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US20080146489A1 - Regional delivery of therapeutic agents for the treatment of vascular diseases - Google Patents

Regional delivery of therapeutic agents for the treatment of vascular diseases Download PDF

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Publication number
US20080146489A1
US20080146489A1 US11/639,512 US63951206A US2008146489A1 US 20080146489 A1 US20080146489 A1 US 20080146489A1 US 63951206 A US63951206 A US 63951206A US 2008146489 A1 US2008146489 A1 US 2008146489A1
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US
United States
Prior art keywords
therapeutic agent
vessel
balloon
delivery interface
afflicted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/639,512
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English (en)
Inventor
Stephen D. Pacetti
Paul M. Consigny
Ronald W. Heil
Florian Niklas Ludwig
Dariush Davalian
Li Zhao
Irina Astafieva
Jinping Wan
Fozan El-Nounou
Katsuyuki Murase
Syed F.A. Hossainy
Rachel Bright
Jeffrey Ellis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Cardiovascular Systems Inc
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to US11/639,512 priority Critical patent/US20080146489A1/en
Assigned to ADVANCED CARDIOVASCULAR SYSTEMS, INC. reassignment ADVANCED CARDIOVASCULAR SYSTEMS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HEIL, RONALD W., JR., CONSIGNY, PAUL M., ELLIS, JEFFREY, EL-NOUNOU, FOZAN, HOSSAINY, SYED F. A., MURASE, KATSUYAKI, PACETTI, STEPHEN D., WANG, JINPING, ZHAO, LI, BRIGHT, RACHEL, DAVALIAN, DARIUSH, ASTAFIEVA, IRINA, LUDWIG, FLORIAN NIKLAS
Assigned to ABBOTT CARDIOVASCULAR SYSTEMS INC. reassignment ABBOTT CARDIOVASCULAR SYSTEMS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HEIL JR., RONALD W., CONSIGNY, PAUL M., ELLIS, JEFFREY, EL-NOUNOU, FOZAN, HOSSAINY, SYED F.A., MURASE, KATSUYUKI, PACETTI, STEPHEN D., WAN, JINPING, ZHAO, LI, BRIGHT, RACHEL, DAVALIAN, DARIUSH, ASTAFIEVA, IRINA, LUDWIG, FLORIAN NIKLAS
Priority to PCT/US2007/087487 priority patent/WO2008076847A2/fr
Publication of US20080146489A1 publication Critical patent/US20080146489A1/en
Priority to US13/725,525 priority patent/US8895056B2/en
Priority to US14/521,126 priority patent/US20150045877A1/en
Abandoned legal-status Critical Current

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Definitions

  • the present invention relates to the regional treatment of vascular diseases.
  • Systemic delivery involves the administration of a therapeutic agent at a discrete location followed by the dispersal of the agent throughout the patient's body including, of course, to the target treatment site or organ.
  • a therapeutically effective amount of the agent at the afflicted site it is usually necessary to administer an initial dose substantially greater than the therapeutically effective amount to account for the dilution the agent undergoes as it travels through the body.
  • Systemic delivery is carried out primarily in two ways: introduction of the therapeutic agent into the digestive tract (enteral administration) or into the vascular system (parenteral administration), either directly such as injection into a vein or an artery or indirectly such as injection into a muscle or into the bone marrow. Delivery by each of these routes is strongly influenced by the so-called ADMET factors: absorption, distribution, metabolism, excretion and toxicity.
  • ADMET factors absorption, distribution, metabolism, excretion and toxicity.
  • enteric administration such factors as a compound's solubility, its stability in the acidic environs of the stomach and its ability to permeate the intestinal wall all affect the extent to which the drug is absorbed and therefore its bioavailability.
  • parenteral delivery factors such as enzymatic degradation, the lipophilic/hydrophilic partitioning coefficient, protein binding, etc. will affect the bioavailability of an agent.
  • Local delivery comprises administration of the therapeutic agent directly to the target site.
  • the ADMET factors tend to be less important than with systemic administration since the agent is being administered essentially directly to the treatment site.
  • the initial dose can be at or very close to the therapeutically effective amount.
  • some of the locally delivered therapeutic agent may diffuse over a wider region but such is not the intent of localized delivery and the concentration of the diffused agent will ordinarily be sub-therapeutic, i.e., too low to have a therapeutic effect.
  • localized delivery targets only the desired treatment site, it is possible that some of the causal factors of the disease that have spread to as yet non-afflicted regions of the organ at the periphery of the afflicted region may not undergo sufficient treatment, resulting in reoccurrence of the disease.
  • the present invention provides devices and compositions for and methods of treating vascular disease by the application of therapeutic agents in a “regional” as opposed to “systemic” or “local” manner.
  • the method comprises providing a device having a regional delivery interface comprising a therapeutic agent, contacting the entire length, or two or more portions of, the delivery interface with a surface of a segment of a vessel that is known or suspected to include a region afflicted with a vascular disease and delivering the therapeutic agent onto or into the surface of the vessel from the portions of the delivery interface in contact with the vessel surface.
  • the portion or portions of the delivery interface in contact with the surface include not only the known or suspected afflicted region but a portion of the non-afflicted region at the periphery of the afflicted region.
  • regional delivery refers to the simultaneous delivery of a therapeutically effective amount of a therapeutic agent to a region of the body, which extends beyond the actual afflicted site. That is, the regional delivery of this invention delivers a therapeutic amount of an agent not only to the specific location known or suspected to be afflicted with a vascular disease but also delivers a therapeutic amount to adjoining non-afflicted tissue. In this manner, sub-clinical causal factors related to the disease may be prevented from developing into clinical symptoms after cessation of treatment.
  • a therapeutic agent is delivered in therapeutically effective amounts simultaneously and in substantially uniform dose to a segment of a vessel, wherein the segment is at least about 40 mm in length.
  • Another non-limiting example of regional delivery would be to apply a fabric mesh wrap, impregnated with a therapeutic agent, around at least a portion of a vessel or an organ such that the agent is simultaneously delivered in therapeutic amounts over substantially the entire contact surface of the wrap with the vessel or organ.
  • a device in an embodiment of the present invention, comprises a regional delivery interface capable of administering a therapeutically effective amount of a therapeutic agent to a segment of a vessel that contains within it a region afflicted with or suspected of being afflicted (hereinafter it is understood that referral to an “afflicted region” refers to both a regions known to be afflicted, a region suspected to be afflicted and/or to a region that is neither known nor suspected to be afflicted but is known or suspected to be particularly susceptible to affliction, i.e., the device and method of this invention may be administered prophylactically) with a vascular disease and a non-afflicted region at the periphery of the afflicted region.
  • the regional delivery interface is greater than about 40 mm, more particularly between about 40 mm and about 200 mm and more particularly still, between 40 mm and 100 mm in length.
  • the regional delivery interface comprises a therapeutic agent wherein one or more portions of the therapeutic agent-containing delivery interface is/are contacted with a surface of a segment of a vessel that includes both afflicted and non-afflicted regions. The therapeutic agent is then delivered onto or into the surface of the vessel from the portions of the delivery interface in contact with the vessel surface.
  • the most distant from one another of the two or more portions contact the surface of the vessel at least in part in the non-afflicted region of the vessel at the periphery of the afflicted region.
  • the delivery interface comprises a single structure portions of which contact the vessel surface and some of which do not as in the case, without limitation, of a balloon with multiple diameters when inflated such that some portions of the balloon contact the vessel surface and some do not (q.v., below)
  • a therapeutic agent may be delivered from the non-contacting portions of the delivery interface into the space defined by the contacting portions of the delivery interface.
  • the therapeutic agent can be administered as a solution in a suitable solvent or as a suspension in a non-solvent carrier using an appropriate delivery interface as described hereinafter.
  • Excipients i.e., inert materials added to a drug formulation usually to provide stability, bulk and/or a dosage form, can be added if desired.
  • the therapeutic agent in another embodiment, can be formulated as an emulsion, which may be, without limitation, a nanoemulsion.
  • the therapeutic agent can be incorporated into a carrier such as a micelle, a worm micelle, a liposome, a polymerosome, a microparticle or a nanoparticle comprised of a material other than the therapeutic agent itself.
  • a carrier such as a micelle, a worm micelle, a liposome, a polymerosome, a microparticle or a nanoparticle comprised of a material other than the therapeutic agent itself.
  • the carrier may be biostable or it may be biodegradable.
  • Microparticles and nanoparticles can be made of any biocompatible material including, but not limited to a natural, semi-synthetic or synthetic polymers, ceramics or glasses.
  • biocompatible refers to a material that in its original intact state and when biologically decomposed into its degradation products is not toxic or at least is minimally toxic to living tissue. A biocompatible material does not, or at least minimally and reparably, injure living tissue. Further, a biocompatible material does not, or at least minimally and controllably, cause an immunological reaction in living tissue.
  • biostable is meant that the material of which the vehicle is comprised does not appreciably decompose in a physiological environment, for example, without limitation, at physiological pHs or in the presence of enzymes.
  • relatively biostable polymers are, without limitation, polyacrylates, polymethacrylates, polyureas, polyurethanes, polyolefins, polyvinylhalides, polyvinylidenehalides, polyvinylethers, polyvinylaromatics, polyvinylesters, polyacrylonitriles, alkyd resins, polysiloxanes and epoxy resins.
  • Biocompatible, biodegradable polymers include naturally-occurring polymers such as, without limitation, collagen, chitosan, alginate, fibrin, fibrinogen, cellulosics, starches, dextran, dextrin, hyaluronic acid, heparin, glycosaminoglycans, polysaccharides and elastin.
  • Synthetic biocompatible, biodegradable polymers include, without limitation, polylactic acid, polyglycolic acid, polyethylene glycol, polycaprolactone, polyanhydrides, polyvinyl alcohol and poly(ester-amides).
  • a synthetic polymer refers to one that is created wholly in the laboratory while a semi-synthetic polymer refers to a naturally-occurring polymer than has been chemically modified in the laboratory.
  • synthetic polymers include, without limitation, polyphosphazines, polyphosphoesters, polyphosphoester urethane, polyhydroxyacids, polyhydroxyalkanoates, polyanhydrides, polyesters, polyorthoesters, polyamino acids, polyoxymethylenes, poly(ester-amides) and polyimides.
