may be coupled together to form a modular radially expandable stent. Optionally, the stent  5  may be comprised of a singular cylindrical body  7 . The radially expandable stent  5  may be manufactured in a variety of sizes, lengths, and diameters (inside diameters as well as outside diameters). Furthermore, the radially expandable stent  5  may be manufactured from a variety of materials, including, without limitation, stainless steel, tantalum, titanium, nickel-titanium alloys, shape-memory alloys, super elastic alloys, low-modulus Ti—Nb—Zr alloys, cobalt-nickel alloy steel (MB-35N), biologically compatible polymers and elastomers, including non-porous, porous, and micro-porous polymers and elastomers.  
       FIG. 2  shows an embodiment of a semi-directional drug delivery stent/stent graft. As shown in  FIG. 2 , the semi-directional drug delivery stent  40  includes a cylindrical body  42  having an internal surface  44  defining an internal passage  46 , and an outer surface  48 . Like the previous embodiments, the internal passage  46  is coaxially positioned along the longitudinal axis L of the semi-directional drug delivery stent  40 . At least one non-permeable membrane or graft  50  may be selectively applied to the internal surface  44 , the outer surface  48 , or both surfaces. In one embodiment, the graft  50  is manufactured from paralyene. Optionally, the graft  50  may be manufactured from any variety of biologically compatible materials, including, without limitation, polyurethane, paralyene, polyester, Teflon, polypropylene, polyethylene, polyamides, polycarbonate, poly-methyl-methacrylate, poly-butyl-methacrylate, polyvinyl alcohol, polyvinyl acetate, silicone elastomer, polytetrafluoroethylene, polyacrylonitrile, polyvinyl chloride, polystyrene, and polyvinyl propylene  
      In the embodiment illustrated in  FIG. 2  the non-permeable graft  50  is applied to the outer surface  48  of the semi-directional drug delivery stent  40  and forms a continuous structure. Optionally, the non-permeable graft  50  may be fenestrated or include one or more surface irregularities thereon. For example, the non-permeable graft  50  may include one or more openings or slits formed thereon. In an alternate embodiment, the non-permeable graft  50  includes one or more attachment bumps or similar surface irregularities to enhance stent placement and attachment.  FIG. 2A  shows an embodiment of the semi-directional drug delivery stent  40  wherein the non-permeable graft  50  includes one or more bumps  51  formed on the outer surface of the non-permeable graft  50 . In one embodiment, the one or more bumps may be formed on the non-permeable graft  50  during the manufacture thereof. Other therapeutic agents that could be used in the treating aneurysms with an embodiment of the present invention include: ACE inhibitor/ARB combination therapy; Doxycycline, and other MMP inhibitors (i.e., tetracycline); COX-2 inhibitors; Cerivastatin; Oleic acid; Selective iNOS inhibitor (ON1714, BBS-2); Roxithromycin; Curcumin, gingerol; Beta blockers (cardioselective or carvedilol); and NSAIDS.  
      Referring again to  FIG. 2 , at least one therapeutic agent  52  may be applied to or otherwise disposed on the non-permeable graft  50 . Exemplary non-permeable graft  50  may be manufactured from a variety of materials. In one embodiment, when a hydrophilic therapeutic agent is being delivered to an area of interest within a body, a hydrophobic membrane or coating may be applied to a graft to prevent the diffusion of drug through the graft. Exemplary hydrophobic materials include, without limitation, polyurethane, polytetrafluoroethylene, fluoro base materials, polyethylene, polypropylene, polyamide, silicon, polydimethylsiloxane, silicon based materials, or a blend or alloy of the above materials. In an alternate embodiment, when a hydrophobic drug is to be delivered, either a hydrophilic and/or a hydrophobic graft or coating may be applied to the stent to prevent the diffusion of drug through the graft, as hydrophilic materials can efficiently block the diffusion of drug. In addition, the hydrophobic coating can be used to block the diffusion of blood (with drug in it) thought the graft. Exemplary hydrophilic materials may include, without limitation, polyvinyl alcohol, poly-ethylene-co-vinyl alcohol, poly vinyl pyrrolidone or a blend or alloy of the above materials. Optionally, the non-permeable graft  50  may also include, without limitation, paralyene, Gore-Tex, or a like material. Those skilled in the art will appreciate that the at least one therapeutic agent  52 , the non-permeable material  50 , or both may be applied to the cylindrical body  42  in any number of ways, including, without limitation, sprayed, dipped, adhesively bonded, mechanically bonded, and vapor deposited. In an alternate embodiment, one or more therapeutic agents  52  may be applied to the internal surface  44 , the outer surface  48 , or the internal and outer surface  44 ,  48  of the semi-directional drug delivery stent  40 . As a result, the semi-directional drug delivery stent  40  is capable of eluding or delivering at least one therapeutic agent  52  to an internal passage formed within a luminal structure, to the vessel wall located proximate to the outer surface  48 , or both.  
