WO2007028053A2 - Methodes de traitement et de prevention de troubles cardiaques - Google Patents

Methodes de traitement et de prevention de troubles cardiaques Download PDF

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Publication number
WO2007028053A2
WO2007028053A2 PCT/US2006/034277 US2006034277W WO2007028053A2 WO 2007028053 A2 WO2007028053 A2 WO 2007028053A2 US 2006034277 W US2006034277 W US 2006034277W WO 2007028053 A2 WO2007028053 A2 WO 2007028053A2
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inhibitor
molecule
therapeutic
cardiac
therapeutic molecule
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PCT/US2006/034277
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WO2007028053A3 (fr
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William R. Baumbach
Hariharan Shankar
Oded Ben-Joseph
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X-Cell Medical Incorporated
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Publication of WO2007028053A3 publication Critical patent/WO2007028053A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • A61L2300/43—Hormones, e.g. dexamethasone
    • 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
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/622—Microcapsules
    • 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
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/626—Liposomes, micelles, vesicles

Definitions

  • the scar region does not contain sufficient cardiomyocytes, vascular cells, fibroblasts, and/or nerve cells to sustain the normal pattern of depolarization propagation and/or contraction for efficiently pumping of blood.
  • Reduced blood flow associated with clinically measurable indications such as decreased contraction force, decreased ejection fraction, increased left ventricular (LV) volume, and increased LV wall stress, are the frequent sequela of AMI.
  • Drug treatment includes delivery of medications intended to reverse the causes of AMI such as thrombolytics, known heart medications such as beta blockers, antihypertensive medications such as ACE inhibitors, or anti-platelet medications such as aspirin.
  • Gene therapy includes, the local or systematic delivery of DNA or viruses encoding genes intended to induce cardiac angiogenesis or myogenesis.
  • Cell therapy includes surgically introducing cells directly into the heart muscle; injecting cells from inside the heart via catheter-mounted syringes using standard interventional techniques; introducing cells into a coronary artery, whence they would be carried by the blood downstream into the injured zone; or introducing cells intravenously.
  • Other techniques include, for example, the enhancement of the healing properties of blood through super- oxygenization or other ex-vivo blood treatment.
  • Cell therapy approaches to AMI present many challenges including, for example, the inefficient injection of cells whereby only a few of the injected cells remain at the site of injection; the poor survival of transplanted cells; the choice or selection of cell type that is the most beneficial; the expensive and time consuming processes for harvesting and ex vivo expansion of autologous cells; and the complex clinical procedures required to introduce these cells into the heart of a patient.
  • gene therapy is an impractical approach due to low efficiency of delivery, the inability to precisely control dose, potential toxicity in non-target tissues, and difficulties in choosing appropriate gene constructs.
  • the first, anti- thromlotic therapy reduces or eliminates coronary artery thrombi that occlude the coronary arteries and cause hypoxia.
  • fibrinolytic agents such as intravenous streptokinase or tissue plasminogen activator
  • anti-coagulant agents such as aspirin, heparin, and factor Xa inhibitors
  • platelet inhibitors GP Ilb/IIIa receptor inhibitors
  • abciximab and tirofiban and other inhibitors of platelet aggregation such as clopidogrel (Antman and Van de Werf, Circulation, 109:2480-2486, 2004).
  • treatment regimens typically consisting of combinations of the above therapeutic agents, both to dissolve occluding thrombi which have formed in coronary arteries (often being the root cause of myocardial infarctions) and for the prevention of subsequent thrombi during and after percutaneous transluminal coronary angioplasty (PTCA) procedures and stent implantation.
  • PTCA percutaneous transluminal coronary angioplasty
  • the second category of drug treatments for AMI is the subject of the present invention, called pharmacological modulators of AMI (PMAMI).
  • PMAMI pharmacological modulators of AMI
  • This consists of therapies intended to reduce the size and extent of myocardial damage due to coronary artery occlusion, prevent or ameliorate injury due to reperfusion of the infarcted zone, reduce post-reperfusion ventricular remodeling, enhance regeneration of damaged tissue, and/or reverse secondary diseases resulting from AMI such as cardiac fibrosis.
  • Such therapies target specific modes of action such as anti-apoptosis, modulation of differentiation, cardio-protection, or angiogenesis.
  • Drug treatments from this category that are intended to ameliorate the effects of AMI. These are usually administered in conjunction with an anti-thrombosis drug regimen.
  • the present in disclosure provides methods and compositions for treating cardiac disorders.
  • the invention provides a method for treating a cardiac disorder in a patient by locally administering to the patient a therapeutic molecule encapsulated in a microparticle.
  • the invention provides an implantable device comprising a therapeutic molecule encapsulated in a microparticle, wherein the therapeutic molecule is capable of treating a cardiac disorder.
  • the therapeutic molecule is an estrogen (e.g., 17 ⁇ -estradiol), estrogen receptor agonists, a prostaglandin EP 3 receptor agonist, a caspase inhibitor, a potassium channel opener, a nitric oxide donor (e.g., nicorandil), an aldosterone receptor antagonist (e.g., spironolactone and eplerenone), a compound that block platelet-endothelial cell adhesion molecules (e.g., PECAM-I), IL-6/sIL-6R or IL-6, a GP130 agonist, an IL- 18 antagonist, a glycosaminoglycan analog (e.g., dextran sulfate), a plasminogen activator inhibitor- 1 antagonist, relaxin, clusterin, a p38 MAP kinase inhibitor (e.g., SB203580), a cardiac regeneration factor (e.g.
