WO2004002548A1 - Utilisation de composes organiques - Google Patents

Utilisation de composes organiques Download PDF

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Publication number
WO2004002548A1
WO2004002548A1 PCT/EP2003/006847 EP0306847W WO2004002548A1 WO 2004002548 A1 WO2004002548 A1 WO 2004002548A1 EP 0306847 W EP0306847 W EP 0306847W WO 2004002548 A1 WO2004002548 A1 WO 2004002548A1
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WO
WIPO (PCT)
Prior art keywords
drug
stent
pharmaceutically acceptable
acei
acceptable salt
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PCT/EP2003/006847
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English (en)
Inventor
Margaret Forney Prescott
Original Assignee
Novartis Ag
Novartis Pharma Gmbh
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Application filed by Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Priority to AU2003242773A priority Critical patent/AU2003242773A1/en
Publication of WO2004002548A1 publication Critical patent/WO2004002548A1/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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—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
    • A61L31/08—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
    • 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
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • 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
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/434—Inhibitors, antagonists of enzymes

Definitions

  • the present invention relates to drug delivery systems, comprising an angiotensin converting enzyme inhibitor (ACE-inhibitor), or a pharmaceutically acceptable salt thereof, for the prevention and treatment of proliferative diseases, particularly vascular diseases.
  • ACE-inhibitor angiotensin converting enzyme inhibitor
  • the invention furthermore relates to the use of such drug delivery systems, for preventing or treating restenosis in diabetic and non-diabetic patients, or for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter in a subject in need thereof.
  • PCT A percutaneous transluminal coronary angioplasty
  • PTA percutaneous transluminal angioplasty
  • stenting atherectomy
  • bypass grafting bypass grafting or other types of vascular grafting procedures
  • PCT A percutaneous transluminal coronary angioplasty
  • PTA percutaneous transluminal angioplasty
  • stenting atherectomy
  • bypass grafting bypass grafting or other types of vascular grafting procedures.
  • a similar growth into the vessel lumen and obstruction of blood flow occurs within bypass grafts, at sites of anastomoses in transplantion and in vessels used to create dialysis access, thus revascularization procedures such angioplasty and/or stenting are also used in these pathologic conditions.
  • vascular access dysfunction in hemodialysis patients is generally caused by outflow stenoses in the venous circulation.
  • Vascular access related morbidity accounts for about 23 percent of all hospital stays for advanced renal disease patients and contributes to as much as half of all hospitalization costs for such patients.
  • vascular access dysfunction in chemotherapy patients is generally caused by outflow stenoses in the venous circulation and results in a decreased ability to administer medications to cancer patients. Often the outflow stenoses is so severe as to require intervention.
  • vascular access dysfunction in total parenteral nutrition (TPN) patients is generally caused by outflow stenoses in the venous circulation and results in reduced ability to care for these patients.
  • TPN total parenteral nutrition
  • Vascular access dysfunction is the most important cause of morbidity and hospitalization in the hemodialysis population.
  • Venous neointimal hyperplasia characterized by stenosis and subsequent thrombosis accounts for the overwhelming majority of pathology resulting in dialysis graft failure.
  • Coronary balloon angioplasty was introduced in the late 1970s as a less invasive method for revascularization of coronary artery disease patients. This has led to a quick progress in the development of new percutaneous devices to treat atherosclerotic vasculopathies.
  • the expanded use of angioplasty has shown that the arteries react to angioplasty by both a constrictive and a proliferative process similar to wound healing that limits the success of the treatment modality. This process is known as restenosis. Restenosis is defined as a re- narrowing of the treated segment, which equals or exceeds 50% of the lumen in the adjacent normal segment of the artery. Depending on the patient population studied, the restenosis rates range from 30% to 44% of lesions treated by balloon dilation.
  • Re-narrowing e.g. of an artherosclerotic coronary artery after various revascularization procedures occurs in 10-80% of patients undergoing this treatment, depending on the procedure used as well as the arterial site.
  • revascularization in general, but especially revasculoarization using a stent also injures endothelial cells and smooth muscle cells within the vessel wall, thus initiating a thrombotic and inflammatory response that is followed by a proliferative response.
  • Cell derived growth factors such as platelet derived growth factors, endothelial derived growth factors, smooth muscle-derived growth factors (e.g.