      The term therapeutic agent as used herein means any component for use in animals having a desired effect. Non-limiting examples include, without limitation, paralyene, anticoagulants, such as an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, aspirin, protaglandin inhibitors, platelet inhibitors, or tick anti-platelet peptide. Other classes of agents include vascular cell antiproliferative agents, such as a growth factor inhibitor, growth factor receptor antagonists, transcriptional repressor or translational repressor, antisense DNA, antisense RNA, replication inhibitor, inhibitory antibodies, antibodies directed against growth factors, cytotoxic agents, cytoskeleton inhibitors, peroxisome proliferator-activated receptor gamma agonists, molecular chaperone inhibitors and bifunctional molecules. The therapeutic agents can also include cholesterol-lowering agents, vasodilating agents, and agents which interfere with endogenous vasoactive mechanisms. Other examples of agents can include anti-inflammatory agents, anti-platelet or fibrinolytic agents, anti-neoplastic agents, anti-allergic agents, anti-rejection agents, metaloprotease inhibitors, anti-microbial or anti-bacterial or anti-viral agents, hormones, vasoactive substances, anti-invasive factors, anti-cancer drugs, antibodies and lymphokines, anti-angiogenic agents, radioactive agents and gene therapy drugs, among others.  
      Specific non-limiting examples of agents that fall under one or more of the above categories include paclitaxel, docetaxel and derivatives, epothilones, nitric oxide release agents, heparin, aspirin, coumadin, D-phenylalanyl-prolyl-arginine chloromethylketone (PPACK), hirudin, polypeptide from angiostatin and endostatin, benzoquinone ansamycins including geldanamycin, herbimycin and macbecin, methotrexate, 5-fluorouracil, estradiol, P-selectin Glycoprotein ligand-1 chimera, abciximab, exochelin, eleutherobin and sarcodictyin, fludarabine, sirolimus, rapamycin, ABT-578, certican, Sulindac, tranilast, thiazolidinediones including rosiglitazone, troglitazone, pioglitazone, darglitazone and englitazone, tetracyclines, VEGF, transforming growth factor (TGF)-beta, insulin-like growth factor (IGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), RGD peptide, estrogens including 17 beta-estradiol and beta or gamma ray emitter (radioactive) agents, and various marking agents including radio-opaque, echogenic, and magnetically resonating materials.  
      Referring again to  FIG. 2 , the therapeutic agent  52  located on the non-permeable graft  50  of the semi-directional drug delivery stent  40  is restricted or otherwise prevented from diffusing into the internal passage  46  formed therein by the non-permeable characteristics of the non-permeable material  50 . Those skilled in the art will appreciate that the non-permeable material may be applied to the internal surface  44 , outer surface  48 , or both the internal and outer surfaces  44 ,  48 , respectively, of the cylindrical body  40 . In an alternate embodiment, at least one therapeutic agent may be applied to the cylindrical body of the semi-directional drug delivery stent prior to the application of the non-permeable material. For example, paralyene may be applied the stent prior to or following the application of the non-permeable material.  
       FIG. 3  shows a detailed cross-sectional view of an embodiment of the cylindrical body. As shown, the body segment  60  includes a cylindrical body portion  62  having a non-permeable material  64  applied to an outer surface  66  thereof. At least one therapeutic agent  68  may be selectively applied to the non-permeable material  64 . The internal surface  70  of the cylindrical body portion  62  defines an internal lumen section  72 . As shown in  FIG. 3 , the therapeutic agent  68  located on the non-permeable material  64  is dispensed in outward direction as shown by arrow  74  from the cylindrical body portion  62 . More specifically, the non-permeable material  64  prevents the therapeutic agent from being dispensed within the internal lumen section  72 , thereby directionally delivering the therapeutic agent  68 . When positioned within a luminal structure, the therapeutic agent  68  will be directionally dispensed into tissue in contact with or positioned proximate to the body segment  60 .  
       FIG. 4  shows a cross-sectional view of an embodiment of semi-directional drug delivery stent. As shown, the stent  80  includes a cylindrical body  82  having an internal surface  84  defining an internal passage  86 , and an outer surface  88  having a non-permeable material  90  applied thereto. At least one therapeutic agent  92  may be selectively applied to the non-permeable material  90 . The therapeutic agent  92  positioned on the non-permeable material  90  will be directionally eluded outwardly from the stent  80  as illustrated by arrows  94 . Optionally, at least one therapeutic agent  96  may be applied to the cylindrical body  82 . For example, at least one therapeutic agent  96  may be applied to the internal surface  84  of the cylindrical body  82  thereby permitting the therapeutic agent  96  to be dispensed into the internal passage  86  as illustrated by arrows  98 . As a result, the semi-directional drug delivery stent  80  may be used to directionally deliver a therapeutic gauge into surrounding vascular tissue or vessel walls, into the vessel lumen, or both simultaneously if desired. An alternate embodiment, at least one therapeutic agent  92  may be applied to the surrounding vascular tissue or vessel walls while an alternate therapeutic agent  96  is delivered into the bloodstream of a patient.  