  • an estrogen e.g., 17 ⁇ -estradiol
  • IGF-I insulin-like growth factor 1
  • HGF hepatocyte growth factor
  • GDF- 15 growth- differentiation factor- 15
  • HGF hepatocyte growth factor
  • HGF hepatocyte growth factor
  • GDF- 15 growth- differentiation factor- 15
  • HNF-I hypoxia inducible factor- 1
  • TNF- ⁇ inhibitor a CD- 147 inhibitor
  • PDGF agonist a neutrophil gelatinase-associated lipocalin (NGAL) inhibitor.
  • NGAL neutrophil gelatinase-associated lipocalin
  • Cardiac disorders amenable to treatment by this method include, for example, acute myocardial infarction, a chronic ischemic condition, reperfusion injury, chronic heart disease, vulnerable plaques, and cardiac fibrosis.
  • the therapeutic molecule is locally administered by any appropriate route or using any appropriate technique including, for example, intravenous or intra-arterial injection, during percutaneous transluminal coronary angioplasty (including delivery using a PCTA balloon), and via an implantable device (e.g., a stent).
  • the therapeutic molecule may be present as a free base, salt, or bound as a conjugate to another molecule.
  • the therapeutic molecule is encapsulated in a liposome or a polymeric microsphere.
  • Useful polymeric microspheres include those produced using an aqueous/aqueous emulsion system.
  • the microspheres contain dextran, PEG, or PLGA.
  • cardiac disorders is meant any disease or disorder of the cardiac tissue, particularly the cardiac muscle, associated with or caused by an ischemic condition, reduction in blood flow, physical trauma (e.g., associated with injury or a surgical procedure). Cardiac disorders include, but are not limited to, AMI, acute or chronic ischemic conditions, reperfusion injury, chronic heart disease (CHD), vulnerable plaques (VP), and cardiac fibrosis.
  • coronary tissue is meant the cardiac muscle, consisting of fused cardiomyocytes, and ancillary cell types whose presence is critical, but are found in much smaller numbers. Examples of such cell types are vascular cells (including endothelial and smooth muscle cells), fibroblasts and other connective tissue cells, neurons and other types of nerve cells, and progenitor cells such as cardiac stem cells (Beltrami et al., Cell, 114:763-776, 2003). Coronary tissue also includes the extracellular matrix and associated molecules surrounding the foregoing cellular components.
  • PTCA percutaneous transluminal coronary angioplasty
  • an “effective amount,” in reference to a therapeutic molecule or composition, is meant an amount of a molecule, compound or composition, alone or in a combination according to the invention, required to affect a therapeutic response (i.e., treatment of cardiac disorders).
  • the effective amount of active compound(s) used to practice the present invention for therapeutic treatment of cardiac disorders varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending medical professional will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount.
  • treating is meant administering a therapeutic molecule for the purpose of improving the condition of a patient by reducing, alleviating, or reversing at least one adverse effect or symptom.
  • FIGURE 1 is a schematic diagram showing components of a system for the treatment of myocardial infarction and its effects.
  • the formulated treatment is introduced by any convenient route (e.g., injection through a catheter into the artery feeding the infarcted zone and/or eluted from a stent placed in the artery feeding the infarcted zone).
  • Targets sites for therapy include the infarcted zone and surrounding border regions that are served by the coronary artery(ies) that had previously been occluded.
  • the present invention provides methods and compositions for treating coronary tissue damaged as a result of a cardiac disorder such as ischemia, AMI, or reperfusion injury.
  • the treatment may be administered by any appropriate method including, for example, via an implantable stent, via a drug-delivery PTCA balloon, as a locally injected bolus during PTCA, or via intracoronary or intravenous injection.
  • Tissue in areas surrounding the scar border regions is reported to be progressively more functional and thus more capable of generating, supporting, and incorporating new cells that form or support functional tissue.
  • Tissue that has undergone ischemia, but has not yet undergone apoptosis, necrosis, or scarring is another target for therapy insofar as timely treatment (e.g. during a PTCA procedure taking place as soon as possible after the onset of symptoms), could slow or reverse the decline of this tissue via ischemia or reperfusion injury.
  • therapeutic molecules that may be used to reduce and/or reverse the damage caused by AMI or another cardiac disorder. Any of these therapeutics may be used in accordance with the principles of this disclosure.