  • PDGF vascular smooth muscle cells
  • tissue factor tissue factor
  • FGF cytokines, chemokines and lymphokines released from endothelial cells, infiltrating macrophages, lymphocytes, or leukocytes or released from the smooth muscle cells themselves provoke proliferative and migratory responses in the smooth muscle cells as well as additional inflammatory events and neovascularization within the vessel wall.
  • Proliferation / migration of vascular smooth muscle cells usually begins within one to two days post-injury and, depending on the revascularization procedure used, continues for days, weeks, or even months.
  • neointima intimal thickening or restenotic lesion and usually results in narrowing of the vessel lumen. Further lumen narrowing may take place due to constructive remodeling, e.g. vascular remodeling, leading to further loss of lumen size.
  • stents A major category of interventional devices called stents has been introduced with the aim of reducing the restenosis rate of balloon angioplasty.
  • Restenosis is the result of the formation of neointima, a composition of smooth muscle-like cells in a collagen matrix. It has been demonstrated that the implantation of stents as part of the standard angioplasty procedure has improved the acute results of percutaneous coronary revascularization, but in-stent restenosis, as well as stenosis proximal and distal to the stent and the inaccessibility of the lesion site for surgical revasculation limits the long-term success of using stents.
  • the absolute number of in-stent restenotic lesions is increasing with the increasing number of stenting procedures, with the complexicity of culprit lesion stented as well as with stenting of ever-smaller sized arteries.
  • Neointima proliferation/growth occurs principally within the stented area or proximal or distal to the stented area within 6 months after stent implantation.
  • Neointima is an accumulation of smooth muslce cells within a proteoglycan matrix that narrows the previously enlarged lumen.
  • a recent successful development in the stent device area is the use of stents that release or elute pharmacological agents having antiproliferative and/or antiinflammatory activity
  • vascular injury including e.g. surgical injury, e.g. revascularization-induced injury, e.g. anastomotic sites for heart or other sites of organ transplantation, e.g. dialysis access grafts or e.g. anastomoses used to create dialysis access.
  • vascular injury including e.g. surgical injury, e.g. revascularization-induced injury, e.g. anastomotic sites for heart or other sites of organ transplantation, e.g. dialysis access grafts or e.g. anastomoses used to create dialysis access.
  • Suitable pharmaceutical drugs that can be used for coating stents for local treatment are angiotensin converting enzyme inhibitors (ACEIs), in each case, in free form or in form of a pharmaceutically acceptable salt have beneficial effects when locally applied to the lesions sites.
  • ACEIs are surprisingly well adapted for delivery especially controlled delivery from a catheter-based device or an intraluminal medical device.
  • ACEIs are particularly stable in any pharmaceutically acceptable polymers at body temperature and in human plasma, permitting an unexpected long storage in a coated stent, indwelling shunt, fistula or catheter. They are particularly well adapted because they are easily secured onto the medical device by the polymer and the rate at which they are released from coating to the body tissue can be easily controlled.
  • our herein described coated stents, indwelling shunt, fistula or catheter permit long-term delivery of the drug(s). It is particularly worthwhile to control the bioeffectiveness of our coated stents, indwelling shunt, fistula or catheter in order to obtain the same biological effect as a liquid dosage.
  • An advantage of using ACEIs as coating material for stents is that a corresponding drug is applied to the vessel at the precise site and at the time of vessel injury. This kind of local drug administration can be used to achieve higher tissue concentrations of the drug without the risk of systemic toxicity.
  • ACE-inhibitors also called angiotensin converting enzyme inhibitors
  • the class of ACE inhibitors comprises compounds having differing structural features.
  • Preferred ACE inhibitors are those agents that have been marketed, most preferred are benazepril, enalapril, lisinopril or ramipril, or, in each case, independently of one another, a pharmaceutically acceptable salt thereof, for example, the hydrochloride thereof. Most preferred ACE inhibitor is benazepril or a pharmaceutically acceptable salt thereof, preferably the hydrochloride thereof.
  • an ACEI may be applied as the sole active ingredient or in conjunction with each other.
  • the present invention relates to a drug-eluting stent for local treatment, e.g. a stent that elutes or is coated with a coating material or impregnated with a material comprising an ACEI or a pharmaceutically acceptable salt thereof.
  • An appropriate stent to be used according to the invention is a commercially available one, especially a drug that has been approved by health authorities, e.g. the Food and Drug Administration in the USA.
  • Corresponding stents comprise those that uses the balloon- expansion and the self-expansion principles, which can especially have a tubular, ring, multi- design, coil or mesh design.