  • Blends or random, alternating, block, random block or graft copolymers of the above polymers may also be used and are within the scope of this invention.
  • a biostable particle is one that does not appreciably degrade in a physiological environment, i.e., it maintains its particulate shape in the presence of physiological factors such as enzymes and other biologically active substances.
  • the therapeutic agent can be in the form of an oil-in-water emulsion, a water-in-oil or a water-in-oil-in-water emulsion.
  • the device comprises a balloon and the vessel surface is a luminal surface.
  • the balloon may further comprise a catheter, to the disal end of which the balloon is coupled.
  • the balloon is contacted with the luminal surface by inflation, wherein the inflated balloon comprises substantially one diameter such that the complete outer surface of the balloon is contacted with the luminal surface.
  • the inflated balloon comprises two or more first diameters that define portions of the outer surface of the balloon that are in contact with the luminal surface and one or more second diameters that define portions of the outer surface that are not in contact with the luminal surface, wherein the furthest apart of the two of the portions of the balloon that are in contact with the luminal surface contact the surface in the non-afflicted region of the vessel at the periphery of the afflicted region.
  • the two furthest apart portions are at least about 40 mm, more particularly from about 40 mm to about 200 mm, and more particularly still, from about 40 mm to about 100 mm, apart.
  • the delivery interface comprises a coating on the outer surface of the balloon, the coating comprising the therapeutic agent.
  • the balloon may be microporous and the therapeutic agent may be contained in a fluid used to inflate the balloon according to methods known in the art.
  • the delivery interface comprises a plurality of micro-needles disposed at an outer surface of a balloon.
  • the delivery interface comprises an implantable medical device such as, without limitation, a stent.
  • regional treatment of vascular diseases comprises treatment of, without limitation, atherosclerosis, restenosis, vulnerable plaque and peripheral arterial disease using, again without limitation, therapeutic agents that induce apoptosis of macrophages, therapeutic agents that initiate reverse cholesterol transport and anti-inflammatory therapeutic agents.
  • therapeutic agents that induce apoptosis of macrophages include, but are not limited to, bisphosphonates.
  • Bisphosphonates useful with this invention include, but are not limited to, etidronate, clodronate, tiludronate, pamidronate, dimethyl pamidronate, alendronate, ibandronate, risedronate and zeledronate.
  • therapeutic agents that initiate reverse cholesterol transport include, but are not limited to, apolipoprotein A1 and mimetic peptides thereof.
  • therapeutic agents that are anti-inflammatory agent include, but are not limited to, corticosteroids and statins.
  • FIG. 1 is a schematic depiction of an embodiment of this invention involving the contact of a circumferentially non-continuous, linearly continuous segment of a vessel with a delivery interface of this invention.
  • FIG. 2 is a schematic depiction of an embodiment of this invention involving the contact of a circumferentially non-continuous, linearly non-continuous segment of a vessel with a delivery interface of this invention.
  • FIG. 3 is a schematic depiction of an embodiment of this invention involving the contact of a circumferentially continuous, linearly continuous segment of a vessel with a delivery interface of this invention.
  • FIG. 4 is a schematic depiction of an embodiment of this invention involving the contact of a circumferentially continuous, linearly non-continuous segment of a vessel with a delivery interface of this invention.
  • FIG. 5 is a schematic depiction of an embodiment of this invention wherein the delivery interface comprises a balloon having substantially one diameter when inflated.
  • FIG. 6 is a schematic depiction of an embodiment of this invention wherein the delivery interface comprises a balloon having a first diameter that, when the balloon is inflated, contacts the surface of a vessel, and a second diameter that, when the balloon is inflated, does not contact the surface of the vessel.
  • FIG. 7 is a schematic depiction of an embodiment of this invention wherein the delivery interface comprises a plurality of separate balloons.
  • therapeutic agent means a single therapeutic agent or two or more therapeutic agents.
  • therapeutic agent refers to any substance that, when administered in a therapeutically effective amount to a patient suffering from a disease, has a therapeutic beneficial effect on the health and well-being of the patient.
  • a therapeutic beneficial effect on the health and well-being of a patient includes, but it not limited to: (1) curing the disease; (2) slowing the progress of the disease; (3) causing the disease to retrogress; or, (4) alleviating one or more symptoms of the disease.
  • a therapeutic agent also includes any substance that when administered to a patient, known or suspected of being particularly susceptible to a disease, in a prophylactically effective amount, has a prophylactic beneficial effect on the health and well-being of the patient.
  • a prophylactic beneficial effect on the health and well-being of a patient includes, but is not limited to: (1) preventing or delaying on-set of the disease in the first place; (2) maintaining a disease at a retrogressed level once such level has been achieved by a therapeutically effective amount of a substance, which may be the same as or different from the substance used in a prophylactically effective amount; or, (3) preventing or delaying recurrence of the disease after a course of treatment with a therapeutically effective amount of a substance, which may be the same as or different from the substance used in a prophylactically effective amount, has concluded.
  • treating refers to the administration of a therapeutically effective amount of a therapeutic agent to a patient known or suspected to be suffering from a vascular disease.
  • a “therapeutically effective amount” refers to that amount of a therapeutic agent that will have a beneficial affect, which may be curative or palliative, on the health and well-being of the patient with regard to the vascular disease with which the patient is known or suspected to be afflicted.
  • a therapeutically effective amount may be administered as a single bolus, as intermittent bolus charges, as short, medium or long term sustained release formulations or as any combination of these.
  • short-term sustained release refers to the administration of a therapeutically effective amount of a therapeutic agent over a period from about several hours to about 3 days.
  • Medium-term sustained release refers to administration of a therapeutically effective amount of a therapeutic agent over a period from about 3 day to about 14 days and long-term refers to the delivery of a therapeutically effective amount over any period in excess of about 14 days.
  • vascular disease refers to a disease of the vessels, primarily arteries and veins, which transport blood to and from the heart, brain and peripheral organs such as, without limitation, the arms, legs, kidneys and liver.
  • vascular disease refers to the coronary arterial system, the carotid arterial system and the peripheral arterial system.
  • the disease that may be treated is any that is amenable to treatment with a therapeutic agent, either as the sole treatment protocol or as an adjunct to other procedures such as surgical intervention.
  • the disease may be, without limitation, atherosclerosis, vulnerable plaque, restenosis or peripheral arterial disease.
  • “Atherosclerosis” refers to the depositing of fatty substances, cholesterol, cellular waste products, calcium and fibrin on the inner lining or intima of an artery. Smooth muscle cell proliferation and lipid accumulation accompany the deposition process. In addition, inflammatory substances that tend to migrate to atherosclerotic regions of an artery are thought to exacerbate the condition. The result of the accumulation of substances on the intima is the formation of fibrous (atheromatous) plaques that occlude the lumen of the artery, a process called stenosis.
  • the blood supply to the organ supplied by the particular artery is depleted resulting is strokes, if the afflicted artery is a carotid artery, heart attack if the artery is a coronary artery or loss of organ function if the artery is peripheral.
  • Restenosis refers to the re-narrowing or blockage of an artery at or near the where angioplasty or another surgical procedure was previously performed to remove a stenosis. It is generally due to smooth muscle cell proliferation at times accompanied by thrombosis. Prior to the advent of implantable stents to maintain the patency of vessels opened by angioplasty, restenosis occurred in 40-50% of patients within 3 to 6 months of undergoing the procedure. Post-angioplasty restenosis before stents was due primarily to thrombosis or blood-clotting at the site of the procedure.
  • stent placement sites are also susceptible to restenosis due to abnormal tissue growth at the site of implantation. This form of restenosis tends also to occur at 3 to 6 months after stent placement but it is not affected by the use of anti-clotting drugs.
  • alternative therapies are continuously being sought to mitigate, preferably eliminate, this type of restenosis.
  • Drug eluting stents (DES) which release a variety of therapeutic agents at the site of stent placement have been in use for some time.
  • stents however, have to date comprised delivery interfaces that are less than 40 mm in length and in any event have delivery interfaces that are not intended, and most often do not, contact the luminal surface of the vessel in which they are implanted at the non-afflicted region at the periphery of the afflicted region.
  • “Vulnerable plaque” refers to an atheromatous plaque that has the potential of causing a thrombotic event and is usually characterized by a very thin wall separating it from the lumen of an artery. The thinness of the wall renders the plaque susceptible to rupture. When the plaque ruptures, the inner core of usually lipid-rich plaque is exposed to blood, with the potential of causing a potentially fatal thrombotic event through adhesion and activation of platelets and plasma proteins to components of the exposed plaque.
  • vulnerable plaque has created new challenges in recent years for the treatment of heart disease. Unlike occlusive plaques that impede blood flow, vulnerable plaque develops within the arterial walls, but it often does so without the characteristic substantial narrowing of the arterial lumen which produces symptoms. As such, conventional methods for detecting heart disease, such as an angiogram, may not detect vulnerable plaque growth into the arterial wall.
  • the intrinsic histological features that may characterize a vulnerable plaque include increased lipid content, increased macrophage, foam cell and T lymphocyte content, and reduced collagen and smooth muscle cell (SMC) content.
  • This fibroatheroma type of vulnerable plaque is often referred to as “soft,” having a large lipid pool of lipoproteins surrounded by a fibrous cap.
  • the fibrous cap contains mostly collagen, whose reduced concentration combined with macrophage-derived enzyme degradations can cause the fibrous cap of these lesions to rupture under unpredictable circumstances.
  • the lipid core contents thought to include tissue factor, contact the arterial bloodstream, causing a blood clot to form that can completely block the artery resulting in an acute coronary syndrome (ACS) event.
  • ACS acute coronary syndrome
  • Atherosclerosis is coined “vulnerable” because of unpredictable tendency of the plaque to rupture. It is thought that hemodynamic and cardiac forces, which yield circumferential stress, shear stress, and flexion stress, may cause disruption of a fibroatheroma type of vulnerable plaque. These forces may rise as the result of simple movements, such as getting out of bed in the morning, in addition to in vivo forces related to blood flow and the beating of the heart. It is thought that plaque vulnerability in fibroatheroma types is determined primarily by factors which include: (1) size and consistency of the lipid core; (2) thickness of the fibrous cap covering the lipid core; and (3) inflammation and repair within the fibrous cap.