  • useful therapeutic molecules include, for example: estrogen (e.g., 17 ⁇ -estradiol), estrogen receptor agonists, prostaglandin EP 3 receptor agonists, caspase inhibitors, potassium channel openers, nitric oxide donors (e.g., nicorandil), aldosterone receptor antagonists (e.g., spironolactone and eplerenone), compounds that block platelet-endothelial cell adhesion molecules (e.g., PECAM-I), IL-6/sIL-6R or IL-6, GP130 agonists, IL-18 antagonists, glycosaminoglycan analogs (e.g., dextran sulfate), plasminogen activator inhibitor-1 antagonists, relaxin, clusterin, inhibitors of p38 MAP kinas
  • estrogen e.g
  • IGF-I insulin-like growth factor 1
  • HGF hepatocyte growth factor
  • GDF- 15 growth-differentiation factor- 15
  • HGF-I insulin-like growth factor 1
  • HGF hepatocyte growth factor
  • GDF- 15 growth-differentiation factor- 15
  • HNF-I hypoxia inducible factor- 1
  • TNF- ⁇ inhibitor a CD- 147 inhibitor
  • CD- 147 inhibitor a PDGF agonist
  • NGAL neutrophil gelatinase-associated lipocalin
  • 17 ⁇ -estradiol (estrogen, E2) is an endogenous steroid hormone found in men and women, and is the predominant female sex hormone.
  • the anti-atherogenic properties of estrogen have been known for many years. Numerous clinical and experimental studies have demonstrated that estrogen improves the lipid profile and has direct protective effects on the vasculature (Barrett-Connor, Circulation, 95:252-264, 1997; Stampfer et al, N Engl J Med, 325:756-762, 1991; Mendelsohn and Karas, N Engl J Med, 340:1801-1811, 1999). Gender differences in cardiovascular disease are well recognized (Farhat et al, FASEB J, 10:615-624, 1996).
  • Cardiovascular disease is rare in premenopausal women and the Framingham Study suggested that prior to menopause the incidence of ischemic heart disease in women is considerably less than that of males (Lerner and Kannel, American Heart Journal, 111:383-390, 1986).
  • the lower mortality from ischemic heart disease among premenopausal women is largely due to endogenous circulating estrogens and, when estrogen production subsides following the menopause, there is a sharp increase in mortality (Colditz et al, NEnglJMed, 316:1105-1110, 1987).
  • Premature menopause from bilateral oophorectomy is also associated with an increase in coronary artery disease (Barrett-Connor and Bush, JAMA, 265:1861-1867).
  • IVUS intravascular ultrasound
  • ACS acute coronary syndrome
  • the therapeutic molecule are delivered such that regions of the coronary arteries containing VP will receive an effective dose of the molecule in addition to the target infarcted region of the heart.
  • the route of administration could be either systemic (whether oral or parenteral) or, as in the present invention, delivered locally to the site of action.
  • local delivery of the therapeutic molecule(s) is the most useful route of administration.
  • the coronary artery whose occlusion is the root cause of AMI or 0 other occlusive ischemic injury provides blood directly and specifically to the site of damage.
  • the effective dose is much reduced for local administration because the target tissue for the therapeutic molecule (diseased portion of the heart) is less than 1% of the body mass served by systemic drug delivery.
  • PTCA vascular endothelial coronary artery graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft graft
  • the therapeutic molecule is delivered from coatings on indwelling devices, such as stents, that are implanted during PTCA, and elute the therapeutic molecule into the coronary artery lumen and hence directly into the infarcted zone.
  • the therapeutic molecule instead may be delivered via other devices such as drug-delivery balloons into the wall or lumen of the coronary artery, either alone, in microparticles or nanoparticles, or in other controlled release formulations.
  • the therapeutic molecule may be delivered via direct injection into the infarcted region of the cardiac wall from an intramyocardial injection catheter (Boston Scientific Corporation StilettoTM endocardial direct injection catheter system; Marshall et al, Molecular Therapy, 1:423-429, 2000; Karmarkar et al, Magnetic Resonance in Medicine, 51 : 1163-1172, 2004).
  • an intramyocardial injection catheter Boston Scientific Corporation StilettoTM endocardial direct injection catheter system
  • Marshall et al Molecular Therapy, 1:423-429, 2000
  • Karmarkar et al Magnetic Resonance in Medicine, 51 : 1163-1172, 2004.
  • the therapeutic molecule used for treating a cardiac disorder are locally administered by any appropriate method.
  • Methods for administration include, for example, intravenous or intra-arterial injection, a bolus injection via a catheter during PCTA, a coated or impregnated implantable device such as a stent, and injection directly into the target tissue, i.e. in and around the infarcted region of the heart.
  • FIGURE 1 is a schematic showing one example of administration by intra-arterial injection.
  • implantable devices and stents that may be used in the present invention include, but are not limited to, those described in U.S. Patent Nos. 6,709,379, 6,273,913, 5,843,172,
  • therapeutic molecules upstream of the site of AMI may be accomplished through the use of standard interventional devices including, but not limited to, drug- eluting stents, drug-delivery balloons, or PTCA catheters.
  • the molecules are ultimately delivered into the lumen of the coronary artery whose occlusion resulted in hypoxia and infarction.
  • Therapeutic molecules may be formulated in a variety of conventional pharmaceutical carriers including saline, emulsifiers, or microparticles.
  • the molecules may be coated on a coronary stent either alone or embedded in polymers or other natural or synthetic carriers, for controlled elution into the lumen of the coronary artery.
  • the therapeutic molecules will be taken via the coronary arterial system into the region of the heart that was subject to damage by ischemia.
  • therapeutic molecules are delivered via one or both of two methods during the same interventional procedure, typically but not limited to PTCA.
