WO2007112354A1 - Procédé de modulation d'un profil de libération de médicaments d'un dispositif - Google Patents

Procédé de modulation d'un profil de libération de médicaments d'un dispositif Download PDF

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Publication number
WO2007112354A1
WO2007112354A1 PCT/US2007/064936 US2007064936W WO2007112354A1 WO 2007112354 A1 WO2007112354 A1 WO 2007112354A1 US 2007064936 W US2007064936 W US 2007064936W WO 2007112354 A1 WO2007112354 A1 WO 2007112354A1
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WIPO (PCT)
Prior art keywords
drug
composition
polymer
solvent
coating
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PCT/US2007/064936
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English (en)
Inventor
Arthur L. Rosenthal
Dymphna Donaghy
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Labcoat, Ltd.
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Publication of WO2007112354A1 publication Critical patent/WO2007112354A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
    • A61F2250/0068—Means for introducing or releasing pharmaceutical products into the body the pharmaceutical product being in a reservoir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers
    • A61L2300/61—Coatings having two or more layers containing two or more active agents in different layers

Definitions

  • Drug eluting medical devices e.g., a stent
  • an engineered surface architecture includes a polymer and a drug and remains fixed to the stent surface as applied so as to provide desired drug release kinetics, drug loading and uses minimal amounts of polymer.
  • the drug release kinetics of the surface architecture are modified by application of a resolvation solution.
  • Implantable medical devices are often used for delivery of a beneficial agent, such as a drug, to an organ or tissue in the body. It is intended that the drug be delivered at a controlled delivery rate over an extended period of time. These devices may deliver agents to a wide variety of bodily systems to provide a wide variety of treatments.
  • vascular stent 100 an example of which is shown in Fig. 1.
  • DES drug-eluting stent
  • vascular stents are typically introduced percutaneously, and transported intraluminally, until positioned at a desired location in the patient. These devices are then expanded either mechanically, such as by the expansion of a mandrel or balloon positioned inside the device, or expand themselves by releasing stored energy upon actuation within the body. Once expanded within the lumen, these devices become encapsulated within the body tissue and remain as a permanent implant.
  • Known stent designs include monofilament wire coil stents, welded metal cages, and thin-walled metal cylinders with axial slots formed around the circumference.
  • Known construction materials for use in stents include polymers
  • restenosis is a wound healing process that reduces the vessel lumen diameter by either extracellular matrix deposition, neointimal hyperplasia, or vascular smooth muscle cell proliferation, and which may ultimately result in renarrowing or even reocclusion of the lumen after intervention.
  • the overall restenosis rate is still reported in the range of 25% to 50% within six to twelve months after an angioplasty procedure. To treat this condition, additional revascularization procedures are frequently required, thereby increasing trauma and risk to the patient.
  • U.S. Pat. No. 5,716,981 discloses a stent that is surface-coated with a composition comprising a polymer carrier and paclitaxel (a well-known compound that is commonly used in the treatment of cancerous tumors).
  • Abluminal With respect to a device placed within a vessel, e.g., a stent, the surface of the stent in contact with the vessel wall, i.e., the outer surface.
  • Angiogenesis The process by which a capillary network gives rise to additional branches, extensions, and connections.
  • Angiogenic agents Agents that act to modulate angiogenesis.
  • Angiogenic factors Angiogenic polypeptides.
  • Anti-inflammatory agent Agents that act to reduce, in intensity or duration, the physiologic process of inflammation.
  • Antiplatelet agents Agents that act to inhibit or decrease platelet aggregation and/or clot formation or otherwise modulate the aggregation and/or clotting activity of platelets. Used herein as synonymous with antithrombotic agents.
  • Antiproliferative agents Agents that act to modulate cell proliferation, including cell proliferation resulting from cell transformation, for example, in the cases of cancer, malignancy, neoplasms, and virus-induced cell transformations.
  • Antirestenotic agents Agents that act to modulate restenosis.
  • Antithrombotic agents Agents that act to modulate thrombin activity.
  • Arteriosclerosis Hardening of the arteries produced by degenerative or hyperplasic changes to the intimal of arteries or a progressive increase in muscle and elastic tissue in arterial walls.
  • Atherosclerosis The most common form of arteriosclerosis characterized by deposits of lipid material in the intima of medium and large diameter arteries, resulting in partial or total occlusion of an affected vessel.
  • beneficial agent As used herein, the term “beneficial agent” is intended to have its broadest possible interpretation and is used to include any therapeutic agent or drug, as well as inactive agents such as barrier layers, carrier layers, therapeutic layers, or protective layers.
  • Beneficial layers Biodegradable layers comprising beneficial agents.
  • Biodegradable See Bioresorbable, below.
  • Bioresorbable The characteristic of being bioresorbable and/or able to be broken down by either chemical or physical processes, upon interaction with a physiological environment. For example, a biodegradable or bioerodible matrix is broken into components that are metabolizable or excretable, over a period of time from minutes to years, preferably less than one year, while maintaining any requisite structural integrity in that same time period.
  • Erosion The process by which components of a medium or matrix are bioresorbed and/or degraded and/or broken down by chemical or physical processes. For example in reference to biodegradable polymer matrices, erosion can occur by cleavage or hydrolysis of the polymer chains, thereby increasing the solubility of the matrix and suspended beneficial agents.
  • Erosion rate A measure of the amount of time it takes for the erosion process to occur, usually reported in unit-area per unit-time.
  • Hypoxia Condition characterized by an abnormally low oxygen concentration in affected tissues.
  • Implantation site A site into which a medical device or stent is physically implanted.
  • Ischemia Local anemia resulting from obstructed blood flow to an affected tissue.
  • Matrix or bioresorbable matrix are used interchangeably to refer to a medium or material that, upon implantation in a subject, does not elicit a detrimental response sufficient to result in the rejection of the matrix.
  • the matrix typically does not provide any therapeutic responses itself, though the matrix may contain or surround a beneficial agent, as defined herein.
  • a matrix is also a medium that may simply provide support, structural integrity or structural barriers.
  • the matrix may be polymeric, non-polymeric, hydrophobic, hydrophilic, lipophilic, amphiphilic, and the like.