  • Peripheral vascular diseases are generally caused by structural changes in blood vessels caused by such conditions as inflammation and tissue damage.
  • a subset of peripheral vascular disease is peripheral artery disease (PAD).
  • PAD is a condition that is similar to carotid and coronary artery disease in that it is caused by the buildup of fatty deposits on the lining or intima of the artery walls.
  • blockage of the carotid artery restricts blood flow to the brain and blockage of the coronary artery restricts blood flow to the heart
  • blockage of the peripheral arteries can lead to restricted blood flow to the kidneys, stomach, arms, legs and feet.
  • an “afflicted region” of a vessel is a region that exhibits clinical manifestations of disease, such as macroscopic evidence in the form of, without limitation, obvious luminal wall thickening, inflammation, etc. or microscopic evidence in the form of, again without limitation, an accumulation of monocytes, macrophages, neutrophiles, smooth muscle cells, inflammatory cytokines, various lipoproteins, etc.
  • a “non-afflicted region” of a vessel is a region that does not exhibit a clinical manifestation of the disease and appears as healthy tissue. “Non-afflicted regions at the periphery of the afflicted region” refers to healthy tissue at the border between afflicted and non-afflicted regions.
  • a “device” refers to any manner of apparatus that is used or that may be used to in conjunction with a delivery interface of this invention.
  • the device may be transitory, that is, it may be a device that is inserted into a patient's body for only so long as is necessary to administer a therapeutic agent to the patient from a delivery interface of the device or it may be an implantable medical device intended to remain in a patient's body for longer than necessary to deliver the therapeutic agent, possibly for as long as the remaining lifetime of the patient.
  • biodegradable implantable medical devices which over time degrade to substances that can either be adsorbed into or excreted by the body.
  • a vascular catheter is a thin, flexible tube with a manipulating means at one end, referred to as the proximal end, which remains outside the patient's body, and an operative device at or near the other end, called the distal end, which is inserted into the patient's artery or vein.
  • the catheter is often introduced into a patient's vasculature at a point remote from the target site, e.g., into the femoral artery of the leg where the target is in the vicinity of the heart.
  • the catheter is steered, assisted by a guide wire than extends through a lumen in the flexible tube, to the target site whereupon the guide wire is withdrawn at which time the lumen may be used for the introduction of fluids, often containing therapeutic agents, to the target site.
  • an “implantable medical device” refers to any type of appliance that is totally or partly introduced, surgically or medically, into a patient's body or by medical intervention into a natural orifice, and which is intended to remain there after the procedure.
  • patient refers to either a medical or veterinary patient.
  • the duration of implantation may be essentially permanent, i.e., intended to remain in place for the remaining lifespan of the patient; until the device biodegrades; or until it is physically removed.
  • implantable medical devices include, without limitation, implantable cardiac pacemakers and defibrillators; leads and electrodes for the preceding; implantable organ stimulators such as nerve, bladder, sphincter and diaphragm stimulators, cochlear implants; prostheses, self-expandable stents, balloon-expandable stents, stent-grafts, grafts, artificial heart valves and cerebrospinal fluid shunts.
  • implantable organ stimulators such as nerve, bladder, sphincter and diaphragm stimulators, cochlear implants
  • prostheses self-expandable stents, balloon-expandable stents, stent-grafts, grafts, artificial heart valves and cerebrospinal fluid shunts.
  • a vessel wrap is a thin sheet of flexible material, which may be fabric, polymer, metal, etc. that is literally wrapped around the outside of a vessel and is in contact with the outer surface.
  • the wrap may be solid or it may be formed in virtually any manner of desired pattern such as, without limitation, a mesh, a ribbed polymeric structure or an embossed metal sheet.
  • a “stent” refers generally to any device used to hold tissue in place in a patient's body. Particularly useful stents, however, are those used for the maintenance of the patency of a vessel in a patient's body when the vessel is narrowed or closed due to diseases including, without limitation, tumors (in, for example, bile ducts, the esophagus, the trachea/bronchi, etc.), benign pancreatic disease, coronary artery disease, carotid artery disease and peripheral arterial disease such as atherosclerosis, restenosis and vulnerable plaque.
  • tumors in, for example, bile ducts, the esophagus, the trachea/bronchi, etc.
  • benign pancreatic disease in, for example, coronary artery disease, carotid artery disease and peripheral arterial disease such as atherosclerosis, restenosis and vulnerable plaque.
  • a stent can be used in, without limitation, neuro, carotid, coronary, pulmonary, aorta, renal, biliary, iliac, femoral and popliteal arteries as well as other peripheral vasculatures.
  • a stent can be used in the treatment or prevention of diseases such as, without limitation, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, chronic total occlusion, claudication, anastomotic proliferation, bile duct obstruction and ureter obstruction.
  • stents may be employed for the delivery of therapeutic agents to specific treatment sites in a patient's body.
  • therapeutic agent delivery may be the sole purpose of the stent or the stent may be primarily intended for another use such as those discussed above with drug delivery providing an ancillary benefit.
  • a stent would be coated with a layer of material comprising one or more therapeutic agents, the layer comprising a delivery interface of this invention that is at least about 40 mm in length.
  • a “delivery interface” refers to a surface region of a device of this invention that is capable of providing treatment to an area of the vessel that is greater than that which is accomplished with local delivery interfaces known in the art. That is, the delivery interface of this invention provides treatment to area of a vessel that includes not only the afflicted region of the vessel but non-afflicted regions at the periphery of the afflicted region.
  • the delivery interface when device according to the present invention is fully deployed, is capable of being placed in intimate contact with all or portions of a surface of an at least about 40 mm long segment of a blood vessel and is further capable of delivering a therapeutic amount of the therapeutic agent onto or into the surface of the segment wherever it is in intimate contact with the vessel surface, with the proviso that if the device is in contact only with portions of the surface, two of the contact regions are located at least partially in the above-mentioned periphery of the afflicted region. At present it is preferred that such contact regions be at least about 40 mm apart.
  • a “delivery interface” of this invention will be capable of delivering a therapeutic agent to the surface in a variety of configurations including, without limitation, the following: (a) FIG.
  • FIG. 1 schematically depicts a segment of a luminal surface of vessel wall 100 contacted by circumferentially non-continuous, linearly continuous surface 300 of delivery interface 10 , which has been directed to the afflicted site by device 200 , which may be, without limitation, a catheter, or an adventitial surface of vessel wall 100 contacted by circumferentially non-continuous, linearly continuous surface 305 of delivery interface 10 ;
  • device 200 which may be, without limitation, a catheter, or an adventitial surface of vessel wall 100 contacted by circumferentially non-continuous, linearly continuous surface 305 of delivery interface 10 ;
  • FIG. 2 schematically depicts a segment of a luminal surface of vessel wall 100 contacted by circumferentially non-continuous, lineally non-continuous surfaces 310 of delivery interface 10 which has been directed to the afflicted site by device 200 , which may be, without limitation, a catheter, or an adventitial surface of vessel 100 contacted by circumferentially non-continuous, lineally non-continuous surfaces 315 of delivery interface 10 ;
  • device 200 may be, without limitation, a catheter, or an adventitial surface of vessel 100 contacted by circumferentially non-continuous, lineally non-continuous surfaces 315 of delivery interface 10 ;
  • FIG. 3 schematically depicts a segment of a luminal surface of vessel wall 100 contacted by circumferentially continuous, linearly continuous surface 320 of delivery interface 10 , which may be directed to the afflicted site by device 200 , which can be, without limitation, a catheter, or an adventitial surface of vessel wall 100 contacted by circumferentially continuous, linearly continuous surface 325 of delivery interface 200 ; or, (d) FIG.
  • FIG. 4 schematically depicts a segment of a luminal surface of vessel 100 contacted by circumferentially continuous, linearly non-continuous surface 330 of delivery interface 10 , wherein the delivery interface may be directed to the afflicted site by device 200 , which can be, without limitation, a catheter, or an adventitial surface of vessel 100 contacted by circumferentially continuous, linearly non-continuous surface 335 of delivery interface 10 .
  • device 200 can be, without limitation, a catheter, or an adventitial surface of vessel 100 contacted by circumferentially continuous, linearly non-continuous surface 335 of delivery interface 10 .
  • the total length of delivery interface 10 be at least about 40 mm, more particularly from about 40 mm to about 200 mm and more particularly still, from about 40 mm to about 100 mm in length.
  • the segment with which the delivery interface is in contact may be afflicted with or suspected to be afflicted with the vascular disease being treated over the entire length of the contact between the surface of the delivery interface or only in certain regions of the segment.
  • a delivery interface may be 40 mm in length, only isolated regions much less than 40 mm, e.g., as few as one or two regions that may each be as small as less than about 1 mm or greater than 1 mm but less than 40 mm, over the 40 mm interface, may actually be afflicted with the vascular disease.
  • the delivery interface fully encompasses all regions of the vessel that are so afflicted and, in addition, encompasses a portion of a non-afflicted region at the periphery of the afflicted region.
  • the delivery interface of this invention would be at least about 61 or 62 mm and presently preferably from about 65 mm to about 70 mm in length to fully encompass the afflicted region and a portion of the non-afflicted region at the periphery of the afflicted region.
  • contacting refers to placing the delivery interface surface in contact with the luminal or adventitial surface a vessel along a regional segment of the vessel, preferably an at least about 40 mm long segment of the vessel, such that a therapeutic agent may be transferred from the delivery interface directly onto or into the surface of the vessel.
  • onto the surface of the vessel is meant that the therapeutic agent is simply released from the surface of the delivery interface and, since the surface of the delivery interface is in contact with the outer surface of the vessel, the therapeutic agent is also in contact with the outer surface, i.e., it has been delivered onto the surface of the vessel.
  • the delivery interface includes some means such as, without limitation, micro-needles that, when the surface of the delivery interface is in contact with the surface of the vessel, penetrate the surface of the vessel and deliver the therapeutic agent into the interior of the wall of the vessel.
  • “known” to be afflicted with a vascular disease refers first to a condition that is relatively readily observable and or diagnosable.
  • An example, without limitation, of such a disease is atherosclerosis, which is a discrete narrowing of a patient's arteries.