  • a first dose is administered via catheter-based injection of therapeutic molecules (formulated in one or more ways, such as in saline, in a pharmaceutical excipient, or encapsulated in microparticles or nanoparticles) directly into the coronary arterial lumen, in the region of PTCA and stent placement, using the balloon catheter itself or a separate catheter (Guzman et al, Circulation, 94:1441-1448, 1996).
  • the second administration of the same or a different therapeutic molecule is via a coating on the coronary stent.
  • At least one therapeutic compound is embedded in a degradable or non- degradable polymer or natural coating, or alternatively formulated as microparticles which are themselves embedded in a polymeric or other type of coating, and subsequently these coatings are applied to the surface of the coronary stent.
  • Therapeutic molecules elute from the coating into the lumen of the coronary artery either by diffusion from the polymeric coating or by degradation of the coating, thus releasing the therapeutic molecules.
  • the therapeutic molecule in a liquid formulation is loaded into devices such as a triple-lumen balloon catheter (Infiltrator, manufactured by Interventional Technology; Kaul et al, Circulation, 107:2551-2554, 2003), or a channel balloon catheter (Boston Scientific) from which the drug is injected into the arterial wall, and thence released into the arterial lumen, from where it flows into the coronary infarcted zone.
  • devices such as a triple-lumen balloon catheter (Infiltrator, manufactured by Interventional Technology; Kaul et al, Circulation, 107:2551-2554, 2003), or a channel balloon catheter (Boston Scientific) from which the drug is injected into the arterial wall, and thence released into the arterial lumen, from where it flows into the coronary infarcted zone.
  • the therapeutic molecules may be formulated in a variety of ways depending upon the route of administration.
  • any standard for direct intravenous or intra-arterial injection any standard for direct intravenous or intra-arterial injection.
  • compositions according to the present invention may also comprise binding agents, filling agents, lubricating agents, disintegrating agents, suspending agents, preservatives, buffers, wetting agents, and other excipients.
  • filling agents are lactose monohydrate, lactose hydrous, and various starches
  • binding agents are various celluloses, preferably low-substituted hydroxylpropyl cellulose, and cross-linked polyvinylpyrrolidone
  • an example of a disintegrating agent is croscarmellose sodium
  • examples of lubricating agents are talc, magnesium stearate, stearic acid, and silica gel.
  • suspending agents are hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methylcellulose, acacia, alginic acid, carrageenin, and other hydrocolloides.
  • preservatives which control microbial contamination
  • examples of preservatives are potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride.
  • therapeutic molecules may be encapsulated in microparticles or nanoparticles, typically between lOOnm and lOOOnm in diameter, that serve to delay release of the molecules into the surrounding serum or tissue.
  • microparticles or nanoparticles containing therapeutic molecules may be taken up by cells in the region of the target tissue, thus improving the efficiency of delivery and/or prolonging the availability of the therapeutic molecule.
  • microparticles or nanoparticles examples are poly lactic acid, poly(D,L-lactide-co-glycolide) (PLGA), liposomes, and dextran (Jiang et al, Adv Drug Deliv Rev, 57:391-410, 2005; BaIa et al, Crit Rev Ther Drug Carrier Syst, 21:387-422; Kayser et al, Curr Pharm Biotechnol, 6:3-5, 2005; U.S. Patent 6,805,879; U.S. Patent Application 20040191325).
  • PLGA poly(D,L-lactide-co-glycolide)
  • PMAMI can be mixed with polymers (co-dissolved or emulsified) and coated on such devices by spraying or dipping.
  • the polymer is typically either bioabsorbable or biostable.
  • Bioabsorbable polymers break down in the body and is not present sufficiently long after implantation to cause an adverse local response.
  • Bioabsorbable polymers are gradually absorbed or eliminated by the body by hydrolysis, metabolic process, bulk erosion, or surface erosion.
  • Examples of bioabsorbable materials include but are not limited to polycaprolactone (PCL), poly-D, L-lactic acid (DL-PLA), poly-L-lactic acid (L-PLA), poly(lactide-co- glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-covalerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolic acid-cotrimethylene carbonate), polyphosphoester, polyphosphoester urethane, poly (amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), copoly(etheresters), polyalkylene oxalates, polyphosphazenes, poly
  • Biomolecules such as heparin, fibrin, fibrinogen, cellulose, starch, and collagen are typically also suitable.
  • biostable polymers include parylene, polyurethane, polyethylene, polyethlyene teraphthalate, ethylene vinyl acetate, silicone and polyethylene oxide (PEO).
  • Therapeutic molecules may also be coated on stents or other devices on which grooves, holes, a micropores or nanopores have been engineered into the surface, such that the formulation to be delivered is sequestered within the pores and released slowly into the lumen of the coronary artery after the device has been implanted.
  • EXAMPLE 1 Treatment of AMI in a Porcine Model Female or castrated male juvenile hybrid farm swine, 10-16 weeks old and weighing 35 +/- 10 kg, are utilized. Fasting is conducted prior to induction of anesthesia for device deployment, sample collection for serum chemistry and necropsy. Food, but not water, is withheld the morning of the procedure. To prevent or reduce the occurrence of thrombotic events, anti-platelet pharmacological therapy consisting of clopidogrel (75 mg per os [PO]) and acetylsalicylic acid (ASA; 325 mg, PO) is administered daily, with the exception of the implantation day, beginning at least 3 days prior to the scheduled procedure date.