  • Openings The term “openings” includes both through openings and recesses.
  • compositions or tissue are suitable for maintaining the stability of a beneficial agent and allowing the delivery of the beneficial agent to target cells or tissue.
  • Radially inner or radially interior surface With respect to medical device struts, a radially inner or interior surface refers to a surface that has a substantially equivalent radius to that of the interior strut surface.
  • Radially intermediate surface With respect to medical device struts, a radially intermediate surface refers to a surface that has a substantially equivalent radius intermediate between that of the interior and exterior strut surfaces.
  • Restenosis The recurrence of stenosis after a surgical procedure, including, but not limited to, the infiltration of smooth muscle cells into the bore of a medical device implanted to correct a previous chronic occlusion.
  • Sequential delivery Delivery of beneficial agents in a specified sequence, for example where about 75% of a first agent is delivered before about 50% of a second agent is delivered.
  • Stenosis A restriction or occlusion of any vessel or orifice.
  • Therapeutic agent refers to any therapeutically active substance that is delivered to a bodily conduit of a living being to produce a desired, usually beneficial, effect.
  • Thrombosis The formation of a thrombus (clot) within a blood vessel, often leading to partial or total occlusion of the blood vessel, leading to a condition of hypoxia in tissues supplied by the occluded blood vessel.
  • Vasodilators (or vasodilative agents): Polypeptides, polynucleotides encoding polypeptides, small molecules, or combinations thereof, that cause blood vessel dilation, i.e., an increase in the lumen of a blood vessel.
  • a method of coating a medical device for insertion in a blood vessel of a body comprises affixing a first material on a portion of the abluminal surface; and depositing a second material on a portion of the affixed first material to alter a first composition of the first material.
  • the first material may comprise a first drug and a first polymer; and the second material may comprise a first solvent in which a solubility of the first drug is greater than a solubility of the first polymer, whereby a portion of the first drug is redistributed within a portion of the first material.
  • the method may further comprise providing a solvent in the second material in which at least one of the first drug and the first polymer is soluble. [0045] The method may further comprise providing a second drug, different from the first drug, in the second material.
  • a method of coating a medical device for insertion in a blood vessel of a body comprising a first surface
  • the method comprises affixing a first composition of material on a first portion of the first surface of the device; and depositing a second composition of material, different from the first composition, on a first portion of the affixed first material, wherein the second composition is configured to alter the first composition.
  • the first composition may comprise a first drug and a first polymer; and the second composition may comprises a first solvent in which at least one of the first drug and the first polymer is soluble.
  • a solubility of the first drug in the first solvent may be different than a solubility of the first polymer in the first solvent.
  • a method of modifying a drug release profile of a medical device for insertion in a blood vessel of a body, the medical device having a first composition of material affixed on a first portion of a first surface of the device, the first composition comprising a first drug and a first polymer the method comprises: depositing a second composition of material, different from the first composition, on a first portion of the affixed first material, wherein the second composition comprises a first solvent in which at least one of the first drug and the first polymer is soluble.
  • the method may further comprise: altering a physical shape of the engineered surface architecture by applying the second composition of material.
  • the method may further comprise: depositing a third composition of material, different from each of the first and second compositions, on the first portion of the affixed first material, wherein the third composition comprises a second solvent in which at least one of the first drug, the second drug, and the first polymer is soluble.
  • the second solvent may selected such that a solubility of the first drug in the second solvent, a solubility of the first polymer in the second solvent, a solubility of the second drug in the second solvent, and a solubility of the third drug in the second solvent, are different from one another.
  • Figure 2 is a graph showing the relative release rates for compositions of different polymer to drug ratios
  • Figure 3 is a representation of a stent with a surface architecture in accordance with one embodiment of the present invention
  • Figure 4 is a representation of a stent with a surface architecture in accordance with another embodiment of the present invention.
  • Figure 5 is an alternate view of the stent with the surface architecture as shown in Fig. 4;
  • Figure 6 is a close-up representation of one of the surface architectural features in accordance with one embodiment of the present invention.
  • Figure 7 is a representation of a stent with a surface architecture in accordance with another embodiment of the present invention.
  • Figure 8 is a representation of a stent with a surface architecture in accordance with another embodiment of the present invention.
  • Figures 9A-9C represent a model of operation in accordance with one embodiment of the present invention.
  • Figures 10A-10C represent a model of operation in accordance with one embodiment of the present invention
  • Figure 11 represents a model of operation in accordance with one embodiment of the present invention
  • Figure 12 represents a model of operation in accordance with one embodiment of the present invention
  • Figures 13A-13D are various embodiments of the present invention.
  • Figure 14 is a flowchart of a method according to an embodiment of the present invention.
  • a coating is meant to refer to application of a material, i.e., a coating material to, for example, a stent. Unless explicitly stated herein, however, coating, or the act of coating, does not imply that an entire surface is necessarily covered.
  • Considerations for selecting polymer and drug candidates include biocompatibility, mechanism of action of drug, stability of drug, kinetics of drug release from polymer, pharmacokinetics of tissue distribution, pharmacodynamics of the drug, persistence of the polymer, physical characteristics of coating, and coatability of polymer/drug formulations.
  • a suitable drug is combined with a suitable polymer that, after application, results in a coating with defined drug loading, drug release kinetics, solids content, and coating thickness.
  • An ideal coating would have predictable release kinetics, release the dose of drug loaded into the coating to the targeted area, and minimize the amount of polymer. It is desirable to establish a ratio of drug to polymer that will give desired drug release kinetics, 100% drug release, and use a minimal quantity of polymer.
  • the properties of surface area and drug loading are important variables relating to selecting the desired drug and polymer ratio for determining a drug flow rate and a total drug flow rate, as will be discussed below.
  • the ratio of drug to polymer, thickness, surface area and integrity of polymer are important variables that affect the rate and amount of drug release.
  • the ratio of polymer to drug is in the range from 0.5:1 to 2:1 , weightweight, with a thickness in the range of 1 - 10 microns.
  • the rate and amount of drug release are measured, experimentally, by placing a coated stent into an elution solution to determine the time course and total amount of drug released from the coating.