  • Restenosis while in its latter stages, like atherosclerosis, is relatively readily diagnosable or directly observable, may not be so in its nascent stage.
  • a patient may be “suspected” of being afflicted or of being susceptible to affliction with restenosis at some time subsequent to a surgical procedure to treat an atherosclerotic lesion.
  • restenosis tends generally to occur at the same locus as a previous atherosclerosis, it may not be exactly so, so a region of a segment of a vessel somewhat distant from the site of the initial atherosclerosis may in fact be the site of a restenosis.
  • Vulnerable plaque on the other hand is quite different from either atherosclerosis or restenosis and would generally come under the designation “suspected” affliction. This is because vulnerable plaque occurs primarily within the wall of a vessel and does not cause prominent protrusions into the lumen of the vessel. It is often not until it is “too late,” i.e., until after a vulnerable plaque has broken and released its components into the vessel that its presence is even known. Numerous methods have and are being investigated for the early diagnosis of vulnerable plaque but to date none have proven completely successful. Thus, the regional treatment of a segment of a vessel suspected of being afflicted with vulnerable plaque may be the best way to address such lesions.
  • delivering a therapeutic agent refers to the transfer of the therapeutic agent from the delivery interface onto or into a surface of a vessel being treated.
  • the transfer may be passive, as in the case, without limitation, of simple diffusion along a concentration gradient or it may be active such as when using, again without limitation, the aforementioned micro-needles through which a therapeutic agent is forceably injected into the surface or surrounding periadventitial space of a vessel.
  • a “vessel wrap” refers to length of flexible material, which may be, without limitation, a fabric, a polymer, a metal and the like. The length is such that the wrap encompasses not only the afflicted region of a vessel being treated but a portion of the non-afflicted region at the periphery of the afflicted region. It is presently preferred that a vessel wrap have a length of at least about 40 mm, preferably from about 40 mm to about 200 mm and presently most preferably from about 40 mm to about 100 mm.
  • the material is simply wrapped around the adventitial surface of a vessel such that a surface of the wrap is in intimate contact with the surface of the vessel over the entire region of the vessel known or suspected to be afflicted with a vascular disease.
  • a therapeutic agent may be carried on the surface of the wrap, either as such or as a pharmaceutically acceptable composition or it may be located within the wrap substance, again, as such or as a pharmaceutical composition.
  • a “balloon” refers to the well-known in the art device, usually associated with a vascular catheter, that comprises a relatively thin, elastomeric material that when positioned at a particular location in a patient's vessel can be expanded or inflated to an outside diameter that is essentially the same as the inside or luminal diameter of the vessel in which it is placed.
  • the difference between the normal balloon as currently understood in the art is that the balloon of this invention achieves the diameter necessary to place it in contact with the luminal surface of the vessel over an area of the vessel that includes not only the afflicted region of the vessel but a portion of the non-afflicted region at the periphery of the afflicted region.
  • a balloon of this invention span at least about a 40 mm, more particularly from about 40 mm to about 200 mm and more particularly still about 40 mm to about 100 mm. segment of the vessel.
  • Inflation of the balloon may be effected by any means known or as shall become known in the art.
  • a balloon of this invention may be inflated using a liquid medium such as water or normal saline solution, that is, saline that is essentially isotonic with blood.
  • a balloon of this invention may have substantially a single diameter over its entire length such that the full length of the balloon is in contact with the luminal surface of the vessel, as shown in FIG. 5 .
  • FIG. 5 also shows what is meant by “substantially” a single diameter.
  • the ends 550 of balloon 520 are not necessarily square so that the balloon does have a large number of diminishing diameters at the ends at it curves down to join the catheter tube but the major portion of balloon length 500 , which comprises delivery interface 10 , has substantially the same diameter.
  • a balloon of this invention may also comprise two different outside diameters.
  • a first diameter which is the same as the diameter of the single diameter balloon described above; the two first diameters being sufficiently separated so as to contact non-afflicted portions of the vessel to either side of the afflicted portion.
  • the two first diameters be at least about 40 mm, more particularly from about 40 mm to about 200 mm and, more particularly still, from about 40 mm to about 100 mm, apart. Between the end first diameters may be any number of additional first diameters. Each such first diameter is separated from each other such diameter by a second diameter which is less than the inside diameter of the vessel and therefore does not contact the luminal surface.
  • a second diameter is nominal; the point is that there are regions between the first diameters that are not in contact with the luminal surface and the diameters of those regions may be identical or all may be different; for the purposes of this discussion it is assumed that they are all the same.
  • balloon 620 has first diameters 600 , which contact vessel wall 100 and second diameters 650 . which do not contact with vessel wall 100 and delivery interface 10 comprises the total length of the balloon including both diameters 600 and 650 .
  • the balloon is delivered to the selected site in the vessel by device 400 , which may be, without limitation, a catheter.
  • a therapeutic agent may be delivered only from those diameters that are substantially the same as the luminal diameter, the second diameters acting as spacers only. It is an aspect of this invention that therapeutic agent may be delivered directly to a luminal surface by those surfaces of the delivery interface in contact with the luminal surface; however, it is also an aspect of this invention that the therapeutic agent may as well be delivered in to the space between those surfaces; that is, from the surfaces comprising the spacer diameters. This is discussed in more detail below.
  • balloons 700 each of which has substantially one diameter that is substantially the same as the luminal diameter of the vessel.
  • the end two separate balloons must contact the luminal wall at non-afflicted portions of the vessel to either side of the afflicted portion.
  • the two balloon be at least about 40 mm, more particularly from about 40 mm to about 200 mm and, more particularly still, from about 140 mm to about 100 mm apart.
  • FIG. 7 Such an arrangement of balloons is illustrated in FIG. 7 where balloons 700, each of which has the same diameter, comprise delivery interface 10 and each balloon is attached separated to device 400 , which may be, without limitation, a catheter.
  • a balloon of this invention may comprise a coating on all or part of its surface, the coating being the delivery interface of this invention.
  • Coated balloons are well-known in the art for the localized delivery of therapeutic agents and any coating construct known or as may in the future become known may be used in the method of this invention with the proviso that at least two contact delivery regions of the balloon must be capable of contacting the luminal surface of the vessel in the non-afflicted region of the vessel at the periphery of the afflicted region.
  • a balloon of this invention may be microporous.
  • a microporous balloon comprises a thin membrane in which a large number; e.g., hundreds, thousands even millions of holes of substantially uniform size have been created.
  • the holes can range in size from tens of nanometers to microns and can be created by a number of techniques including, but not limited to, laser drilling and ab initio synthesis. In the latter case, the membrane is synthesized from molecules that assemble in such a manner than voids are left in the structure formed.
  • a microporous balloon formed by these or any other procedure may be used in the method of this invention.
  • the therapeutic agent or agents are delivered to the balloon at the distal end of a catheter in the fluid used to expand the balloon.
  • the balloon is expanded, rather than simply leaking out of the balloon in an uncontrolled manner, the size of the holes results in a slow, controlled “weeping” of fluid from the holes and carried along with the fluid are the therapeutic agents.
  • the fluid and therapeutic agents then spread out over the surface of the balloon in a thin film and when the surface of the balloon is contacted with the luminal surface of a vessel, the therapeutic agents are brought into contact with the luminal surface and held there until they penetrate the surface of the vessel wall.
  • a balloon having two diameters as discussed above only those portions of the balloon having the first diameter, that is, the portions that are in contact with the luminal surface can be microporous with the regions characterized by the second diameter are non-porous.
  • therapeutic agent will be delivered to the luminal surface only by those regions of the balloon that are in contact with it.
  • one or more of the regions of the balloon having the second diameter can also be microporous in which case therapeutic agents will be delivered into the arterial lumen and not directly onto the luminal surface.
  • the balloon comprises micro-needles.
  • Micro-needles are exceeding small needles, often a millimeter or less in length and less than 150 microns in diameter.
  • the micro-needles may be constructed of permanent materials such as stainless steel or they may be constructed of biodegradable polymers that exhibit thread-forming properties such that they might be attached to an implantable medical device which is left in place but from which the micro-needles eventually biodegrade and their degradation products are either adsorbed or excreted.
  • One or a large plurality numbering in the hundreds, thousands or even more, of these micro-needles can be coupled to the surface of a balloon such that, when the balloon is deflated, the needles lie substantially parallel to the surface of the catheter tube to which they and the balloon are attached.
  • the needles As the balloon is being inflated the needles splay out to substantially right angles to the surface of the expanding balloon and then, when the balloon approaches a vessel surface, they are forced through the outer surface into the interior of the vessel wall.
  • Therapeutic agents may then be injected directly into the subsurface tissues and cells of the vessel. This can have a distinct advantage when delivering therapeutic agents to luminal wall of an artery.
  • the inner surface of arteries comprises a layer of cells called the endothelium.
  • the endothelium is a smooth, slippery surface designed to facilitate blood flow through the arteries. As a result, it can be difficult to get therapeutic agents past the endothelium to the underlying cells.
  • the protective outer surface of the arterial lumen is effectively by-passed and the therapeutic agent can be delivered directly into the adventia, a layer of fat and elastic fibers that surrounds and protects the artery.
  • the adventitia is very receptive to therapeutic agents, which then relatively easily permeates and surrounds the cells in the vicinity of the injection.
  • a “therapeutic agent” refers to a substance that, when administered to a patient has a beneficial effect on the health and well-being of the patient.
  • Therapeutic agents may be, without limitation, small molecule drugs, large molecule drugs, peptides, antibodies, proteins, enzymes, oligonucleotides, DNAs or RNAs.
  • Representative therapeutic agents for use with the method hereof include but are not limited to anti-inflammatory compounds, cytostatic compounds, cytokine inhibiting compounds, growth factor inhibiting compounds, enzyme inhibiting compounds, signaling pathway inhibiting compounds and cytotoxic compounds.
  • a presently preferred therapeutic agent for use in the method of this invention is apolipoprotein A1 (apoA1), apoA1 mutants such as, without limitation, apoA1-milano or apoA1 mimetics such as, again without limitation, amphipathic helical peptides.
  • ApoA1 is synthesized in the liver and small intestine and is the primary protein constituent of high density lipoprotein (HDL), making up 70% of the latter. ApoA1 is responsible for most of HDL's defining characteristics including its participation in reverse cholesterol transport.