  • biodegragable and biocompatible stents comprise e.g. metals, metal-alloys or polymers having a surface that can be coated.
  • biocompatible is meant a material, which elicits no or minimal negative tissue reaction including e.g. thrombus formation and/or inflammation.
  • a corresponding coating system according to the present invention should be suitable to be used as vehicles for local drug delivery.
  • An appropriate delivery vehicle is to be used that allows the release a predictable and controllable concentration.
  • a delivery vehicle according to the present invention must ensure a controlled release within a time span to be defined by a person skilled in the art and must be suitable for sterilisation.
  • Drug delivery vehicles comprise a pharmaceutically acceptable polymer selected from the group consisting of polyvinyl pyrrolidone/cellulose esters, polyvinyl pyrrolidone/polyurethane, polymethylidene maloeate, polyactide/glycoloide co-polymers, polyethylene glycol copolymers, polyethylene vinyl alcohol, and polydimethylsiloxane (silicone rubber).
  • a pharmaceutically acceptable polymer selected from the group consisting of polyvinyl pyrrolidone/cellulose esters, polyvinyl pyrrolidone/polyurethane, polymethylidene maloeate, polyactide/glycoloide co-polymers, polyethylene glycol copolymers, polyethylene vinyl alcohol, and polydimethylsiloxane (silicone rubber).
  • polymeric materials include biocompatible degradable materials, e.g. lactone- based polyesters or copolyesters, e.g. polylactide; polylactide-glycolide; polycaprolactone- glycolide; polyorthoesters; polyanhydrides; polyaminoacids; polysaccharides; polyphosphazenes; poly(ether-ester) copolymers, e.g. PEO-PLLA, or mixtures thereof; and biocompatible non-degrading materials, e.g. polydimethylsiloxane; poly(ethyIene- vinylacetate); acrylate based polymers or coplymers, e.g. polybutylmethacrylate, poly(hydroxyethyl methylmethacrylate); polyvinyl pyrrolidinone; fluorinated polymers such as polytetrafluoethylene; cellulose esters.
  • biocompatible degradable materials e.g. lactone- based polyesters or cop
  • a polymeric matrix When a polymeric matrix is used, it may comprise 2 layers, e.g. a base layer in which the drug(s) is/are incorporated, e.g. ethylene-co-vinylacetate and polybutylmethacrylate, and a top coat, e.g. polybutylmethacrylate, which is drug(s)-free and acts as a diffusion-control of the drug(s).
  • the drug may be comprised in the base layer and the adjunct may be incorporated in the outlayer, or vice versa.
  • Total thickness of the polymeric matrix may be from about 1 to 500 ⁇ , preferably 1 to 20 ⁇ or greater.
  • the amount of a drug to be used accordinging to the present invention is about 1 ⁇ g to about 500 ⁇ g, preferably 10 ⁇ g to about 200 ⁇ g, per stent.
  • the surface of a stent is loaded with about 1 ⁇ g to about 250 ⁇ g, preferably about 10 ⁇ g to 150 ⁇ g, per square centimeter of a compound to be used according the present invention.
  • ACEIs do not alter or adversely impact the therapeutic properties of an ACEI.
  • ACEIs are particularly stable in any pharmaceutically acceptable polymers at body temperature and in human plasma, permitting an unexpected long storage in a coated stents.
  • ACEIs are particularly well adapted because it is easily secured onto the medical device by the polymer and the rate at which it is released from coating to the body tissue can be easily controlled. Furthermore, stents coated with an ACEI permit long-term delivery of the drug. It is particularly worthwhile to control the bioeffectiveness of stents coated with an ACEI in order to obtain the same biological effect as a liquid dosage.
  • the invention relates to drug-containing delivery systems for the prevention and treatment of proliferative diseases, particularly vascular diseases.
  • a drug-releasing stent or medical devices to allow the timed or prolonged application of the drug to body tissue. It is a further object of the invention to provide methods for making a drug-releasing medical device, which permit timed-delivery or long-term delivery of a drug.
  • biocompatible complexed drug coatings which enhance the biostability, abrasion-resistance, lubricating characteristics, and bio- activity of the surface of implantable medical devices, especially complexed drug coatings, which contain heat-sensitive biomolecules.