  • the amount of drug that may elute from a coating is dependent on the coating's ability to release the drug either by diffusion or disintegration of the coating over time.
  • diffusion is the primary mechanism for release of the drug from the coating.
  • a solvent in the body this is blood or tissue fluids
  • low film porosity and excessive thickness may prevent quantitative drug release.
  • bioerodible polymer it is believed that diffusion is the dominant mechanism for delivery of therapeutic material when the thickness is in the range of 1 - 3 microns whereas, for thicknesses greater than 3 microns, the dominant delivery mechanism is believed to be degradation.
  • biostable polymer some drug is sequestered, i.e., never delivered, when the thickness is in the range of 4 - 10 microns.
  • the ratio of polymer to drug in the composition affects the rate at which the drug is released. As shown in Fig. 2, as the ratio of polymer to drug (by weight) goes from 2:1 to 1 :1 , the amount of drug released increases. As a result, the amount of drug that is released, and the rate, can be controlled by choosing the ratio of polymer to drug.
  • Polymer/drug formulations applied to stents are intended to administer an active drug locally and directly to the putative site of restenosis.
  • the chemical and physical characteristics of polymer and drug in the coating can affect the rate of kinetic release and persistence of the polymer and drug on the stent.
  • Such characteristics that may affect coating persistence and kinetic drug release include, but are not limited to: polymer chemistry, i.e., bioerodible or biostable, coating thickness, coating porosity, polymer basis weight, drug basis weight, and the ratio of polymer to drug.
  • Polymers suitable for coatings include: silicones, polyesters, polyacrylamides, SIBS, polystyrene, EVA and other such polymers with biocompatibility that can be demonstrated in, for example, porcine pig implant models.
  • Biocompatibility of a polymer coating is greatly affected by the amount of material in contact with tissue and blood. In the case of bioerodible polymers, the amount of material also affects persistence of the polymer. For an optimal stent coating, it is necessary to control: the amount of polymer, the thickness of coating, the consistency of coating, and to minimize the amount of coating in contact with blood. [0086] The thickness of the coating is related to the amount of solids in the coating and the surface area over which the coating is applied. An amount of drug is chosen based on biological activity and toxicity of the drug. Polymer is added to the drug coating solution in a proportion determined to provide a desired kinetic release for a desired thickness of the dried coating.
  • the amount of drug that may be mixed with polymer is dependent on solubility conditions of the solvent coating solution and the limitations of the coating process. Even though the ratio of drug to polymer may be controlled in the coating solution, it may not be possible to dissolve the desired amount of drug and the desired amount of polymer in a solvent at the desired concentration. In order to apply the desired amount of drug to the stent surface, successive applications of coating solution may be applied to the stent surface. [0087]
  • the thickness of drug and polymer must be sufficient to provide coating integrity and predictable kinetic release. For a given amount of coating material, thickness of the coating will vary as a function of stent surface area coated and the amount of solids in the coating. Coating physical properties and surface concentrations of a drug are variables that affect kinetic drug delivery.
  • bioerodible polymers are used in the coating, an excessive amount of drug and polymer may be present in the coating that prolongs drug delivery and increase potential for toxicity. If biostable polymers are used, the additional amount of drug may not be accessible for kinetic drug release and may be sequestered for an indefinite period of time.
  • Controlling the thickness of the surface coating has the beneficial effects of improving drug release kinetics including the ability to control drug release and to allow increased drug loading.
  • Increasing coating thickness results in increased overall thickness of the stent. This is undesirable for a number of reasons, including increased trauma to the vessel wall during implantation, reduced flow cross-section of the lumen after implantation, and increased vulnerability of the coating to mechanical failure or damage during expansion and implantation.
  • Coating thickness is one of several factors that affect the release kinetics of the beneficial agent, and limitations on thickness thereby limit the range of release rates, duration of drug delivery, and the like that can be achieved. It is therefore desirable to determine a thickness to provide predictable drug release kinetics, while minimizing the amounts of drug and polymer being used.
  • dipping, spraying, and microdroplet dispensing i.e., the ejection of a microdroplet from a dispenser.
  • microdroplet dispensing i.e., the ejection of a microdroplet from a dispenser.
  • the dipping or spraying methods deposit the material indiscriminately on all surfaces of the stent without limitation or control.
  • Each of these methods, i.e., spraying and dipping has limitations with respect to at least: thickness consistency, loading accuracy, location precision and resolution.
  • Microdroplet deposition methods for coating provide for volumetric metering of a coating solution, thus precision and accuracy in respect of coating amount are possible.
  • the drop volume may be controlled by ejection force, solution viscosity and tip size.
  • Microdroplet deposition requires additional mechanisms to locate the stent surface and provide coating consistency. For example, direct visual guidance, computer aided controllers, and precision metering may be necessary to apply a repeatable pattern of drops to the stent surface.
  • Microdroplet deposition cannot independently control coating thickness nor spreading on the stent surface.
  • Viscosity, ejection force, solvent, and drop size are variables that may independently affect spreading of a coating once applied.
  • Coating applied to the outer (abluminal) surface of the stent may spread in all directions resulting in coating on the luminal side of the stent.
  • a coating on the luminal side of a stent might be disadvantageous.
  • a coating topology, or engineered surface architecture that may be referred to as a microdroplet deposited engineered surface architecture is provided.
  • a plurality of drops are placed on the stent with the purpose, in one embodiment, of "building up" individual units of coating material on the outer stent surface, i.e., the abluminal surface.
  • a microdrop structure is provided having relatively thin and thick areas from which drug may be released at a relatively fast and slow rate, respectively.
  • this architecture results in a coating that uses less material, i.e., polymer, solvent, medicine, while at the same time providing for better, and determinable, drug kinetics, approaching 100% delivery, and better mechanical operation of the coating binding to the stent.
  • drops with different compositions e.g., a different drug, a different polymer, and/or a different ratio of polymer to drug, may be alternatingly deposited, either laterally along the surface of the device, or vertically, i.e., one atop another or overlapped to an extent.
  • Specific coating parameters may be controlled to produce the desired size and/or characteristics of the engineered surface architecture.