  • HDL high density lipoprotein
  • apoA1 defines the size and shape of the HDL molecule: discoid in its nascent stage, consisting of a phosphatidylcholine bilayer and a protein shell that shields the hydrophobic lipid tails from the aqueous environment, and spherical in its mature form, consisting of a hydrophobic core of cholesterol esters shielded by a combination of lipid and protein.
  • HDLs When mature, HDLs cease to collect cholesterol and are recognized by the liver for excretion.
  • ApoA1 is also responsible for solubilizing of HDL's lipid components, removing cholesterol from peripheral cells, activating lecithin-cholesterol acyl transferase (LCAT) enzyme and delivering the resulting cholesterol esters to the liver.
  • LCAT lecithin-cholesterol acyl transferase
  • Cholesterol is a major component of atherosclerotic plaque. Cholesterol accumulates in the arterial wall as the result of the influx of lipoproteins containing apoB. When influx exceeds natural efflux, artherosclerotic plaque begins to form. Reverse cholesterol transport refers to the active efflux and transportation to the liver for excretion of cholesterol from arterial walls to counter the influx from the apoB-containing lipoproteins. While increased levels of HDL have been known for some time to correlate with a decreased risk of atherosclerosis, it has recently been demonstrated that purified apoA1 is capable of reducing free cholesterol accumulation in vivo in atherosclerotic lesions. (Boisvert, W.
  • ApoA1 is a relatively large protein consisting of 243 amino acids.
  • the problems associated with working with such large proteins in terms of stability, bioavailability, etc. are well-known. It would be preferable to use apoA1 mimetic peptides having substantially less amino acids.
  • One such apoA1 mimetic peptide has been reported, an 18-mer that has been shown to promote reverse cholesterol transport in cultured cholesterol-laden fibroblasts and macrophages and to interact with cell surface HDL binding sites thereby stimulating an HDL-like response. Mendez, A. J., et al, J. Clin. Invest., 1994, 94:1698-1705.
  • Other such apoA1 mimetics are being actively sought (see for instance, Mishra, V. K., Biochemistry, 1998, 37:10313-324) and any such compounds discovered would be expected to provide a beneficial effect as a therapeutic agent administered regionally by means of a delivery interface of this invention.
  • a presently preferred family of therapeutic agents useful in the method of this invention is the bisphosphonates.
  • Bisphosphonates are known to induce apoptosis in macrophages. Apoptosis is best described as a sort of cell suicide whereby specialized cellular machinery already present in the cell but previously quiescent is activated, causing the cell to disintegrate into fragments that are then eliminated from the organism containing the cell.
  • Macrophages are phagocytotic tissue cells of the reticuloendothelial system that ingest, by engulfing or “cytosing,” foreign substances such as bacteria, cellular debris, viruses, toxins, particulates, etc.
  • macrophages are important to the health and well-being of humans, With regard to the above-described increased influx of cholesterol into the arterial wall, however, which is accompanied by an increased influx of monocytes/macrophages (monocytes differentiate into macrophages) that take up oxidized and aggregated low density lipoprotein (LDL) and store the cholesterol as esters, macrophages perform a disservice to the system. That is, whereas parenchymal cells maintain cholesterol balance by down-regulating de novo cholesterol synthesis and LDL receptor expression, macrophages continue to take up cholesterol from apoB-containing lipoproteins by pathways that are not subject to sterol-mediated feedback control. Spady, Circulation, 1999, 576-78.
  • macrophages In addition to accumulating cholesterol, macrophages play a role in inducing plaque rupture, blood coagulation and fibrinolysis through the production of various enzymes, activators, inhibitors and therapeutic mediators. Takahashi, et al., Med. Electron Microsc., 2002, 35(4):179-203. Thus, in the context of vascular disease, the presence of macrophages is undesirable and their elimination from vessels known or suspected to be accumulating cholesterol and therefore to likely be pre-atherosclerotic or in vessels that in fact contain atherosclerotic lesions by regional delivery of bisphosphonates should be of benefit to patients so afflicted.
  • Bisphosphonates have the general structure:
  • Atherosclerosis actually involves an on-going inflammatory response.
  • inflammation has been established as having a fundamental role in mediating virtually all stages of the disease from initiation through progression and ultimately to the thrombotic complications associated with atherosclerosis.
  • blood leukocytes mediators of host defenses and inflammation, have been shown to localize in the earliest lesions of atherosclerosis.
  • the normal endothelium does not in general support binding of white blood cells but in the early stages of atherosclerosis patches of arterial endothelial cells have been observed to express on their surface selective adhesion molecules that bind to various classes of leukocytes.
  • VCAM-1 vascular cell adhesions molecule-1
  • monocytes macrophage precursors
  • T lymphocytes both of which are involved in inflammatory responses.
  • Anti-inflammatory agents useful herein include, but are not limited to, statins, corticosteroids, and antioxidants.
  • a presently preferred class of anti-inflammatory agents for use in the method of this invention is the statins.
  • Statins are of particular interest because of their potential dual role in the treatment of atherosclerosis. That is, the primary function for which they are generally prescribed is to lower the production of cholesterol by the liver by blocking the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) A.
  • HMG-CoA reductase 3-hydroxy-3-methylglutaryl-coenzyme A reductase
  • cholesterol plays a key role in the formation of atherosclerotic lesions so a reduction in its production should be a major benefit to patients susceptible to or afflicted with atherosclerosis.
  • statins have an inhibitory effect on the monocyte-endothelial interaction discussed above suggesting an anti-inflammatory effect as well as a cholesterol lowering effect.
  • Useful statins include, but are not limited to, atorvastatin (Lipitor®), lovastatin (Mevacor®), simvastatin (Zocor®), fluvastatin (Lescol®) and pravastatin (Pravachol®).
  • Corticosteroids include cortisol, an adrenal hormone found naturally in the body, as well as synthetic drugs. They all are potent anti-inflammatory compounds with the synthetic corticosteroids exerting the strongest effects.
  • Corticosteroids potentially useful in the method of this invention include, but are not limited to, alclometasone, amcinonide, betamethasone, clobestasole, clocortalone, desonide, desoxymetasone, diflorasone, fluocinolone, fluocinonide, flurandrenolide, fluticasone, halcinonide, halobetasol, hydrocortisone, methylprednisolone, mometasoneprednicarbate, triamcinolone.
  • Corticosteroids for use herein are clobestesol and desoxymetasone.
  • Additional therapeutic agents that are presently preferred for use in the method of this invention are rapamycin and its analogs, sirolimus, biolimus, everolimus, paclitaxel and 17-allylamino-17-demethoxygelanamycin (17-AAG).
  • therapeutic agents include, without limitation, synthetic inorganic and organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, DNA and RNA nucleic acid sequences including siRNA, antisense oligonucleotides, antibodies, receptor ligands, enzymes, adhesion peptides, blood clot agents such as streptokinase and tissue plasminogen activator, antigens, hormones, growth factors, ribozymes, retroviral vectors, anti-proliferative agents such as rapamycin (sirolimus), 40-O-(2-hydroxyethyl)rapamycin (everolimus), 40-O-(3-hydroxypropyl)rapamycin, 40-O-(2-hydroxyethyoxy)ethylrapamycin, 40-O-tetrazoly
  • vascular smooth muscle cells Activation of immune cells and unregulated proliferation and motility of vascular smooth muscle cells are known to contribute to neointimal lesion development during the pathogenesis of atherosclerosis and restenosis.
  • Vascular smooth muscle cells migrate from the sub-endothelium into the arterial wall intimal layer where they proliferate and lay down an extracellular matrix that causes vascular wall thickening and reduced vessel patency.
  • inhibition of this process would be expected then to have a salutary effect in a vessel afflicted with or suspected to be afflicted with actual or nascent atherosclerotic or restenotic lesion(s).
  • Rapamycin also known as sirolimus, is a macrolide compound which has been shown to have antiproliferative activity toward smooth muscle cells and to inhibit neointimal formation. Thus sirolimus would be expected to be a beneficial therapeutic agent for use with the method of this invention.
  • Everolimus (40-O-2-hydroxyethylrapamycin), has, however, has better pharmacokinetics that sirolimus; i.e., a shorter half-life, a higher bioavailability and a stronger correlation between bioavailability and administered dose.
  • everolimus is presently preferred over sirolimus for use in the method of this invention.
  • Geldanamycin a benzoquinone ansamycin isolated from Streptomyces hygroscopicus in the early 1970s, has developed into a promising chemotherapeutic with activity against a number of cancers.
  • Both geldanamycin and 17-AAG bind to heat shock protein 90 (Hsp90) and alter its function. Hsp90 plays a key role in regulating the physiology of cells exposed to environmental stress and in maintaining the malignant phenotype of tumor cells.
  • Hsp90 participates in the regulation of the cell cycle, cell growth, cell survival and apoptosis.
  • Geldanamycin and 17-AAG bind to the ATP-binding pocket of Hsp-90 and induce degradation of proteins that require this chaperone for conformational maturation.
  • 17-MG has been shown to be selectively anti-proliferative toward smooth muscle cells and not endothelial cells and is being investigated as a potential inhibitor of restenosis and therefore would be expected to have a beneficial effect in patients being treated using the method herein.
  • the therapeutic agent herein may be provided simply as particles or a film of the agent adhered to the surface of the delivery interface. Or it may be provided as a solution or suspension of the agent in a polymeric matrix adhered to the surface of a delivery interface of this invention. Or it may be provided as a pharmaceutically acceptable composition adhered to the surface of the delivery interface or entrapped in a polymeric matrix adhered to the surface of the delivery interface.
  • a “pharmaceutically acceptable composition” refers to composition that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the therapeutic agent.
  • pharmaceutically acceptable compositions for use in the methods of this invention comprise encapsulation of the therapeutic agent in a pharmaceutically acceptable carrier.
  • Examples of pharmaceutically acceptable carriers include but are not limited to micelle encapsulated therapeutic agent, liposome encapsulated therapeutic agent, polymerosome encapsulated therapeutic agent, therapeutic agent encapsulated in polymeric micro- or nanoparticles, preferably in particles comprising biodegradable or bioerodable polymer, therapeutic agent encapsulated in micro- or nanoparticles comprising porous glass and/or silica, preferably in particles comprising biodegradable or bioerodable glass and/or silica, therapeutic agent encapsulated in porous metal micro- or nanoparticles, preferably in particles comprising biodegradable or bioerodable metal.