  • a drug delivery device or system comprising a) a medical device adapted for local application or administration in hollow tubes, e.g. a catheter-based delivery device or intraluminal medical device, and b) a therapeutic dosage of an ACEI or a pharmaceutically acceptable salt thereof, being releasably affixed to the catheter-based delivery device or medical device.
  • Such a local delivery device or system can be used to reduce stenosis or restenosis as an adjunct to revascularization, bypass or grafting procedures performed in any vascular location including coronary arteries, carotid arteries, renal arteries, peripheral arteries, cerebral arteries or any other arterial or venous location, to reduce anastomic stenosis such as in the case of arterial-venous dialysis access with or without polytetrafluoroethylene grafting and with or without stenting, or in in conjunction with any other heart or transplantation procedures, or congenital vascular interventions.
  • the local administration preferably takes place at or near the vascular lesions sites. Local administration or application may reduce the risk of remote or systemic toxicity.
  • the smooth muscle cell proliferation or migration is inhibited or reduced according to the invention immediately proximal or distal to the locally treated or stented area.
  • the administration may be by one or more of the following routes: via catheter or other intravascular delivery system, intranasally, intrabronchially, interperitoneally or eosophagal.
  • Hollow tubes include circulatory system vessels such as blood vessels (arteries or veins), tissue lumen, lymphatic pathways, digestive tract including alimentary canal, respiratory tract, excretory system tubes, reproductive system tubes and ducts, body cavity tubes, etc.
  • Local administration or application of the drug(s) affords concentrated delivery of said drug(s), achieving tissue levels in target tissues not otherwise obtainable through other administration route.
  • Means for local drug(s) delivery to hollow tubes can be by physical delivery of the drug(s) either internally or externally to the hollow tube.
  • Local drug(s) delivery includes catheter delivery systems, local injection devices or systems or indwelling devices. Such devices or systems would include, but not be limited to, stents, coated stents, endolumenal sleeves, stent-grafts, liposomes, controlled release matrices, polymeric endoluminal paving, or other endovascular devices, embolic delivery particles, cell targeting such as affinity based delivery, internal patches around the hollow tube, external patches around the hollow tube, hollow tube cuff, external paving, external stent sleeves, and the like. See, Eccleston et al.
  • stents or sleeves or sheathes Delivery or application of the drug(s) can occur using stents or sleeves or sheathes.
  • An intraluminal stent composed of or coated with a polymer or other biocompatible materials, e.g. porous ceramic, e.g. nanoporous ceramic, into which the drug(s) has been impregnated or incorporated can be used.
  • stents can be biodegradable or can be made of metal or alloy, e.g. Ni and Ti, or another stable substance when intended for permanent use.
  • the drug(s) may also be entrapped into the metal of the stent or graft body which has been modified to contain micropores or channels.
  • lumenal and/or ablumenal coating or external sleeve made of polymer or other biocompatible materials, e.g. as disclosed above, that contain the drug(s) can also be used for local delivery.
  • polymeric materials include hydrophilic, hydrophobic or biocompatible biodegradable materials, e.g. polycarboxylic acids; cellulosic polymers; starch; collagen; hyaluronic acid; gelatin; lactone-based polyesters or copolyesters, e.g.
  • polylactide polyglycolide; polylactide-glycolide; polycaprolactone; polycaprolactone-glycolide; poly(hydroxybutyrate); poly(hydroxyvalerate); polyhydroxy(butyrate-co-valerate); polyglycolide-co-trimethylene carbonate; poly(diaxanone); polyorthoesters; polyanhydrides; polyaminoacids; polysaccharides; polyphospoeters; polyphosphoester-urethane; polycyanoacrylates; polyphosphazenes; poly(ether-ester) copolymers, e.g.
  • PEO-PLLA fibrin; fibrinogen; or mixtures thereof; and biocompatible non-degrading materials, e.g. polyurethane; polyolefins; polyesters; polyamides; polycaprolactame; polyimide; polyvinyl chloride; polyvinyl methyl ether; polyvinyl alcohol or vinyl alcohol/olefin copolymers, e.g. vinyl alcohol/ethylene copolymers; polyacrylonitrile; polystyrene copolymers of vinyl monomers with olefins, e.g.
  • styrene acrylonitrile copolymers ethylene methyl methacrylate copolymers; polydimethylsiloxane; poly(ethylene-vinylacetate); acrylate based polymers or coplymers, e.g. polybutylmethacrylate, poly(hydroxyethyl methylmethacrylate); polyvinyl pyrrolidinone; fluorinated polymers such as polytetrafluoethylene; cellulose esters e.g. cellulose acetate, cellulose nitrate or cellulose propionate; or mixtures thereof.