  • a solution of drug and polymer are dissolved in a compatible solvent at a desired ratio and placed into the JACTM System from Labcoat, Ltd., of Galway, IR as described in US Patent 6,645,547 to Shekalim, et al., issued November 11 , 2003 and titled “Stent Coating Device,” and US Publication 20030207019A1 to Shekalim et al., published November 6, 2003 and titled "Stent Coating Device.”
  • a drop size i.e., the size of the drop or microdroplet to be ejected from an applicator and toward the stent, is chosen to be in the range of 30 - 60 microns depending on the width of the stent surface.
  • the viscosity of the solution is adjusted so as to produce microdroplets of coating solution in the range of 20 - 100 picoliters as ejected.
  • the coating process via ejection of microdroplets, first places an index microstructure on the surface at each of the target points.
  • the formulation is provided such that the drops remain only on the abluminal surface and do not spread to a sidewall of a stent strut.
  • the thickness of the engineered surface architecture may be controlled by the drops' diameter and by the amount of solids in the coating solution.
  • the index drop may comprise a primer or other material to facilitate placement of subsequent drops.
  • the index drop may comprise polymer that is the same as the polymer of subsequent drops.
  • a drug is chosen based on desired chemical and biological characteristics including therapeutic index, solubility and compatibility with polymer carrier.
  • the polymer and drug are dissolved in a solvent in which both agents are miscible at the desired final concentration of both polymer and drug.
  • the polymer and drug are solubilized at a fixed ratio to prepare a coating solution.
  • the concentrations of both polymer and drug in the coating solution are adjusted so as to result in a stent coating of known amount of drug and polymer and coating thickness after deposition and drying.
  • the amount of drug applied in the stent coating is determined by knowing the therapeutic dosage of the drug, the toxicity level of the drug and the surface area of vessel wall of the vessel after full stent expansion.
  • polymers may provide the appropriate chemical properties for formulating stent coatings. Such polymers may have desired chemical properties yet are not sufficiently biologically compatibility because the amount and physical characteristics of the coating may affect biocompatibility. In addition, for bioerodible polymers, the amount of polymer in the coating may affect the rate of degradation of the coating. Choosing appropriate polymers and amount of polymer in the coating requires careful testing in suitable animal models, typically, rabbit and porcine implant studies. For example, a polylactic acid, a high molecular weight bioerodible organic ester, is known to have suitable chemical and physical properties for stents and stent coatings. In studies conducted with high amounts of polylactic acid and other such polyesters, tissue inflammation has been correlated with the amount of polymer associated with the tissue.
  • Stents coated with 10ug/75mm 2 - 30ug/75 mm 2 vessel wall polylactic acid polymer are essentially indistinguishable from stents without coatings.
  • the topology of the present invention is created by placing microdroplets substantially concentrically co-located on the stent surface. In other words, microdroplets are repeatedly placed at substantially the same locations to either "stack-up," i.e., build additively, as islands of coating material or to create discoids of coating material. These will be discussed below in more detail.
  • the ratio of polymer to drug and the volume of each drop are known, then the amount of drug in a drop is determinable.
  • the structure of the present invention provides the desired amount of medicine with the minimum amount of polymer. As is known, reducing the amount of polymer introduced into the vasculature can be beneficial.
  • a stent 100 includes an abluminal surface 302 and a sidewall surface 304.
  • a first island 306-1 is separated from an adjacent island 306-2 by a space on the abluminal surface 302.
  • a number of these islands 306, generally, are placed substantially along the abluminal surface 302 of the stent 100.
  • the choice of solvent, solvent ratio to polymer, ratio of medicine or drug to polymer, microdroplet size at ejection, drop ejection velocity, and other characteristics of the coating material contribute to aspects of the island building.
  • the islands have a center portion that is higher than its periphery.
  • the island is substantially planar.
  • the islands are positioned such that adjacent islands overlap with one another. As shown in Fig. 3, adjacent islands 306-3 and 306-4 are positioned to overlap. According to one embodiment of the present invention, overlapping and non-overlapping islands of material can be placed on the same medical device or stent. The determination to overlap or not, on a specific section of the stent, may be a function of the geometry of the stent as well as the intended placement location within the vasculature. It is further envisioned that portions of a stent will be coated differently than other portions.
  • a surface architecture comprising a plurality of discoids, i.e., a disc-shaped deposit or microstructure.
  • a discoid may be considered as a type of island.
  • a stent 100 has, on its abluminal surface 302, a first discoid 402 that includes a central portion 404 where substantially most of the coating material has either evaporated away, due to the flash point of the solvent, or has "splashed” or “spread out” to create the side portions, or a ring 406 about the central portion 404.
  • the choice of solvent, drop velocity and drop size contribute to the discoid's shape and size.
  • the discoid 402 includes the central portion 404 and the side portion 406, as shown in a close-up view in Fig. 6.
  • the central portion 404 is a result of the combination of the evaporation of solvent used to dissolve the drug in the polymer and the velocity with which the successive droplets impact the abluminal surface 302 of the stent 100.
  • the material is effectively placed within a determinable location.
  • the amount of drug, accumulated by the successive placement of the drops, to be found within the side portion 406 is known.
  • the rate at which the drug will be released is determinable as a function of the polymer to drug ratio.
  • discoids 402 may be placed in proximity to one another in order to overlap.
  • a time period between placement of adjacent drops on the surface of the stent 100 is chosen, taking into consideration evaporation rates, boiling point, etc., in order to cause the overlapping.
  • the locations of the adjacent drops can be chosen to cause a "joining" of the two discoids into one, as represented by a discoid 702 shown in Fig. 7.
  • the discoid 702 in one embodiment, is created by placing respective drops at locations 704 and 706. The subsequent spreading and evaporation, that is, the "blending" or “merging” together of side portions, results in the "elongated" discoid 702.
  • separated, overlapped discoids 402 and/or elongated discoids 702 may be placed at specific regions of the stent 100 to accommodate mechanical attributes of the stent 100.
  • the discoids 402 may be non- overlapped to provide resistance to axial stress crack propagation and better mechanical integrity of the coating on the stent.
  • the discoids may be overlapped to deliver the drug.