  • water-in-oil emulsions of therapeutic agent oil-in-water emulsions of therapeutic agent, water-in-oil-in-water emulsions of therapeutic agent and oil-in-water-in-oil emulsions of therapeutic agent.
  • a therapeutic agent being provided simply as a solution and being administered regionally in that form by means of a delivery interface of this invention would be the dissolution of a water-soluble bisphosphonate, a di-sodium or ammonium salt for instance, in water or isotonic saline and delivery by means of a microporous balloon as described above.
  • the therapeutic agent must be soluble in water or saline for this means of delivery to be useful because other solvents may have a deleterious effect on the vessel at the point of delivery. Since many, if not most, therapeutic agents are generally poorly soluble in water, the utility of this means of delivery is somewhat limited.
  • the means of administration may comprise a suspension of the therapeutic agent in a polymeric matrix which is applied to the surface of a device such as, without limitation, a balloon or stent, which will be in contact with the wall of a vessel.
  • a device such as, without limitation, a balloon or stent, which will be in contact with the wall of a vessel.
  • the polymer/therapeutic agent layer becomes the delivery interface of this invention. Any polymer presently known in the art or as such may become known in the future may be used for this mode of administration.
  • an effective pharmaceutically acceptable composition can be a micelle.
  • a micelle is a spherical colloidal nanoparticle spontaneous formed by many amphiphilic molecules in an aqueous medium when the Critical Micelle Concentration (CMC) is exceeded.
  • CMC Critical Micelle Concentration
  • Amphiphilic molecules have two distinct components, differing in their affinity for a solute, most particularly water. The part of the molecule that has an affinity for water, a polar solute, is said to be hydrophilic. The part of the molecule that has an affinity for non-polar solutes such as hydrocarbons is said to be hydrophobic.
  • amphiphilic molecules When amphiphilic molecules are placed in water, the hydrophilic moiety seeks to interact with the water while the hydrophobic moiety seeks to avoid the water. To accomplish this, the hydrophilic moiety remains in the water while the hydrophobic moiety is held above the surface of the water in the air or in a non-polar, non-miscible liquid floating on the water. The presence of this layer of molecules at the water's surface disrupts the cohesive energy at the surface and lowers surface tension. Amphiphilic molecules that have this effect are known as “surfactants.” Only so many surfactant molecules can align as just described at the water/air or water/hydrocarbon interface.
  • any remaining surfactant molecules will form into spheres with the hydrophilic ends of the molecules facing out, that is, in contact with the water forming the micelle corona and with the hydrophobic “tails” facing toward the center of the of the sphere.
  • Therapeutic agents suspended in the aqueous medium can be entrapped and solubilized in the hydrophobic center of micelles which can result in an increase in the bioavailability as well as improving the stability in biological surroundings, improving the pharmacokinetics and possibly decreasing the toxicity of the therapeutic agent.
  • micelles In addition because of their nanoscale size, generally from about 5 nm to about 50 nm, micelles have been shown to exhibit spontaneous accumulation in pathological areas with leaky vasculature and impaired lymphatic drainage, a phenomenon known as the Enhanced Permeability and Retention or EPR effect.
  • Polymeric micelles have been prepared that exhibit CMCs as low as 10 ⁇ 6 M (molar). Thus, they tend to be very stable while at the same time showing the same beneficial characteristics as surfactant micelles. Any micelle-forming polymer presently known in the art or as such may become known in the future may be used in the method of this invention. Since micelles are nano-scale particles, they may be administered using the porous balloon discussed above as well as in polymeric matrices.
  • micelle-forming polymers are, without limitation, methoxy poly(ethylene glycol)-b-poly( ⁇ -caprolactone), conjugates of poly(ethylene glycol) with phosphatidylethanolamine, poly(ethylene glycol)-b-polyesters, poly(ethylene glycol)-b-poly(L-aminoacids), poly(N-vinylpyrrolidone)-bl-poly(orthoesters), poly(N-vinylpyrrolidone)-b-polyanhydrides and poly(N-vinylpyrrolidone)-b-poly(alkyl acrylates).
  • Worm micelles are cylindrical in shape rather than spherical. They are prepared by varying the weight fraction of the hydrophilic polymer block to the total block copolymer molecular weight in the hydrophilic polymer-b-hydrophobic polymer structure discussed above for preparing spherical micelles. Worm micelles have the potential advantage of not only being bio-inert and stable as are spherical polymeric micelles but also of being flexible.
  • Polyethylene oxide has been used extensively to create worm micelles with a number of hydrophobic polymers such as, without limitation, poly(lactic acid), poly( ⁇ -caprolactone), poly(ethylethylene) and polybutadiene.
  • hydrophobic polymers such as, without limitation, poly(lactic acid), poly( ⁇ -caprolactone), poly(ethylethylene) and polybutadiene.
  • a representative description of worm micelle formation, characterization and drug loading can be found in Kim, Y., et al., Nanotechnology, 2005, 16:S484-S491.
  • the techniques described there as well an any other that is currently known or may become known in the future may be used in the regional delivery method of this invention.
  • therapeutic agents may be present in or on a delivery interface of this invention as a composition comprising liposomes.
  • Phospholipids are molecules that have two primary regions, a hydrophilic head region comprised of a phosphate of an organic molecule and one or more hydrophobic fatty acid tails.
  • naturally-occurring phospholipids have a hydrophilic region comprised of choline, glycerol and a phosphate and two hydrophobic regions comprised of fatty acid.
  • the hydrophilic heads come together in a linear configuration with their hydrophobic tails aligned essentially parallel to one another.
  • a second line of molecules then aligns tail-to-tail with the first line as the hydrophobic tails attempt to avoid the aqueous environment.
  • the two lines of phospholipids know as a phospholipid bilayer or a lamella, converge into a sphere and in doing so entrap some of the aqueous medium, and whatever may be dissolved or suspended in it, in the core of the sphere.
  • phospholipids that may be used to create liposomes are, without limitation, 1,2-dimyristroyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphate monosodium salt, 1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-(1-glycerol)]sodium salt, 1,2-dimyristoyl-sn-glycero-3-[phospho-L-serine]sodium salt, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-gluta
  • Liposomes may be unilamellar, composed of a single bilayer, or they may be multilamellar, composed of two or more concentric bilayers. Liposomes range from about 20-100 nm diameter for small unilamellar vesicles (SUVs), about 100-5000 nm for large multilamellar vesicles and ultimately to about 100 microns for giant multilamellar vesicles (GMVs). LMVs form spontaneously upon hydration with agitation of dry lipid films/cakes which are generally formed by dissolving a lipid in an organic solvent, coating a vessel wall with the solution and evaporating the solvent. Energy is then applied to convert the LMVs to SUVs, LUVs, etc.
  • SUVs small unilamellar vesicles
  • GMVs giant multilamellar vesicles
  • the energy can be in the form of, without limitation, sonication, high pressure, elevated temperatures and extrusion to provide smaller single and multi-lamellar vesicles.
  • some of the aqueous medium is entrapped in the vesicle.
  • the fraction of total solute and therefore the amount of therapeutic agent entrapped tends to be rather low, typically in the range of a few percent.
  • liposome preparation by emulsion templating (Pautot, et al., Langmuir, 2003, 19:2870) has been shown to result in the entrapment of virtually 100% of aqueous solute.
  • Emulsion templating comprises, in brief, the preparation of a water-in-oil emulsion stabilized by a lipid, layering of the emulsion onto an aqueous phase, centrifugation of the water/oil droplets into the water phase and removal of the oil phase to give a dispersion of unilamellar liposomes.
  • This method can be used to make asymmetric liposomes in which the inner and outer monolayers of the single bilayer contain different lipids. Any of the preceding techniques as well as any others known in the art or as may become known in the future may be used as compositions of therapeutic agents in or on a delivery interface of this invention.
  • Liposomes comprising phospho- and/or sphingolipids may be used to deliver hydrophilic (water-soluble) or precipitated therapeutic compounds encapsulated within the inner liposomal volume and/or to deliver hydrophobic therapeutic agents dispersed within the hydrophobic core of the bilayer membrane.
  • the diblock copolymers discussed above with regard to micelle formation can be further modified to form bilayer structures similar to liposomes.
  • the structures are referred to as polymerosomes.
  • polymerosomes can be substantially more robust that liposomes.
  • the ability to control completely the chemical nature of each block of the diblock copolymer permits tuning of the polymerosome's composition to fit the desired application.
  • membrane thickness can be controlled by varying the degree of polymerization of the individual blocks. Adjusting the glass transition temperatures of the blocks will affect the fluidity and therefore the permeability of the membrane. Even the mechanism of release can be modified by altering the nature of the polymers.
  • Polymerosomes can be prepared in the same manner as liposomes. That is, a film of the diblock copolymer can be formed by dissolving the copolymer in an organic solvent, applying a film of the copolymer-containing solvent to a vessel surface, removing the solvent to leave a film of the copolymer and then hydrating the film. This procedure, however, tends to result is a polydispersion of micelles, worm micelles and vesicles of varying sizes. Polymerosomes can also be prepared by dissolving the diblock copolymer in a solvent and then adding a poor solvent for one of the blocks, which will result in the spontaneous formation of polymerosomes.
  • polymerosomes can be used to encapsulate therapeutic agents by including the therapeutic agent in the water used to rehydrate the copolymer film.
  • Polymerosomes can also be force-loaded by osmotically driving the therapeutic agent into the core of the vesicle. Also as with liposomes, the loading efficiency is generally low.
  • a technique has been reported that provides polymerosomes of relative monodispersivity and high loading efficiency; generation of polymerisomes from double emulsions. Lorenceau, et al., Langmuir, 2005, 21:9183-86. The technique involves the use of microfluidic technology to generate double emulsions consisting of water droplets surrounded by a layer of organic solvent.
  • a therapeutic agent may also be entrapped in water-in-oil (WO), an oil-in-water (OW), a water-in-oil-in-water (WOW) or an oil-in-water-in-oil (OWO) emulsion.