  • Stents are commonly used as a tubular structure left inside the lumen of a duct or vessel to relieve an obstruction. They may be inserted into the duct lumen in a non-expanded form and are then expanded autonomously (self-expanding stents) or with the aid of a second device in situ, e.g. a catheter-mounted angioplasty balloon which is inflated within the stenosed vessel or body passageway in order to disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen.
  • a catheter-mounted angioplasty balloon which is inflated within the stenosed vessel or body passageway in order to disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen.
  • the drug(s) may be incorporated into or affixed to the stent in a number of ways and utilizing any biocompatible materials; it may be incorporated into e.g. a polymer or a polymeric matrix and sprayed onto the outer surface of the stent.
  • a mixture of the drug(s) and the polymeric material may be prepared in a solvent or a mixture of solvents and applied to the surfaces of the stents also by dip-coating, brush coating and/or dip/spin coating, the solvent (s) being allowed to evaporate to leave a film with entrapped drug(s).
  • a solution of a polymer may additionally be applied as an outlayer to control the drug(s) release; alternatively, the drug may be comprised in the micropores, struts or channels and the adjunct may be incorporated in the outlayer, or vice versa.
  • the drug may also be affixed in an inner layer of the stent and the adjunct in an outer layer, or vice versa.
  • the drug(s) may also be attached by a covalent bond, e.g. esters, amides or anhydrides, to the stent surface, involving chemical derivatization.
  • the drug(s) may also be incorporated into a biocompatible porous ceramic coating, e.g. a nanoporous ceramic coating.
  • the drug(s) may elute passively, actively or under activation, e.g. light-activation.
  • the drug(s) elutes from the polymeric material or the stent over time and enters the surrounding tissue, e.g. up to ca. 1 month to 1 year.
  • the local delivery according to the present invention allows for high concentration of the drug(s) at the disease site with low concentration of circulating compound.
  • the amount of drug(s) used for local delivery applications will vary depending on the compounds used, the condition to be treated and the desired effect.
  • a therapeutically effective amount will be administered.
  • therapeutically effective amount is intended an amount sufficient to inhibit cellular proliferation and resulting in the prevention and treatment of the disease state.
  • local delivery may require less compound than systemic administration.
  • the invention relates to;
  • a method for preventing or treating macrophage, lymphocyte and/or neutrophil accumulation and/or smooth muscle cell proliferation and migration in hollow tubes such as arteries or veins, or increased cell proliferation or decreased apoptosis or increased matrix deposition in a mammal in need thereof for local administration comprising administering a therapeutically effective amount of an ACEI or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of intimal thickening in vessel walls comprising the controlled delivery from any catheter-based device or intraluminal medical device of a therapeutically effective amount of an ACEI or a pharmaceutically acceptable salt thereof.
  • the administration or delivery is made using a catheter delivery system, a local injection device, an indwelling device, a stent, a coated stent, a sleeve, a stent-graft, polymeric endoluminal paving or a controlled release matrix.
  • a drug-eluting or drug-releasing stent according to the present invention or a drug-delivery vehicle according to the present invention, or a drug delivery device or system according to the present invention for the manufacture of a medicament for local administration, for preventing or treating macrophage, lymphocyte and/or neutrophil accumulation and/or smooth muscle cell proliferation and migration in hollow tubes such as arteries or veins, or increased cell proliferation or decreased apoptosis or increased matrix deposition in a mammal in need thereof .
  • the invention concerns a method or use as described above for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, into a vein or artery, or actual treatment, in a subject in need thereof,
  • the invention relates to the prevention or reduction of vascular access dysfunction in hemodialysis, such as restenosis of the anastamosis of a dialysis access graft.
  • the treatment of intimal thickening in vessel walls is stenosis, restenosis, e.g. following revascularization or neovascularization, and/or inflammation and/or thrombosis.
  • an ACEI or pharmaceutically acceptable salt thereof for the manufacture of a drug- eluting or drug-releasing stent, a drug-delivery vehicle, drug delivery device or system according to the present invention.