  • discoids 402 are deposited on the abluminal surface 302 of the stent 100 with a spacing that causes the outer portions 406 of adjacent discoids 402 to abut. As shown in Fig. 8, a "chain" of discoids 402 is provided on the abluminal surface 302. The placement of multiple droplets at substantially the same locations allows for the "buildup" of the outer portions 406. As described above, because the amount of drug in each droplets is known, a desired total amount of drug can be deposited by choosing the necessary number of droplets. Further, the elution profile can be tailored as a function of the polymer to drug ratio of the droplet composition.
  • parameters which may affect the microdrop structure and drug dispersion within the microdrop include solvent evaporation, frequency of jetted drops, time of flight for drop to land, distance between microdrops on the stent surface and time between sequential deposition of drops.
  • the drop as jetted must be stable in order to repeatably deposit a predictable and regular quantity of material. From the time the drop is jetted until it lands, evaporation must be minimal. Therefore, time of flight must be small compared to the evaporation rate of solvent in the formulation. Once the drop lands, the solvent must evaporate to "fix" the coating to the stent surface and this spot becomes the foundation of the microdrop for the remainder of the sequential passes.
  • each subsequent drop must be applied after the previous drop is dry and/or at a sufficient distance from the previous drop to insure that drops remain discrete from each other. Accordingly, by controlling the time and/or distance between adjacent drops, one can control the surface microdrop structure.
  • Drops can be applied by controlling either the spacing or the time between sequential drops so that each previous drop has sufficiently dried prior to the application of a further sequential drop.
  • each microdrop has a homogenous composition, i.e., a first composition, wherein the drug to polymer ratio is fixed through the entire volume of the drop.
  • the release rate is then determined by surface area to volume ratio of the microdrop in general and the relative surface area and volume of the relatively thin (fast) and thick (slow) regions of the microdrop, specifically.
  • the drug distribution or shape of the microdrop is altered after formation of the microdrop thereby altering the controlled drug release properties of the architecture. This alteration is accomplished by exposure of the microdrop structure to selected solvents that have a differential affinity for the drug and polymer.
  • the process uses the Labcoat coating system to apply one or more sequential drops of a solvent to the surface of a previously applied and dried microdrop architecture, the solvent being selected so that the Solubility of Polymer (Sp) is much greater than the Solubility of Drug (Sd).
  • the sequential application of solvent will redissolve the surface polymer independent of the drug therein, causing a redistribution of polymer and drug with respect to each other. Such redistribution will alter the polymer to drug ratio in the "resolvated" portion as well as alter the shape and surface area of the thin and thick areas of the microdrop.
  • the amount of solvent applied and the evaporation rate of the solvent would affect the depth of surface resolvation and the spreading of the resolvated surface coating components.
  • a solvent may be selected where Sd is much greater than Sp, resulting in a resolvated portion wherein the drug will redistribute independently of the polymer.
  • a solvent may be selected whereby Sd and Sp are such that both drug and solvent may be resolvated.
  • the solvent applied could contain a second drug or combinations of drug that would allow the so applied drug(s) to disperse within the resolvated surface portion thereby adding these drugs to the coating.
  • the solvent may be applied to a continuous coating, i.e., one that is not the engineered surface architecture of the present invention, to change the ratio of drug to solvent, or add additional drug(s) in specific portions of that coating.
  • a method 1400 includes a step 1402 of depositing the plurality of drops, as described above, to create the engineered surface architecture.
  • a second composition of material in one embodiment containing solvent and/or a drug, is then applied to a portion of the coated surface of the device, step 1404. If the second composition is to be applied to another portion of the device, step 1406, then step 1404 is repeated on another portion of the device.
  • a third composition of material is applied to a portion of the coated device.
  • the third composition may be different from the second composition and may include a solvent in which either, or both, of the drug and polymer is soluble.
  • the determination is made as to whether or not the third composition will be deposited. If so, the third composition is applied, step 1412.
  • the third composition may be applied to the portions where the second composition was deposited and include a solvent in which the drug and/or polymer of the second combination is soluble.
  • the third combination may be applied to a portion of the surface architecture that has not been modified by the second composition.
  • portions of the device can be "tuned" by the selective application of a composition with a solvent and/or drug combination on different portions of the device and/or on other deposited compositions.
  • a composition with a solvent and/or drug combination on different portions of the device and/or on other deposited compositions.
  • an active surface 902 represents the top of the discoid or island of material.
  • a boundary layer 904, a sub-boundary layer 906 and a bulk region 908 include varying amounts of drug 910. It is assumed that: a) the drug 910 is released from the boundary layer 904 so quickly that it does not noticeably affect the dynamics of drug release from the sub-boundary layer 906; b) after the drug 910 is gone from the boundary layer 904, the porosity of the boundary layer 904 increases to such an extent that the drug 910 that leaves the sub-boundary layer 906 and enters the boundary layer 904 can be considered as entering the outside bulk liquid, i.e., the tissue; c) concentration of drug 910 in the bulk region 908 does not change; d) the initial drug concentration in the coating is assumed to be constant throughout the coating domain; and e) there is no drug elution through the side boundaries of the coating domain.
  • the creation of islands of coating material has been modeled to characterize the dynamics of the kinetics of the medicinal component of the coating.
  • the surface topology or engineered surface architecture (ESA) described herein has been modeled as two parallelepipeds 1000, 1002 with constant volume that are either disconnected, connected vertically, or connected horizontally as shown in Figs. 10A, 10B, and 10C, respectively.
  • ESA engineered surface architecture
  • the mathematical modeling analysis showed that the fastest time decay of the total amount of drug is observed for two disconnected elementary domains. For shorter elementary heights of a certain ratio of height L to volume V, the drug decay is slower for vertically connected domains, while for taller elementary domains, a different ratio of height L to volume V, the drug decay is slower for horizontally connected domains.
  • the slowest possible drug decay rate for vertically connected domains corresponds a calculable ratio of height L to volume V as does the drug decay rate for horizontally connected elementary domains.
  • the discoid 402 as shown in the figures can be schematically represented as shown in Fig. 1 1 . As shown, the discoid 402 has an outer radius R 2 and an inner radius Ri .