       FIG. 5  shows an alternate embodiment of a cylindrical body section  100  of the semi-directional drug delivery stent. As shown in  FIG. 5 , the cylindrical body section  100  includes a cylindrical body portion  102  having an internal surface  104  defining an internal lumen section  106 . At least one non-permeable material  108  may be selectively applied to the internal surface  104  of the cylindrical body portion  102  and located within the internal lumen section  106 . The cylindrical body portion  102  further includes an outer surface  110  having at least one therapeutic agent  112  selectively applied thereto. Like the previous embodiments, the non-permeable material  108  directionally restricts the disbursement of the therapeutic agent  112  as illustrated by arrow  114 .  
       FIG. 6  shows a side cross-sectional view of a semi-directional drug delivery stent  120  positioned within a luminal structure  122 . As shown, the luminal structure  122  includes an aneurismal sac  124 . The stent  120  includes a cylindrical body  126  having an internal surface  128  defining an internal passage  130  therethrough. Further, the outer surface  132  of the cylindrical body  126  includes a non-permeable material  134  applied thereto. At least one therapeutic agent  136  may be applied to the stent  120 . In the illustrated embodiment, the therapeutic agent  136  is applied to an outer surface of the non-permeable material  134 . However, the therapeutic agent  136  may be applied to the internal surface  128 , the outer surface  132 , the non-permeable material  134 , or any combination thereof. As shown in  FIG. 6 , the therapeutic agent  136  applied to the outer surface of the non-permeable material  134  is eluded into the walls of the luminal structure  122  and the aneurismal sac  124 , thereby directionally delivering the therapeutic agent  136  as illustrated by directional arrow  138 . When implanted in a blood vessel, the semi-directional drug delivery stent  120  permits the directed delivery of drugs to a selected area within a luminal structure, while permitting the flow of blood to the internal passage  128  as illustrated by directional arrow  140 .  
      Optionally, the semi-directional drug delivery stent/stent graft may include one or more materials applied thereto or one or more areas formed thereon configured to restrict or prevent the flow of blood through a space between the stent/stent graft and the vessel wall when implanted. As such, the semi-directional drug delivery stent/stent graft may be configured to restrict or prevent endovascular leakage around the stent/stent graft once implanted within a vascular region. For example,  FIG. 7  shows an embodiment of a semi-directional drug delivery stent  140  comprising a cylindrical body  142  having an internal surface  144  defining an internal passage  146 , and an outer surface  148 . Like the previous embodiments, the internal passage  146  is coaxially positioned along the longitudinal axis L of the semi-directional drug delivery stent  140 . At least one non-permeable membrane or graft  150  having one or more therapeutic agents  152  applied thereto is selectively applied to the outer surface  148  of the cylindrical body  142 . At least one sealing layer may be selectively applied to the stent membrane or graft  150 . In the illustrated embodiment a first sealing layer  156  is positioned on a first portion  154  of the graft  150 , and a second sealing layer  160  is positioned to a second portion  158  of the graft  150 . Optionally, any number of sealing layers may be applied to the graft  150  at various locations. During use, the sealing layers  156 ,  160  may be configured to provide an essentially fluid-tight seal over at least a circumferential portion of the stent/stent graft. Optionally, the sealing layer may be applied to a portion of the stent/stent graft less than the entire stent/stent graft. In the alternative, the sealing layer may be applied to the entire stent/stent graft. Exemplary materials useful in forming the sealing layer include, without limitation, hydrogels, non-permeable materials, and the like. For example, U.S. Pat. No. 6,656,214, issued to Fogarty et al, which is hereby incorporated by reference in its entirety herein, describes various methods and devices useful in preventing endovascular leakage around an implanted device. More specifically, Col. 6, lines 35 through Col. 8, line 41 describes configurations and materials useful in preventing endovascular leakage which may be applied to the stent/stent graft of the prevent application.  
       FIG. 8  shows an alternate embodiment of a semi-directional drug delivery stent/stent graft configured to be implanted within a vascular structure while limiting endovascular leakage therearound. Like the previous embodiment, the stent  240  includes a cylindrical body  242  having an internal surface  244  defining an internal passage  246 , and an outer surface  248 . At least one non-permeable membrane or graft  250  having one or more therapeutic agents  252  applied thereto is selectively applied to the outer surface  248  of the cylindrical body  242 . The stent  240  has a distal portion  260  and a medial portion  262 . As illustrated, the distal portion may have a first diameter D 1  which is greater than the diameter D 2  of the medial portion. As such, the distal portion  260  may sealably engage the vascular lumen when expanded, thereby preventing or limiting the effects of endovascular leakage. Optionally, the distal portion  260  may include one or more sealing layers thereon. Further, any number of devices or other mechanism may be utilized with the various embodiments of the stents/stent grafts disclosed herein to prevent or otherwise restrict endovascular leakage.  
      In closing, it is understood that the embodiments of the semi-directional drug delivery stent disclosed herein are illustrative of principles of the invention. Other modifications may be employed which are within the scope of the present invention. Accordingly, the semi-directional drug delivery stent is not limited to that precisely as shown and described in the present disclosure.