  • clopidogrel 75 mg per os [PO]
  • ASA acetylsalicylic acid
  • Prophylactic antibiotic duplocillin LA ® 0.05 ml/kg is given intramuscular [IM].
  • Intravenous fluid therapy is initiated and maintained throughout the procedure with saline (1 ml/kg/hour). The rate may be increased to replace blood loss or low systemic blood pressure.
  • the animal is placed in dorsal recumbency, and hair removed from access areas.
  • Animals are kept warm throughout the preparation and the procedure. Limb-leads are placed, and electrocardiography established.
  • the access site is prepared with chlorexidine, 70% isopropyl alcohol and proviodine, and the area is appropriately draped to maintain a sterile field.
  • the femoral artery is accessed using a percutaneous approach. Alternatively, an incision will be made in the inguinal region to expose the femoral artery.
  • An infiltration of bupivacain 0.5% (5 ml IM) on the femoral access site is performed to achieve local anesthesia and manage pain after surgery.
  • a 7F or 8F- introducer arterial sheath is introduced and advanced into the artery.
  • the sheath is connected to a pressure transducer for monitoring arterial pressure.
  • An initial bolus of heparin 400 U/kg IV
  • ACT performed approximately 5 minutes later. IfACT is under 300 seconds, an additional 100 to 400 U/kg of heparin is given. ACT is tested approximately every 20 minutes.
  • a 7F guide catheter is inserted through the sheath and advanced to the appropriate location. After placement of the guide catheter, angiographic images of the coronary vessels are obtained with contrast media to identify the proper location for the deployment site. Quantitative angiography will be performed after injection of nitroglycerin 500 ⁇ g intracoronary [IC] to determine the appropriate vessel size for implantation and/or occlusion.
  • a segment of artery ranging from 2.6 mm to 3.5 mm mid-segment diameter is chosen, and a 0.014" guidewire will be inserted into the chosen artery.
  • QCA is performed to accurately document the reference diameter for balloon angioplasty and/or stent placement.
  • Each stent delivery system or balloon catheter is prepared by applying vacuum to the balloon port; contrast/flush solution (50:50) is then introduced by releasing the vacuum.
  • contrast/flush solution 50:50
  • the appropriately sized balloon will be introduced into the appropriate artery by advancing the balloon catheter through the guide catheter and over the guidewire to the
  • the balloon is then inflated at a steady rate to a pressure sufficient to target a balloon:artery ratio of 1.1:1 (acceptable range of about 1.05:1 to about 1.15:1) and held for 60 minutes.
  • a contrast injection is performed during full inflation to demonstrate occlusion with the balloon.
  • monitoring is performed for heart functions, and other monitoring parameters include isoflurane level, SaO 2 , pulse rate, blood pressure, temperature, O 2 flow, and tidal volume.
  • vacuum is applied to the inflation device in order to deflate the balloon. Complete balloon deflation is verified with fluoroscopy.
  • a coated stent containing a therapeutic molecule is placed (target balloon:artery of about
  • the therapeutic molecule is administered through the balloon catheter (or other injection catheter) into the region of the balloon occlusion.
  • a drug delivery balloon is utilized to introduce the therapeutic molecule into the region of the balloon occlusion.
  • Another embodiment administers a bolus injection via catheter and simultaneously provides the same, similar, or complementary therapeutic molecule in a stent coating, which elutes over a period of hours, days, or weeks.
  • the animals are placed in a pen and monitored during recovery from anesthesia for four to five hours following the procedure. Medical treatment including analgesia will be given as needed. Animals in apparent severe pain or distress, as determined by clinical observation and consultation with the facility veterinarian will be euthanized. ASA (325 mg/day PO) and clopidogrel (75 mg/day PO) are administered for the duration of the study. Moribidity/mortality checks and clinical observations are performed twice daily.
  • the animals are analyzed by MRI for LV function. Animals are then euthanized, the heart is excised, and the atria and great vessels are trimmed away. Next, the RV free wall is trimmed away from the LV (with septum intact). The LV is blotted dry, weighed and indexed by body weight
  • the LV is sectioned transversely into five equal segments from apex to base, immersed in 10% buffered formalin, dehydrated at room temperature through ethanol series, and embedded in paraffin.
  • Infarct length is measured along the endo- and epicardial surfaces from each of the five LV segments (three sections per segment).
  • Total LV circumference is measured along the endo- and epicardial surfaces from each of the five LV segments (three sections per segment).
  • Infarct size is determined as percentage of total LV circumference. The ratio of scar length to body weight is calculated to exclude the potential influence of differences in body weight on infarct size.
  • Remodeling parameters The maximum longitudinal dimension is measured before left ventricular sectioning.
  • the LV is sectioned transversely into five equal segments from apex to base, and the maximum short-axis dimension after sectioning is measured.
  • Outlines of the section rings and infarct scars are made on plastic overlays.