  • the discoid 402 between R 2 and Ri has an outer height of L 2 and the inner radius has an inner height L 1 .
  • the discoid is positioned on the stent surface 302. It is possible that, in one embodiment, the inner height Li is substantially zero (0) when measured from the stent's surface 302.
  • the discoid 402 can be mathematically modeled as shown in Fig. 12 by normalizing its shape to that of a cylinder 1202 with a missing or diminished portion 1204 in the middle.
  • the mathematical analysis showed that, where the total volume of a droplet, and thus the total drug load is constant, the amount of drug released on a fast time scale is going to be defined by the height and width of the interior part of the discoid (with smaller height) and the amount of drug released on a slow time scale is going to be defined by the height and width of the exterior part of the discoid (with greater height.)
  • the discoid may be constructed so that L2 may be constructed to have multi boundary layer conditions such that the diffusion rate from L2 is not uniform.
  • the height of L2 may be constructed so that the upper portion is a fast release domain, the sublayer is a moderate release domain and the lower is essentially a no release domain within certain defined time points. It follows that a discoid may be constructed to tailor the rate and amount of drug release by varying its diameter, height and volumes of the inner and outer discoid components.
  • a discoid may be constructed with multiple drugs and different polymers so that either the inner portion or outer portion may act as independent drug delivery mechanisms having a respective amount and rate of drug release.
  • a discoid can be considered to release drug from all surfaces or specifically defined surfaces.
  • the microdroplet architecture has other advantages.
  • the coating may be placed on only a portion of the stent in order to "tune" the application of the medicine.
  • a bare stent may be "primed” with an underlying coating of material or "primer” that is allowed to set prior to the coating containing the medicinal coating being applied.
  • the areas of the abluminal surface between the islands 302 or discoids 402 may be covered with the primer material and not be a bare stent surface.
  • the primer may include a first medicine, different from any medicine or medicines or drugs, in the coating of the engineered surface architecture.
  • a stent or medical device may be coated over all of its surfaces, e.g., for a stent - there may be coating on the luminal and abluminal surfaces in addition to the sides of the struts. This coating may be found on a device that has been coated by a dipping process. It is known to provide a stent over all surfaces with a first coating solution containing heparin. Thus, a stent already coated with heparin, for example, would then have the coating with the engineered surface architecture applied thereon. Further, a stent or device may be initially provided with a bio-beneficial coating such as titanium oxide on which the engineered surface architecture can be deposited.
  • a bio-beneficial coating such as titanium oxide on which the engineered surface architecture can be deposited.
  • the present topology allows for the placement of the coating to accommodate known stress points on the stent.
  • the number of drops in these areas can be adjusted to minimize the chance of the coating being separated from the stent when the stent is mechanically stressed. This tailoring of coating placement leads to higher reliability of the stent coating.
  • the topology described above allows for the elution rate to be controlled by defining the shape, size and number of locations at which the coating material is placed. In this manner, the surface area from which the drug is eluted is controlled and predetermined. The stent architecture no longer controls the amount of coating material that will be deposited.
  • Stents must be mounted on a delivery device to implant the stent within the vessel.
  • stents are mounted on catheter balloons by mechanical crimping causing the inner surface of the stent to adhere to the balloon surface.
  • coating material on the inner surface
  • direct contact of the balloon and the coating material results.
  • Such contact of the balloon and the coating material is an undesirable result and may cause migration of drug into the balloon material, transfer of balloon materials to the coating, sticking of the balloon and stent coating, or mechanical disruption of the inner coating surface upon balloon expansion. The result of such balloon and coating material interactions may cause difficulty in placing the stent or undesirable biological consequences to the patient.
  • Microdroplet surface structures applied substantially to the outer surface of the stent to create the engineered surface architecture avoid the interaction between balloon material and coating and thus eliminates a potential downside of stent coatings.
  • embodiments of the foregoing description were directed to placing the engineered architecture upon the stent surface by microdroplet deposition, it is envisioned that other mechanisms for creating the architecture are possible. It may be possible to use a dipping or spraying method with masking techniques in addition to vapor deposition or plasma etching of some type. Any one of a number of lithographic techniques may also be suitable for creating the engineered architecture. Further laser etching may also be used in conjunction with, for example, a photoresist polymer.
  • the resulting engineered architecture is not limited to a particular mechanism of manufacture.
  • the engineered surface architecture can be applied to almost any medical device, e.g., a stent, as has been described.
  • a normally uncoated stent i.e., one that has not been coated by its manufacturer, may have the ESA placed thereon without need for any mechanical modification to the stent.
  • reservoirs or holes in a stent's struts are known for being filled with medicine to be released into the vessel. These holes, however, can affect the mechanical performance of the stent and add to the manufacturing complexity of the stent.
  • the ESA described herein can be applied to a known stent without the need for mechanical modifications such as the adding of holes.
  • a physician may be able to choose a known stent and apply a customized ESA to coat the stent for a particular patient's requirements.
  • the engineered surface architecture of the present invention may be applied to a device having a porous surface.
  • the drops placed on the surface do not comprise any polymer.
  • Vulnerable plaque is a condition that cannot usually be easily seen but which is detectable and, in some cases, treatable. With vulnerable plaque, a lesion forms in the vessel and may go undetected until the lesion bursts quickly, often leading to a sudden death.
  • Drugs are available to treat vulnerable plaque, however, delivery to the site of the lesion is problematic.
  • a delivery device or drug applicator with the engineered architecture of this disclosure may be manufactured and delivered to the site of the lesion. The device does not have to be a stent, as the "scaffolding" function of a stent may be unnecessary at the location of vulnerable plaque. Rather, an erodible structure may be provided at the site of the lesion.
  • the engineered architecture is suitable for intraluminal devices in order to provide a topology with better drug delivery characteristics
  • the topology is also applicable to devices that may be delivered sub-dermally.
  • the desired delivery dynamics can be tailored based upon the shape(s) of the engineered architecture.
  • a cylinder 2902 either hollow or solid, and made from a bio-compatible material, is envisioned to have the engineered architecture including the discoids 402 and/or the islands 302, described above.