  • Rats are dosed orally with placebo or an ACEI. Daily dosing starts 1-5 days prior to surgery and continues for and additional 28 days. Rat carotid arteries are balloon injured using a method described by Clowes et al. Lab. Invest. 1983; 49; 208-215. BrDU is administered for 24 hours prior to sacrifice. Sacrifice is performed at 9 or 21 days post-balloon injury. Carotid arteries are removed and processed for histologic and morphometric evaluation. In this assay, the ability of the compounds used according to the present invention can be demonstrated to significantly reduce neointimal lesion formation following balloon injury at 9 and 12 days. However, by 21 days the reduction in neotintimal lesion size is no longer statistically significant . Statistical analysis of the histologic data is accomplished using analysis of variance (ANOVA). A P ⁇ 0.05 is considered statistically significant.
  • a combined angioplasty and stenting procedure is performed in New Zealand White rabbit iliac arteries.
  • Iliac artery balloon injury is performed by inflating a 3.0 x 9.0 mm angioplasty balloon in the mid-portion of the artery followed by "pull-back" of the catheter for 1 balloon length.
  • Balloon injury is repeated 2 times, and a 3.0 x 12 mm stent is deployed at 6 atm for 30 seconds in the iliac artery. Balloon injury and stent placement is then performed on the contralateral iliac artery in the same manner.
  • a post-stent deployment angiogram is performed.
  • All animals are fed standard low-cholesterol rabbit chow, receive oral aspirin 40 mg/day daily as anti-platelet therapy and receive a compound used according to the present invention either dosed orally starting 1 - 3 days prior to stenting or a compound used according to the present invention that is delivered locally by coating it onto the stents.
  • BrDU is administered for 24 hours prior to sacrifice and at either seven or twenty-eight days after stenting, animals are anesthetized and euthanized and the arterial tree is perfused at 100 mmHg with lactated Ringer's for several minutes, then perfused with 10% formalin at 100 mmHg for 15 minutes.
  • the vascular section between the distal aorta and the proximal femoral arteries is excised and cleaned of periadventitial tissue.
  • the stented section of artery is embedded in plastic and sections are taken from the proximal, middle, and distal portions of each stent. All sections are stained with hematoxylin-eosin and Movat pentachrome stains or special immunohistochemical stains are used to allow identification of macrophages or lymphocytes or sections are specially processed to allow analysis of cell proliferation by quantification of BrDU positive cells.
  • the number of macrophages, lymphocytes or BrDU positive smooth muscle cells is quantitated and/ or computerized planimetry is performed to determine the area of the internal elastic lamina (IEL), external elastic lamina (EEL) and lumen.
  • the neointimal area and neointimal thickness is measured both at and between the stent struts.
  • the vessel area is measured as the area within the EEL.
  • Data are expressed as mean ⁇ SEM.
  • Statistical analysis of the histologic data is accomplished using analysis of variance (ANOVA) due to the fact that two stented arteries are measured per animal with a mean generated per animal. A P ⁇ 0.05 is considered statistically significant.
  • treatment with a compound used according to the present invention causes areduction in restenotic lesion formation at 7 and 28 days post-stenting. Both mean neointimal thickness and percent stent stenosis was reduced when arteries from valsartan- treated animals were compared with those from placebo-treated animals. In contrast, there is extensive smooth muscle proliferation, macrophage and lymphocyte accumulation and neointimal formation in placebo-treated animals at both 7 and 28 days.
  • LDLr-/- mice Male or female, 4- 6 week old LDL receptor deficient (LDLr-/-) or ApoE deficient (ApoE-/-) mice from Jackson Labs, Bar Harbor, ME., are divided into treatment groups of 18 animals each. All animals are fed a modified western diet containing 21% butter fat & 1.25 % cholesterol for up to 19 weeks. At 15 weeks, one group of animals of each strain is sacrificed to serve as pretreatment, baseline controls. The remaining three groups of LDLr-/- or ApoE-/- animals are dosed orally once a day with vehicle or benazepril, from week 15 through week 19 of diet administration.
  • mice are sacrificed at the end of week 19.
  • arterial samples included the entire aorta and its major branches including the innominate/brachiocephalic, right and left carotids, and the left subclavian.
  • Atherosclerosis extent is quantified for both the aorta and innominate arteries.
  • the number of inflammatory cellos (macrophages and lymphocytes) is quantitated within the arterial samples using special immunohistochemical stains.
  • aorta are pinned out and gross lesion extent, expressed as a percent of aorta covered by lesion, is determined.
  • Innominate and carotid arteries are embedded in parafin, cross-sectioned, and stained with hemotoxylin and eosin, elastin stains or special stains used to identify and quantitate the number of macrophages or lymphocytes.