  • "Thinning" ratio ratio of average thickness of infarcted wall to average thickness of the normal wall
  • the maximum depth of infarct scar bulge in millimeters is measured on the contoured sections as an index of regional dilation. Bulging normalized to body weight is calculated.
  • Ventricular volumes are computed from the short-axis areas and the long-axis length by the modified Simpson's rule, as used for echocardiographic studies during remodeling (Jugdutt et al, Circulation, 89:2297-2307, 1994).
  • volume collagen fraction is calculated as the sum of all connective tissue areas divided by the total area of the image.
  • Therapeutically effective amounts of a therapeutic molecule are administered via intra-arterial injection, intravenous injection, PTCA catheter, PTCA balloon, or indwelling device such as a stent. It is contemplated that the therapeutic molecule is administered using one or more of these methods, e.g. in a coating on a coronary stent and additionally injected through a PTCA catheter. Thus, in one embodiment, the therapeutic molecule is delivered both immediately by injection and over a prolonged period by elution from a stent. Alternatively, a therapeutically effective dose is administered solely by intra-arterial injection, but formulated in particles that in themselves deliver the therapeutic molecule over a prolonged period of time.
  • the local drug delivery devices of this invention contain between about 0.001 mg and about 1.0 mg of a therapeutic molecule.
  • intra-arterial or intravenous injection typically deliver between about 0.001 mg and about 10 mg of a therapeutic molecule.
  • the exact dosage varies by disease severity, route of administration and the particular therapeutic molecule used.
  • the therapeutic agents disclosed herein may be formulated along with pharmaceutically acceptable carriers and/or polymers, e.g. polyglycolic acid (PGLA), polylactic acid (PLA), PGLA-PLA copolymers, polysaccharides, and/or phospholipids, as spherical particles with diameters of about 100 nm to about 1,000 nm. Such particles are referred to commonly and interchangeably as either microparticles and/or nanoparticles.
  • Many particles in this size range have the capability of entering living cells, and thus delivering the formulated therapeutic agent into cells of the target tissue.
  • delivery of the therapeutic agent is controlled in several ways: by the elution of the therapeutic agent via diffusion from the particle into the blood; by sequestration and subsequent release of the particles containing therapeutic agents in cells and extracellular matrix upstream of and in the target tissue; and by release of the therapeutic agent via biological breakdown, or degradation, of the particle itself. Details of such processes are described below ("Device Coatings").
  • Microparticles containing therapeutic agents may be produced by a variety of methods known in the art (Lemke and Hernandez-Trejo, Curr Pharm Biotechnol, 6:3-5, 2005), e.g. the emulsion-solvent evaporation technique (Sengupta et al, Nature, 436:568- 572, 2005) or the stable aqueous/aqueous emulsion system (U.S. Patent 6,805,879). Different techniques are chosen based on the chemical, electrical, and hydrophobic properties of a given therapeutic agent.
  • Microparticles are administered by themselves suspended in an appropriate solvent/buffer system (Jiang et al, Adv Drug Deliv Rev, 10:391-410, 2005), by intra-arterial injection (Guzman et al, Circulation, 94:1441-1448, 1996), by PTCA balloon delivery (Kaul et al, Circulation, 107:2551-2554, 2003), or any suitable method.
  • microparticles are incorporated into a device coating such as those described herein.
  • Microparticles themselves may incorporate more than one layer, with each layer possessing unique characteristics with regard to formulation and delivery of therapeutic agents.
  • any suitable microparticle known in the art may be used to encapsulate the therapeutic molecules in accordance with this disclosure.
  • Stable aqueous/aqueous emulsion systems such as those described in U.S. Patent 6,805,879, are particularly useful for microparticle formulations.
  • the basis of this system is the selection of two aqueous polymer solutions (a dispersed polymer solution and a continuous polymer solution) that are immiscible with each other, and, optionally, a surface modifier that is charged and relatively immiscible with the first two.
  • the dispersed polymer solution is dispersed as microparticles within the continuous polymer solution by mixing under conditions of high shear stress. The amount shear stress controls the size of the microparticles.
  • the surface modifier is added in low amounts relative to the first two in order that it becomes enriched in at the surface of the microparticles formed by the dispersed polymer solution.
  • the charged nature of the surface modifier prevents aggregation of the microparticles.
  • the microparticles are lyophilized for preservation and storage.
  • Therapeutic solutions and device coatings are made from the lyophilized micropaticles.
  • Hydrophilic polymers useful for the continuous and/or dispersed phases include, for example, dextran (MW 100,000 - 1,000,000), PEG, PEG/PLGA mixtures, and sodium alginate.
  • Useful surface modifiers include, for example, phospholipids.
  • the therapeutic molecules used in accordance with the principles of this disclosure are associated with the implantable device by suitable methods known in the art.
  • the therapeutic molecules are attached to the device by way of a polymeric coating having known and controllable release characteristics, being biocompatible when implanted in animals and humans, and being non-thrombogenic when in contact with blood and the vascular system.
  • the reactants and reaction conditions used to generate the polymer compositions disclosed herein may be modified to alter the properties of the final polymer composition.
  • properties such as the diffusion coefficients (e.g., the rate at which the therapeutic molecules are able to diffuse through the polymer matrix), the rate of degradation of one or more of the polymer components, and the rate of the release of the therapeutic molecules are manipulated by altering the reaction conditions and reagents, and hence the final polymer properties, used to generate the coating polymers.