  • WO water-in-oil
  • OW oil-in-water
  • WOW water-in-oil-in-water
  • OEO oil-in-water-in-oil
  • An emulsion is simply a dispersion of droplets of a liquid in a second liquid where the liquids are immiscible. Whether a WO or an OW forms from a mixture of water and oil depends to some extent on the volume fraction of each phase but more so on the type of surfactant (sometimes called an emulsifier) used. That is, according to Bancroft's Rule, the phase in which an emulsifier is more soluble will constitute the continuous phase. Which phase a particular emulsifier will be more soluble in is determined by its hydrophilic-lipophilic balance (HLB) number. HLB by definition range from 1-20.
  • HLB hydrophilic-lipophilic balance
  • Emulsifiers with a low HLB i.e., one that is more soluble in oil that in water
  • emulsifiers with a high HLB will tend to give a WO
  • emulsifiers with a high HLB will give OWs.
  • Some common emulsifiers and their HLBs are, without limitation, acetylated monoglycerides (1.5), sorbitan trioleate (1.8), polyethyleneglycol monostearate (3.4), sorbitan monostearate (4.7), soy lecithin (8.0, polyoxyethylene (20) sorbitan 10.5 and sucrose monolaurate (15.0).
  • emulsifiers listed as GRAS (generally regarded as safe) by the FDA: diacetyl tartaric acid ester of mono- and di-glycerides, glycerol monostearate, glycerol monooleate, glycerol behenate, lecithin and monosodium phosphate derivatives of mono and di-glycerides.
  • GRAS generally regarded as safe
  • Still other emulsifiers include, without limitation, phosphatidyl choline, stearylamine, deoxycholic acid and polyvinyl alcohol.
  • the lipid phase of an emulsion may comprise any number of hydrophobic materials well-known to those skilled in the art. Among these, without limitation, are such substances as isopropyl myristate, soybean oil, garlic oil and coconut oil.
  • an emulsion may be stabilized by incorporation of finely divided inorganic particles of materials such as, without limitation, carbon, silica or clay in the dispersion (called a Pickering emulsion).
  • the particles adsorb to the surface of the droplets of the dispersed phase, thereby discouraging coalescence of droplets and thus stabilize the emulsion.
  • viscosity enhancers such as, without limitation, polyethylene oxide (PEO 50K), hyaluronic acid or polyvinylpyrrolidine
  • Droplet sizes in emulsions can vary from nano- to macro-scale, i.e., from about 10 nanometers (nm) to 100 nm (a nanoemulsion), about 100 nm (0.1 micron) to 100 microns (a microemulsions) or from about 100 microns to as much as 10 mm (a macroemulsion) in diameter.
  • Droplet size can be controlled by the use of a homogenizer, a device having a very small tube through which the droplets are forced, the larger ones being distorted such that, upon emergence from the tube they can be shaken apart to form smaller droplets.
  • Other techniques and devices are well-known in the art and may be used to prepare emulsions of an appropriate size for use with the delivery interface of this invention. In general droplets in the submicron diameter range are presently preferred although larger droplets may be used if desired.
  • WOW/OWO emulsions are also called double emulsions because they consist of droplets of one liquid encased in a second immiscible liquid that in turn is dispersed a third liquid that is immiscible with the second liquid; e.g., water-in-oil-in-water or oil-in-water-in-oil.
  • Double emulsions can be prepared by a variety of mixing techniques or by forcing single emulsions through membranes or nozzles. The size distribution of the droplets tends to be quite dispersed which can limit the utility of such emulsions for pharmaceutical applications.
  • microfluidics has been used to create double emulsions of precisely controlled droplet size.
  • the technique consists of a series of T-junctions through which the various liquids are forced.
  • junctions were designed so that the water flowed into a channel through which oil was flowing where it was pinched off to form a WO.
  • the WO emulsion was then directed into a second channel through which water was flowing thus creating the water-in-oil-in-water double emulsion.
  • a therapeutic agent for use with the delivery interface of this invention may comprise a coacervate.
  • Coacervation is a colloidal phenomenon involving the separation of a colloidal system into two liquid phases. The phase more concentrated in colloidal component is the coacervate while the other phase is the equilibrium solution.
  • a core material that is, a material to be encapsulated
  • the coacervate spontaneously forms a shell around the core material resulting in the formation of a microcapsule.
  • coacervation involves the mixing together under constant agitation of a core material (therapeutic agent) in a liquid in which the core material is not, or is minimally, soluble.
  • a second solvent containing the coating material, which is likewise not soluble in the first liquid is added upon which the coating material is deposited around the core material forming a shell.
  • the shell can be “hardened” by various means such as thermal treatment or desolvation.
  • bisphosphonates are particularly amenable to such delivery techniques. This is because it has long been known that liposomes containing bisphosphonate are readily engulfed by macrophages whereupon the liposomes are decomposed by resulting in the release of the bisphosphonate which then inactivates and/or limits the growth of the macrophage (e.g., see Monkkonen, J., et al., J. Drug Target., 2003, 11(5):279-86).
  • particulate bisphosphonates should be cytosed by macrophages and should have the same effect once in the macrophage as liposome-transported bisphosphonate.
  • insoluble particulate bisphosphonates are also pharmaceutically acceptable compositions for use with the delivery interface of this invention.
  • high concentrations of extracellular calcium enhances the potency of bisphosphonates against macrophage-type cells (Monkennon, J., et al., J. Drug Target., 1994, 2(4):299-308).
  • Bisphosphonates are known calcium scavengers so it is most likely that in the presence of extracellular calcium the insoluble calcium salt of the bisphosphonate is formed, thus it is presently preferred that the insoluble bisphosphonate composition for use herein is a calcium salt, in particular the dicalcium salt.
  • the insoluble particle can be a calcium salt of a synthetic bisphosphonate
  • naturally-occurring calcium phosphate minerals can serve as a pharmaceutically acceptable composition for use with a delivery interface hereof.
  • Such minerals include, without limitation, brushite, octacalcium phosphate, monetite, whitlocktite, tricalcium phosphate and hydroxyapatite. Of these, hydroxyapatite is presently preferred.
  • the technique involves the loading of liposomes with calcium ions by any number of known means such as, without limitation, that described in Messersmith, P. B., et al., Chem. Mater., 1998, 10:109-16.
  • a soluble bisphosphonate that is capable of crossing the liposomal lamella, for example without limitation, an ammonium salt, is introduced into the system and bisphosphonate anion is transported across the lamella.
  • the soluble bisphosphonate reacts with the calcium ions present and precipitates.
  • the lamella of the liposome is destroyed by a macrophage the calcium bisphosphonate is released and can affect the macrophage as discussed above.
  • An advantage of filing a liposome or other encapsulating shell-type carrier with an insoluble salt of a bioactive such as a bisphosphonate is improved shelf life of the resulting delivery system. That is, micelles, liposomes and to some extent polymerosomes are susceptible to loss of small molecule encapsulated therapeutic agent as it slowly leaks through the membrane of the capsule. If the therapeutic agent is precipitated within the capsule, the precipitate particle size would be expected to be too large to transgress the membrane or at least large enough to significantly reduce the rate of leakage.
  • small molecule therapeutic agents with acidic functionality might also be rendered less likely to leak from shell-type carriers by making a salt of the therapeutic agent with a relatively bulky counter-ion.
  • a counter-ion is, without limitation, an ammonium salt having the chemical structure:
  • R 1 , R 2 , R 3 and R 4 may be the same or different and are selected from groups that will provide the requisite bulkiness.
  • groups include, without limitation, straight or branched chain alkyl groups, in particular at present groups such at t-butyl, optionally substituted aralkyl groups (aryl-Y— where aryl refers to a ring or two or more fused rings having a fully delocalized ⁇ -electron system and Y is an alkyl group) wherein the optional substituent increases the bulk of the molecule without adding reactivity, e.g., a straight chain or branched alkyl group, an optionally substituted alicyclic group (a ring or two or more fused rings that does not contain a fully delocalized ⁇ -electron system and a polymeric unit such as polyethylene glycol.
  • Other such bulk-enhancing groups will be immediately evident to those skilled in the art based on the disclosure herein.
  • R 1 , R 2 and R 3 have the same meaning as set forth above and M is virtually any type of separator entity imaginable.
  • M is virtually any type of separator entity imaginable.
  • Coacervates of bisphosphonates may also be used as pharmaceutically acceptable compositions for regional delivery of a therapeutic agent using a delivery interface of this invention. While any coacervate known in the art and that is pharmaceutically acceptable may be used, polycationic biopolymers are presently preferred. A presently preferred polycationic biopolymer is chitosan.
  • the therapeutic effect can be enhanced by including a targeting moiety into the carrier system.
  • a targeting moiety into the carrier system.
  • Such targeting moieties and techniques are well-known in the art.
  • the surface of a carrier could be modified with antibodies to surface receptors known to be associated with the disease being treated. Interaction between the antibody and the receptor would result in the carrier being bound to the surface at the target site permitting release of the therapeutic agent over virtually any desired time period.
  • NHS N-hydroxysuccinimidyl
  • NHS-biotin might be conjugated to amine groups in proteins known to populate the diseased tissue. This would render the tissue in that region particularly adhesive with regard to carriers, the surface of which has been modified with avidin.