  • Intimal lesion area is quantified using a computerized image analysis system.Treatment with a compound used according to the present invention reduces both atherosclerotic lesion extent and atherosclerotic lesion progression compared with placebo treatment.
  • angiogenesis has been shown to be a key mechanism in the development of restenotic lesions following stenting (Farb et al, Circulation 105:2974, 2002) the anti-angiogenic effect of benazepril or the hydrochloride thereof are involved in the inhibition of restenotic lesion formation in the rabbit stent model described in Section 2.
  • benazepril or the hydrochloride thereof administed both orally and locally via diffusion from a benazepril-coated stent markedly inhibited the angiogenic response at 7 and 28 days post- stenting.
  • the favorable effects of the compounds used according to the present invention can furthermore be demonstrated in a randomized, double-blind multi-center trial for revascularization of single, primary lesions in native coronary arteries.
  • the primary endpoint is in-stent late luminal loss (difference between the minimal luminal diameter immediately after the procedure and the diameter at six months).
  • Secondary endpoints include the percentage of in-stent stenosis of the luminal diameter and the rate of restenosis.
  • the degree of neointimal proliferation manifested as the mean late luminal loss in the group treated with a coated stent comprising a compound used according to the present invention versus the placebo group treated with a non-coated stent is determined, e.g.
  • a stent can be manufactured from medical 316LS stainless steel and is composed of a series of cylindrically oriented rings aligned along a common longitudinal axis. Each ring consists of 3 connecting bars and 6 expanding elements. The stent is premounted on a delivery system.
  • Benazepril (0.50 mg/ml) optionally together with 2,6-di-tert.-butyl-4- methylphenol (0.001 mg/ml), is incorporated into a polymer matrix based on a semi- crystalline ethylene-vinyl alcohol copolymer.
  • the stent is coated with this matrix.
  • a stent is weighed and then mounted for coating. While the stent is rotating, a solution of polylactide glycolide, 0.70 mg/ml of benazepril or a pharmaceutically acceptable salt thereof, dissolved in a mixture of methanol and tetrahydrofuran, is sprayed onto it. The coated stent is removed from the spray and allowed to air-dry. After a final weighing the amount of coating on the stent is determined.
  • phosphate buffer solution PBS
  • PEG polyethylene glycol
  • the stent pieces are incubated at 37° C. in a shaker.
  • the buffer and PEG solutions are changed daily and different assays are performed on the solution to determine the released active compounds concentrations.
  • Such assays can show a stable active compounds release from coated stents for more than 45 days.
  • stable active compounds release we mean less than 20% preferably less than 10% of variation of the drug release rate.
  • Controlled release techniques used by the person skilled in the art allow an unexpected easy adaptation of the required active compounds release rate.
  • the drug may be eluted from coating passively, actively or by light activation.
  • Release of the active compound in plasma can also be studied. 1 cm pieces of a coated stent are put into 1 mL of citrated human plasma (from Helena Labs.), which is in lyophilized form and is reconstituted by adding 1 mL of sterile deionized water. Three sets of stent plasma solutions are incubated at 37° C. and the plasma is changed daily. In a separate study, it is found that the active compounds in human plasma is stable at 37°C for 72 hours. Angiotensin converting enzyme assay are performed on the last piece of each sample to determine the active compounds activity (inhibition of Angiotensin converting enzymes). The inhibition of Angiotensin converting enzyme activity in vitro is measured.
  • Such assays can show that the activity of the active compound, i.e.benazepril, released from stent after 45 days is still 89% of that of the normal activity of the active compound. These assays can prove the unexpected high stability of our preferred active compounds in polymer coatings.
  • One hundred prospective dialysis patients, who undergo successful insertion of an indwelling, large bore catheter (coated according to the present invention), into a vein are selected for study. These patients are divided into two groups, and both groups do not differ significantly with sex, distribution of vascular condition or condition of lesions after insertion.
  • One group (about 50 patients) receives benazepril coated catheters (hereinafter identified as group 1), and another group (about 50 patients) receives non-coated catheters (hereinafter identified as group H).
  • groups may also be given a calcium antagonist, nitrates, anti-platelet agents, etc.
  • the comparative clinical data collected over the observation period of 6 months demonstrate the efficacy of 3 month use of coated catheters for the prevention or reduction of vascular access dysfunction in patients after catheter insertion.