  • biostable coatings Two major classes of polymeric coatings may be used with implantable devices: biostable (non-erodable) coatings; and bioabsorbable (biodegradable) coatings.
  • biostable coatings are fluorosilicone, silicone co-polymers, polyethylene glycol (PEG), ⁇ oly(butyl methacrylate), poly(ethylene-co-vinyl acetate), polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, polyacrylamide, polyacrylic acid, polyhydroxyethyl methacrylate, polyethylene oxide.
  • bioabsorbable coatings are polyglycolic acid (PGLA), polylactic acid (PLA), PGLA-PLA copolymers, polysaccharides, and phospholipids.
  • therapeutic agents may be applied directly to implantable devices without polymeric carriers, where the surface of the device is equipped with holes, crevices, micropores, or channels in which the therapeutic agents are sequestered to varying degrees, thus allowing controlled release in vivo.
  • biostable coatings Delivery of therapeutic molecules from biostable coatings occurs via diffusion from the surface and/or interior of the coating into surrounding tissue, interstitial space, or vascular lumen.
  • hydrolytic degradation of the polymeric coating is an additional mechanism for release of the therapeutic agent, whereby metabolism of the polymeric coating by endogenous enzymes may also play a role
  • hydrolytic degradation Important factors influencing hydrolytic degradation include water permeability, chemical structure, molecular weight, morphology, glass transition temperature, additives, and other environmental factors such as pH, ionic strength, site of implantation, etc.
  • the duration of sustained delivery can be adjusted from few days up to one year by a person of ordinary skill in the art through proper selection of polymer and fabrication method.
  • preparation of coated implantable devices is accomplished by dissolving the dried polymer in a suitable solvent and spin-coating, dipping, or spraying the medical device, typically using, for example, a 5 wt % in 2-propanol solution of the polymer.
  • suitable solvents for coating the medical devices will typically depend on the particular polymer as well as the volatility of the solvent.
  • One method of modulating the properties of the polymer compositions is to control the diffusion coefficient of the one or more polymer coating layers.
  • the diffusion coefficient relates to the rate at which a compound diffuses through a coating matrix.
  • One method for coating a local delivery device includes sequentially applying a plurality of relatively thin outer layers of a coating composition comprising a solvent mixture of polymeric silicone material, a crosslinking agent, and one or more of the therapeutic agents (see, for example, U.S. Patent No. 6,358,556).
  • the polymeric coatings are cured in situ and the coated, cured prosthesis is sterilized in a step that includes pretreatment with argon gas plasma and exposure to gamma radiation, electron beam, ethylene oxide, and/or steam.
  • the polymeric coating is applied as a mixture, solution or suspension of polymeric material and one or more of the therapeutic molecules is dispersed in an organic vehicle or a solution or partial solution of such agents in a solvent or vehicle for the polymer and/or the therapeutic molecules.
  • the various therapeutic agents are placed within different polymer layers.
  • the therapeutic molecules are dispersed in a carrier material which is variously the polymer, a solvent, or both.
  • the coating is applied sequentially in one or more relatively thin layers.
  • the coating is further characterized as an undercoat and a topcoat. The coating thickness
  • the coating on the medical device includes one or more base coatings and a top coating (see, for example, U.S. Patent No. 6,287,285).
  • linking agents are used to encapsulate and/or link the therapeutic molecule to the polymer matrix or link the various components of the polymer matrix together (e.g., the different polymers that comprise the various coating layers, the bioactive agents in the polymer matrices etc.).
  • Such linking agents include, for example, polyester amide (PEA), polyethylene imine (PEI), avidin-biotin complexes, photolinking, functionalized liposomes, microsponges and microspheres.
  • therapeutic molecules are modified by chemically linking them to a high molecular weight, water-soluble polymer carrier.
  • This modified therapeutic molecule is termed herein an agent-polymer conjugate.
  • the agent-polymer conjugate is that the chemical linkage of the agent to the water-soluble polymer can be manipulated to hydro lytically degrade, thereby releasing biologically active agent into the environment in which they are placed.
  • the agent-polymer conjugate is incorporated into a controlled release matrix, formulated from a second biocompatible polymer.
  • the controlled-release matrix releases the agent-polymer conjugate which further releases free agent (therapeutic) molecules to treat the area of the tissue in the immediate vicinity of the polymer.
  • the agent-polymer conjugates also diffuses within the tissue. As the agent conjugates diffuse, in blood or tissue, the bond between the polymer and the agent degrades in a controlled pattern, releasing the active agent.
  • a first variable is the size and characteristics of the water-soluble polymer carrier.
  • Either synthetic or naturally occurring polymers may be used. While not limited to this group, some types of useful polymers include are polysaccharides (e.g., dextran and ficoll), proteins (e.g., poly-lysine), poly(ethylene glycol), and poly(methacrylates). Different polymers produce different diffusion characteristics in the target tissue or organ as a result of their different size and shape.
  • the rate of hydrolytic degradation, and thus of agent release, may be altered from minutes to months by altering the physico-chemical properties of the bonds between the agents and the polymer.