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US20070123923A1 (en) * 2005-11-30 2007-05-31 Lindstrom Curtis C Implantable medical device minimizing rotation and dislocation
US20090297577A1 (en) * 2008-06-02 2009-12-03 Medtronic Vascular, Inc. Local Delivery of Apolipoproteins and Their Derivatives
US20100069879A1 (en) * 2008-09-15 2010-03-18 Michal Eugene T Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US20100068170A1 (en) * 2008-09-15 2010-03-18 Michal Eugene T Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US20100198190A1 (en) * 2008-09-15 2010-08-05 Michal Eugene T Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US20100203114A1 (en) * 2007-07-09 2010-08-12 Warf - Wisconsin Alumni Research Foundation Micelle encapsulation of therapeutic agents
US20100331819A1 (en) * 2009-06-24 2010-12-30 Abbott Cardiovascular Systems Inc. Drug Delivery System and Method of Treatment of Vascular Diseases Using Photodynamic Therapy
WO2011089619A3 (fr) * 2010-01-22 2011-10-06 Concept Medical Research Private Limited Méthode et ensemble cathéter à ballonnet pour traiter des lésions de bifurcation
US8049061B2 (en) 2008-09-25 2011-11-01 Abbott Cardiovascular Systems, Inc. Expandable member formed of a fibrous matrix having hydrogel polymer for intraluminal drug delivery
US8076529B2 (en) 2008-09-26 2011-12-13 Abbott Cardiovascular Systems, Inc. Expandable member formed of a fibrous matrix for intraluminal drug delivery
US8114429B2 (en) 2008-09-15 2012-02-14 Cv Ingenuity Corp. Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
WO2012084007A1 (fr) 2010-12-20 2012-06-28 Graftcraft I Göteborg Ab Stent amovible et procédé de fabrication
US8226603B2 (en) 2008-09-25 2012-07-24 Abbott Cardiovascular Systems Inc. Expandable member having a covering formed of a fibrous matrix for intraluminal drug delivery
WO2013101908A1 (fr) * 2011-12-27 2013-07-04 Massachusetts Institute Of Technology Dispositifs à micro-aiguilles et leurs utilisations
US8500687B2 (en) 2008-09-25 2013-08-06 Abbott Cardiovascular Systems Inc. Stent delivery system having a fibrous matrix covering with improved stent retention
WO2014004692A1 (fr) * 2012-06-26 2014-01-03 Sarah Bacus Compositions et procédés pour le traitement du vitiligo
US8911766B2 (en) 2009-06-26 2014-12-16 Abbott Cardiovascular Systems Inc. Drug delivery compositions including nanoshells for triggered drug release
US8945207B2 (en) 2010-12-20 2015-02-03 Graftcraft I Göteborg Ab Removable stent and method of production
WO2014127278A3 (fr) * 2013-02-18 2015-10-29 Elutin, Inc. Enveloppes d'administration de médicaments spécifique d'un site, leurs systèmes et procédés d'utilisation
US9867838B2 (en) 2009-09-01 2018-01-16 Duke University Methods for treating heart failure using bisphosphonate compositions
US9949992B2 (en) 2011-11-16 2018-04-24 Duke University Bisphosphonate compositions and methods for treating and\or reducing cardiac dysfunction
US9949944B2 (en) * 2008-04-11 2018-04-24 Celonova Biosciences, Inc. Drug eluting expandable devices
US9956385B2 (en) 2012-06-28 2018-05-01 The Spectranetics Corporation Post-processing of a medical device to control morphology and mechanical properties
US10525171B2 (en) 2014-01-24 2020-01-07 The Spectranetics Corporation Coatings for medical devices
WO2021156773A1 (fr) * 2020-02-03 2021-08-12 Universidad Pontificia Bolivariana Endoprothèse
US12144945B2 (en) 2009-12-30 2024-11-19 Caliber Therapeutics, Llc Balloon catheter systems for delivery of dry drug delivery vesicles to a vessel in the body

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US8900603B2 (en) 2009-12-18 2014-12-02 Interface Biologics, Inc. Local delivery of drugs from self assembled coatings
US9220759B2 (en) 2012-02-23 2015-12-29 Abbott Cardiovascular Systems Inc. Treatment of diabetic patients with a drug eluting stent and adjunctive therapy
US9220584B2 (en) 2012-03-30 2015-12-29 Abbott Cardiovascular Systems Inc. Treatment of diabetic patients with a stent and locally administered adjunctive therapy
WO2017139757A1 (fr) * 2016-02-12 2017-08-17 The General Hospital Corporation Ciblage de macrophages pour moduler la conduction électrique dans le coeur
EP3796948A4 (fr) 2018-05-22 2022-03-02 Interface Biologics Inc. Compositions et procédés d'administration de médicaments à une paroi de vaisseau

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US5273536A (en) * 1992-04-02 1993-12-28 Vicky Savas Tapered balloon catheter
US6632196B1 (en) * 1995-07-18 2003-10-14 Russell A. Houser Dual balloon catheter and method of use
US20020187184A1 (en) * 1998-07-14 2002-12-12 Gershon Golomb Method of treating restenosis using bisphosphonate nanoparticles
US6790372B2 (en) * 2000-08-21 2004-09-14 Cleveland Clinic Foundation Microneedle array module and method of fabricating the same
US20060280858A1 (en) * 2001-01-05 2006-12-14 Lyudmila Kokish Balloon catheter for delivering therapeutic agents

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US20070123923A1 (en) * 2005-11-30 2007-05-31 Lindstrom Curtis C Implantable medical device minimizing rotation and dislocation
US20100203114A1 (en) * 2007-07-09 2010-08-12 Warf - Wisconsin Alumni Research Foundation Micelle encapsulation of therapeutic agents
US10285968B2 (en) 2008-04-11 2019-05-14 Celonova Biosciences, Inc. Drug eluting expandable devices
US9949944B2 (en) * 2008-04-11 2018-04-24 Celonova Biosciences, Inc. Drug eluting expandable devices
US20090297577A1 (en) * 2008-06-02 2009-12-03 Medtronic Vascular, Inc. Local Delivery of Apolipoproteins and Their Derivatives
US8734825B2 (en) 2008-09-15 2014-05-27 Covidien Lp Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US10314948B2 (en) 2008-09-15 2019-06-11 The Spectranetics Coporation Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US10046093B2 (en) 2008-09-15 2018-08-14 The Spectranetics Corporation Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US20100069879A1 (en) * 2008-09-15 2010-03-18 Michal Eugene T Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US20100068170A1 (en) * 2008-09-15 2010-03-18 Michal Eugene T Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US8114429B2 (en) 2008-09-15 2012-02-14 Cv Ingenuity Corp. Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US8128951B2 (en) 2008-09-15 2012-03-06 Cv Ingenuity Corp. Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US9603973B2 (en) 2008-09-15 2017-03-28 The Spectranetics Corporation Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US9198968B2 (en) 2008-09-15 2015-12-01 The Spectranetics Corporation Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US8257722B2 (en) 2008-09-15 2012-09-04 Cv Ingenuity Corp. Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US10117970B2 (en) 2008-09-15 2018-11-06 The Spectranetics Corporation Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US8491925B2 (en) 2008-09-15 2013-07-23 Cv Ingenuity Corp. Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US9132211B2 (en) 2008-09-15 2015-09-15 The Spectranetics Corporation Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US8563023B2 (en) 2008-09-15 2013-10-22 Covidien Lp Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US9034362B2 (en) 2008-09-15 2015-05-19 The Spectranetics Corporation Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US10987452B2 (en) 2008-09-15 2021-04-27 The Spectranetics Corporation Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US8673332B2 (en) 2008-09-15 2014-03-18 Covidien Lp Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US20100198190A1 (en) * 2008-09-15 2010-08-05 Michal Eugene T Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens
US8226603B2 (en) 2008-09-25 2012-07-24 Abbott Cardiovascular Systems Inc. Expandable member having a covering formed of a fibrous matrix for intraluminal drug delivery
US8049061B2 (en) 2008-09-25 2011-11-01 Abbott Cardiovascular Systems, Inc. Expandable member formed of a fibrous matrix having hydrogel polymer for intraluminal drug delivery
US8500687B2 (en) 2008-09-25 2013-08-06 Abbott Cardiovascular Systems Inc. Stent delivery system having a fibrous matrix covering with improved stent retention
US9730820B2 (en) 2008-09-25 2017-08-15 Abbott Cardiovascular Systems Inc. Stent delivery system having a fibrous matrix covering with improved stent retention
US8076529B2 (en) 2008-09-26 2011-12-13 Abbott Cardiovascular Systems, Inc. Expandable member formed of a fibrous matrix for intraluminal drug delivery
US9572795B2 (en) 2009-06-24 2017-02-21 Abbott Cardiovascular Systems Inc. Drug delivery system and method of treatment of vascular diseases using photodynamic therapy
US20100331819A1 (en) * 2009-06-24 2010-12-30 Abbott Cardiovascular Systems Inc. Drug Delivery System and Method of Treatment of Vascular Diseases Using Photodynamic Therapy
US8911766B2 (en) 2009-06-26 2014-12-16 Abbott Cardiovascular Systems Inc. Drug delivery compositions including nanoshells for triggered drug release
US9867838B2 (en) 2009-09-01 2018-01-16 Duke University Methods for treating heart failure using bisphosphonate compositions
US12144945B2 (en) 2009-12-30 2024-11-19 Caliber Therapeutics, Llc Balloon catheter systems for delivery of dry drug delivery vesicles to a vessel in the body
US8585642B2 (en) 2010-01-22 2013-11-19 Concept Medical Research Private Limited Method and a balloon catheter assembly for treating bifurcation lesions
WO2011089619A3 (fr) * 2010-01-22 2011-10-06 Concept Medical Research Private Limited Méthode et ensemble cathéter à ballonnet pour traiter des lésions de bifurcation
WO2012084007A1 (fr) 2010-12-20 2012-06-28 Graftcraft I Göteborg Ab Stent amovible et procédé de fabrication
US8945207B2 (en) 2010-12-20 2015-02-03 Graftcraft I Göteborg Ab Removable stent and method of production
US9949992B2 (en) 2011-11-16 2018-04-24 Duke University Bisphosphonate compositions and methods for treating and\or reducing cardiac dysfunction
US10814115B2 (en) 2011-12-27 2020-10-27 Massachusetts Institute Of Technology Microneedle devices and uses thereof
WO2013101908A1 (fr) * 2011-12-27 2013-07-04 Massachusetts Institute Of Technology Dispositifs à micro-aiguilles et leurs utilisations
WO2014004692A1 (fr) * 2012-06-26 2014-01-03 Sarah Bacus Compositions et procédés pour le traitement du vitiligo
US9956385B2 (en) 2012-06-28 2018-05-01 The Spectranetics Corporation Post-processing of a medical device to control morphology and mechanical properties
WO2014127278A3 (fr) * 2013-02-18 2015-10-29 Elutin, Inc. Enveloppes d'administration de médicaments spécifique d'un site, leurs systèmes et procédés d'utilisation
US10525171B2 (en) 2014-01-24 2020-01-07 The Spectranetics Corporation Coatings for medical devices
WO2021156773A1 (fr) * 2020-02-03 2021-08-12 Universidad Pontificia Bolivariana Endoprothèse

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US20150045877A1 (en) 2015-02-12

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