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Abstract

L'invention concerne des systèmes de distribution de médicaments comprenant un inhibiteur d'enzyme convertissant une angiotensine (inhibiteur de ACE) ou un sel de celui-ci pharmaceutiquement acceptable qui permet de prévenir et de traiter des maladies prolifératives, en particulier, les maladies vasculaires. L'invention concerne également l'utilisation de ces systèmes de distribution de médicaments pour prévenir ou traiter la resténose chez des patients diabétiques et non diabétiques ou pour prévenir ou réduire un dysfonctionnement d'accès vasculaire ainsi que pour introduire ou réparer une dérivation, une fistule ou un cathéter à demeure chez un sujet qui en a besoin.
PCT/EP2003/006847 2002-06-28 2003-06-27 Utilisation de composes organiques WO2004002548A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107715203A (zh) * 2017-09-18 2018-02-23 上海交通大学医学院附属上海儿童医学中心 一种单支点磁动力驱动式离心泵

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EP0701802A1 (fr) * 1994-09-15 1996-03-20 Medtronic, Inc. Stent éluant un médicament
EP0734721A2 (fr) * 1995-03-30 1996-10-02 Advanced Cardiovascular Systems, Inc. Procédé pour incorporer des médicaments dans un composant polymère des endoprothèses autoexpansives
EP0875218A2 (fr) * 1997-04-15 1998-11-04 Advanced Cardiovascular Systems, Inc. Prothèses métalliques poreuses renfermant des substances actives
EP0897701A2 (fr) * 1997-08-11 1999-02-24 Advanced Cardiovascular Systems, Inc. Structure de stent avec revêtement polymère
WO1999055396A1 (fr) * 1998-04-27 1999-11-04 Surmodics, Inc. Revetement destine a liberer des agents bioactifs
EP1084721A2 (fr) * 1994-12-13 2001-03-21 Advanced Cardiovascular Systems, Inc. Film polymère pour envelopper un stent
US6287628B1 (en) * 1999-09-03 2001-09-11 Advanced Cardiovascular Systems, Inc. Porous prosthesis and a method of depositing substances into the pores
WO2002024247A1 (fr) * 2000-09-22 2002-03-28 Kensey Nash Corporation Protheses d'administration de medicaments et procedes d'utilisation
WO2002047739A2 (fr) * 2000-12-15 2002-06-20 Md3, Inc. Revetement de protection pour extenseur
WO2002047731A2 (fr) * 2000-12-12 2002-06-20 Scimed Life Systems, Inc. Compositions d'administration de medicaments et dispositifs medicaux contenant un copolymere bloc

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0701802A1 (fr) * 1994-09-15 1996-03-20 Medtronic, Inc. Stent éluant un médicament
EP1084721A2 (fr) * 1994-12-13 2001-03-21 Advanced Cardiovascular Systems, Inc. Film polymère pour envelopper un stent
EP0734721A2 (fr) * 1995-03-30 1996-10-02 Advanced Cardiovascular Systems, Inc. Procédé pour incorporer des médicaments dans un composant polymère des endoprothèses autoexpansives
EP0875218A2 (fr) * 1997-04-15 1998-11-04 Advanced Cardiovascular Systems, Inc. Prothèses métalliques poreuses renfermant des substances actives
EP0897701A2 (fr) * 1997-08-11 1999-02-24 Advanced Cardiovascular Systems, Inc. Structure de stent avec revêtement polymère
WO1999055396A1 (fr) * 1998-04-27 1999-11-04 Surmodics, Inc. Revetement destine a liberer des agents bioactifs
US6287628B1 (en) * 1999-09-03 2001-09-11 Advanced Cardiovascular Systems, Inc. Porous prosthesis and a method of depositing substances into the pores
WO2002024247A1 (fr) * 2000-09-22 2002-03-28 Kensey Nash Corporation Protheses d'administration de medicaments et procedes d'utilisation
WO2002047731A2 (fr) * 2000-12-12 2002-06-20 Scimed Life Systems, Inc. Compositions d'administration de medicaments et dispositifs medicaux contenant un copolymere bloc
WO2002047739A2 (fr) * 2000-12-15 2002-06-20 Md3, Inc. Revetement de protection pour extenseur

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107715203A (zh) * 2017-09-18 2018-02-23 上海交通大学医学院附属上海儿童医学中心 一种单支点磁动力驱动式离心泵

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