  • the discoids 402 and islands 302 are either separated from adjacent ones or deposited upon one another, depending upon the desired performance characteristics.
  • a planar device 2904 is also provided with the engineered surface architecture including discoids 402 and islands 302 either separately, together, overlapping or adjacently positioned.
  • a mesh structure 2906 is also provided with the engineered surface architecture including discoids 402 and islands 302 either separately, together, overlapping or adjacently positioned.
  • a sphere 2908 is also provided with the engineered surface architecture including discoids 402 and islands 302 either separately, together, overlapping or adjacently positioned.
  • the cylinder, planar device, mesh structure and sphere can be made of any material that can be placed within the body, either intraluminally or subdermally. This material, as known to one of ordinary skill in the art, includes, but is not limited to, stainless steel and Nitinol. Further, any one or more of these embodiments may be made from a biodegradable material that dissolves at some point in time after implantation.
  • the engineered architecture is useful for, for example, delivering antirestenotic, antithrombotic, antiplatelet, antiproliferative, antineoplastic, immunosuppressive, angiogenic, antiangiogenic agents, anti-inflammatories, and/or vasodilators, in addition to other compounds listed below, to a blood vessel.
  • the present invention is particularly well suited for the delivery of antineoplastic, angiogenic factors, immuno-suppressants, and antiproliferatives (anti-restenosis agents) such as paclitaxel and Rapamycin for example, and antithrombins such as heparin, for example.
  • Therapeutic agents for use with the described embodiments may, for example, take the form of small molecules, peptides, lipoproteins, polypeptides, polynucleotides encoding polypeptides, lipids, protein-drugs, protein conjugate drugs, enzymes, oligonucleotides and their derivatives, ribozymes, other genetic material, cells, antisense oligonucleotides, monoclonal antibodies, platelets, prions, viruses, bacteria, eukaryotic cells such as endothelial cells, stem cells, ACE inhibitors, monocyte/macrophages and vascular smooth muscle cells. Such agents can be used alone or in various combinations with one another.
  • antiinflammatories may be used in combination with antiproliferatives to mitigate the reaction of tissue to the antiproliferative.
  • the therapeutic agent may also be a pro- drug, which metabolizes into the desired drug when administered to a host.
  • therapeutic agents may be pre-formulated as microcapsules, microspheres, microbubbles, liposomes, niosomes, emulsions, dispersions or the like before they are incorporated into the matrix.
  • Therapeutic agents may also be radioactive isotopes or agents activated by some other form of energy such as light or ultrasonic energy, or by other circulating molecules that can be systemically administered.
  • Exemplary classes of therapeutic agents include antiproliferatives, antithrombins (i.e., thrombolytics), immunosuppressants, antilipid agents, antiinflammatory agents, antineoplastics including antimetabolites, antiplatelets, angiogenic agents, anti-angiogenic agents, vitamins, antimitotics, metalloproteinase inhibitors, NO donors, nitric oxide release stimulators, anti-sclerosing agents, vasoactive agents, endothelial growth factors, beta blockers, hormones, statins, insulin growth factors, antioxidants, membrane stabilizing agents, calcium antagonists (i.e., calcium channel antagonists), retinoids, anti-macrophage substances, antilymphocytes, cyclooxygenase inhibitors, immunomodulatory agents, angiotensin converting enzyme (ACE) inhibitors, anti-leukocytes, high-density lipoproteins (HDL) and derivatives, cell sensitizers to insulin, prostaglandins and derivatives,
  • Antiproliferatives include, without limitation, sirolimus, paclitaxel, actinomycin D, rapamycin, and cyclosporin.
  • Antithrombins include, without limitation, heparin, plasminogen,
  • tissue plasminogen activator t-PA
  • Immunosuppressants include, without limitation, cyclospohne, rapamycin and tacrolimus (FK-506), sirolumus, everolimus, etoposide, and mitoxantrone.
  • Antilipid agents include, without limitation, HMG CoA reductase inhibitors, nicotinic acid, probucol, and fibric acid derivatives (e.g., clofibrate, gemfibrozil, gemfibrozil, fenofibrate, ciprofibrate, and bezafibrate).
  • Anti-inflammatory agents include, without limitation, salicylic acid derivatives (e.g., aspirin, insulin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazine), para-amino phenol derivatives (e.g., acetaminophen), indole and indene acetic acids (e.g., indomethacin, sulindac, and etodolac), heteroaryl acetic acids (e.g., tolmetin, diclofenac, and ketorolac), arylpropionic acids (e.g., ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, and oxaprozin), anthranilic acids (e.g., mefenamic acid and meclofenamic acid
  • Antineoplastics include, without limitation, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan, and chlorambucil), methylnitrosoureas (e.g., streptozocin), 2-chloroethylnitrosoureas (e.g., carmustine, lomustine, semustine, and chlorozotocin), alkanesulfonic acids (e.g., busulfan), ethylenimines and methylmelamines (e.g., thethylenemelamine, thiotepa and altretamine), thazines (e.g., dacarbazine), folic acid analogs (e.g., methotrexate), pyhmidine analogs (5-fluorouracil, 5-fluorodeoxyuridine, 5-fluorodeoxyuhdine monophosphate, cytosine arabinoside
  • Antiplatelets include, without limitation, insulin, dipyridamole, tirofiban, eptifibatide, abciximab, and ticlopidine
  • Angiogenic agents include, without limitation, phospholipids, ceramides, cerebrosides, neutral lipids, triglycerides, diglycehdes, monoglycehdes lecithin, sphingosides, angiotensin fragments, nicotine, pyruvate thiolesters, glycerol- pyruvate esters, dihydoxyacetone-pyruvate esters and monobutyrin.
  • Anti-angiogenic agents include, without limitation, endostatin, angiostatin, fumagillin and ovalicin.
  • Vitamins include, without limitation, water-soluble vitamins (e.g., thiamin, nicotinic acid, pyhdoxine, and ascorbic acid) and fat-soluble vitamins (e.g., retinal, retinoic acid, retinaldehyde, phytonadione, menaqinone, menadione, and alpha tocopherol).
  • water-soluble vitamins e.g., thiamin, nicotinic acid, pyhdoxine, and ascorbic acid
  • fat-soluble vitamins e.g., retinal, retinoic acid, retinaldehyde, phytonadione, menaqinone, menadione, and alpha tocopherol.
  • Antimitotics include, without limitation, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, epipodophyllotoxins, dactinomycin, daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycins, plicamycin and mitomycin.
  • Metalloproteinase inhibitors include, without limitation, TIMP-1 , TIMP- 2, TIMP-3, and SmaPI.
  • NO donors include, without limitation, L-arginine, amyl nitrite, glyceryl trinitrate, sodium nitroprusside, molsidomine, diazeniumdiolates, S-nitrosothiols, and mesoionic oxatriazole derivatives
  • NO release stimulators include, without limitation, adenosine.
  • Anti-sclerosing agents include, without limitation, collagenases, metalloproteinases and collagen synthesis inhibitors including halofuginone.
  • Vasoactive agents include, without limitation, nitric oxide, adenosine, nitroglycerine, sodium nitroprusside, hydralazine, phentolamine, methoxamine, metaraminol, ephedhne, trapadil, dipyridamole, vasoactive intestinal polypeptides (VIP), arginine, and vasopressin.
  • Endothelial growth factors include, without limitation, VEGF (Vascular Endothelial Growth Factor) including VEGF-121 and VEG-165, FGF (Fibroblast Growth Factor) including FGF-1 and FGF-2, HGF (Hepatocyte Growth Factor), and Ang1 (Angiopoietin 1 ).
  • VEGF Vascular Endothelial Growth Factor
  • FGF Fibroblast Growth Factor
  • HGF Hepatocyte Growth Factor
  • Ang1 Angiopoietin 1
  • Beta blockers include, without limitation, propranolol, nadolol, timolol, pindolol, labetalol, metoprolol, atenolol, esmolol, and acebutolol.
  • Hormones include, without limitation, progestin, insulin, the estrogens and estradiols (e.g., estradiol, estradiol valerate, estradiol cypionate, ethinyl estradiol, mestranol, quinestrol, estrond, estrone sulfate, and equilin).
  • estradiols e.g., estradiol, estradiol valerate, estradiol cypionate, ethinyl estradiol, mestranol, quinestrol, estrond, estrone sulfate, and equilin.
  • Statins include, without limitation, mevastatin, lovastatin, simvastatin, pravastatin, atorvastatin, and fluvastatin.
  • Insulin growth factors include, without limitation, IGF-1 and IGF-2.
  • Antioxidants include, without limitation, vitamin A, carotenoids and vitamin E.
  • Membrane stabilizing agents include, without limitation, certain beta blockers such as propranolol, acebutolol, labetalol, oxprenolol, pindolol and alprenololi.
  • Calcium antagonists include, without limitation, amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine and verapamil.
  • Retinoids include, without limitation, all-trans-retinol, all-trans-14- hydroxyretroretinol, all-trans-retinaldehyde, all-trans-retinoic acid, all-trans-3,4- didehydroretinoic acid, 9-cis-retinoic acid, 1 1 -cis-retinal, 13-cis-retinal, and 13-cis- retinoic acid.
  • Anti-macrophage substances include, without limitation, NO donors.
  • Anti-leukocytes include, without limitation, 2-CdA, IL-1 inhibitors, anti- CD 1 16/CD 18 monoclonal antibodies, monoclonal antibodies to VCAM, monoclonal antibodies to ICAM, and zinc protoporphyrin.
  • Cyclooxygenase inhibitors include, without limitation, Cox-1 inhibitors and Cox-2 inhibitors (e.g., CELEBREX.RTM. and VIOXX.RTM.).
  • immunomodulatory agents include, without limitation, immunosuppressants (see above) and immunostimulants (e.g., levamisole, isophnosine, Interferon alpha, and lnterleukin-2).
  • ACE inhibitors include, without limitation, benazepril, captopril, enalapril, fosinopril sodium, lisinopril, quinapril, ramipril, and spirapril.
  • Cell sensitizers to insulin include, without limitation, glitazones, P par agonists and metformin.
  • Antisense oligonucleotides include, without limitation, resten-NG.
  • Cardio protectants include, without limitation, VIP, pituitary adenylate cyclase-activating peptide (PACAP), apoA-l milano, amlodipine, nicorandil, cilostaxone, and thienopyridine.
  • PACAP pituitary adenylate cyclase-activating peptide
  • apoA-l milano amlodipine
  • nicorandil cilostaxone
  • thienopyridine thienopyridine
  • Petidose inhibitors include, without limitation, omnipatrilat.
  • Anti-restenotics include, without limitation, include vincristine, vinblastine, actinomycin, epothilone, paclitaxel, and paclitaxel derivatives (e.g., docetaxel).
  • Miscellaneous compounds include, without limitation, Adiponectin.

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Abstract

Le profil d'élution de médicament d'un dispositif médical revêtu, tel qu'un stent, est modifié par exposition du revêtement à une matière qui modifie la composition du revêtement. Le revêtement enrobant le dispositif comprend un polymère et un médicament, et la matière à laquelle le revêtement est exposé comprend un solvant dans lequel le médicament ou le polymère est soluble. Le solvant peut être choisi de telle sorte que le médicament et le polymère soient l'un et l'autre soluble, mais à des niveaux de solubilité différents. L'application du solvant sur le revêtement redistribue la polymère et/ou le médicament dans le revêtement pour en modifier la cinétique de libération.
PCT/US2007/064936 2006-03-27 2007-03-26 Procédé de modulation d'un profil de libération de médicaments d'un dispositif WO2007112354A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6055521A (en) * 1995-03-13 2000-04-25 Jtw Operations Unattended automated system for selling and dispensing fluids, with change-dispensing capability
US20020128988A1 (en) * 2000-02-28 2002-09-12 Steve Covington System and method for controlling an automated fueling station

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6055521A (en) * 1995-03-13 2000-04-25 Jtw Operations Unattended automated system for selling and dispensing fluids, with change-dispensing capability
US20020128988A1 (en) * 2000-02-28 2002-09-12 Steve Covington System and method for controlling an automated fueling station

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