  • artisans can bond therapeutic agents to water-soluble polymers using covalent bonds, such 5 as ester, amide, amidoester, and urethane bonds. Ionic conjugates are also used.
  • covalent bonds such 5 as ester, amide, amidoester, and urethane bonds.
  • Ionic conjugates are also used.
  • the half-life of carrier-agent association is varied. This half-life of the agent-polymer conjugate in the environment in which it is placed determines the rate of active agent release from the polymer and, therefore, the degree of penetration that the agent-polymer 10 conjugate can achieve in the target tissue.
  • hydrolytically labile bonds which can be used to link the agent to the water soluble polymer include thioester, acid anhydride, carbamide, carbonate, semicarbazone, hydrazone, oxime, iminocarbonate, phosphoester, phophazene, and anhydride bonds.
  • the rate of release is also affected by (a) stereochemical control (varying amounts
  • the properties of the controlled release matrix vary the rate of polymeric agent conjugate release into the tissue (Dang, et al., Biotechnol. Prog., 8: 527-532, 1992; Powell, et al., Brain Res., 515: 309-311, 1990; Radomsky, et al., Biol, of Repro., 47: 133-140,
  • Suitable polymer components for use as controlled-release matrices include poly(ethylene-co-vinyl acetate), poly(DL-lactide), polyglycolide, copolymers of lactide and glycolide, and polyanhydride copolymers.
  • hydroxypolycarbonates are used as hydroxyl functional polymers that bind therapeutic agents or carbohydrate polymers chemically or via hydrogen bonding.
  • HPC hydroxypolycarbonates
  • These copolymers have properties attractive to the biomedical area as is or by conversion to the HPC product provided by hydrolysis or by in vivo enzymatic attack.
  • a feature of these polymers is their tendency to undergo surface erosion. Heterogeneous hydrolysis theoretically would better preserve the mechanical strength and physical integrity of the matrix during biodegradation, which is highly desirable in terms of predictable performance.
  • the polymer compositions disclosed herein allow for the controlled release of therapeutic agents.
  • This controlled release is modulated by the pH of the environment in which the polymer compositions function.
  • one embodiment includes the controlled release of the therapeutic agents from a hydrophobic, pH-sensitive polymer matrix (see, for example, U.S. Patent No. 6,306,422).
  • a polymer of hydrophobic and weakly acidic comonomers is used in the controlled release system. Weakly basic comonomers are used and the active agent is released as the pH drops.
  • a pH- sensitive polymer releases the therapeutic agents when exposed to a higher pH environment as the polymer gel swells. Such release can be made slow enough so that the therapeutic agent remains at significant levels for a clinically useful period of time.
  • compositions for releasing therapeutic agents using a dual phase polymeric agent-delivery composition comprise a continuous biocompatible gel phase, a discontinuous particulate phase comprising defined microparticles, and the therapeutic agents to be delivered (see, for example, U.S. Patent No. 6,287,588).
  • a microparticle containing a therapeutic agent is entrained within a biocompatible polymeric
  • the therapeutic agent release is contained in the microparticle phase alone or in both the microparticles and the gel matrix.
  • the release of the therapeutic agent is prolonged o ⁇ er a period of time, and the delivery is modulated and/or controlled.
  • the second agent is loaded in the same or different microparticles and/or in the gel matrix.
  • layered microparticles may be produced in which, for example, the inner core consists of a particular polymer carrying the therapeutic agent while an outer layer consisting of the same or a different material may either carry the therapeutic agent and release it with different release kinetics (Sengupta et al, Nature, 436:568-572, 2005), or not carry the therapeutic agent and serve to control its release from the inner core.
  • Drug-eluting devices of this invention release therapeutic agents. These agents are released at a constant rate or at a multi-phasic rate.
  • the release comprises an initial burst (immediate release) of the therapeutic agents present at or near the surface of the coating layer, a second phase during which the release rate is slower or sometimes no therapeutic agent is released, and a third phase during which most of the remainder of the therapeutic agents is released as erosion proceeds.

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Abstract

La présente invention concerne des méthodes et des compositions destinées au traitement de tissus coronariens endommagés suite à un trouble cardiaque tel que l'ischémie, l'infarctus aigu du myocarde, les plaques vulnérables, ou la lésion de reperfusion. Spécifiquement, le trouble cardiaque est traité à l'aide d'une molécule thérapeutique administrée localement.
PCT/US2006/034277 2005-09-02 2006-09-01 Methodes de traitement et de prevention de troubles cardiaques WO2007028053A2 (fr)

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WO2014049152A1 (fr) * 2012-09-28 2014-04-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques pour le traitement de la fibrose cardiovasculaire
US8846099B2 (en) 2008-08-05 2014-09-30 Coretherapix, Slu Parenteral composition comprising microspheres with a diameter between 10 and 20 microns
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US8602998B2 (en) 2004-03-18 2013-12-10 University of Pittsburgh—of the Commonwealth System of Higher Education Use of relaxin to increase arterial compliance
US7878978B2 (en) 2004-03-18 2011-02-01 University Of Pittsburgh- Of The Commonwealth System Of Higher Education Use of relaxin to increase arterial compliance
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WO2010064222A3 (fr) * 2008-12-01 2010-08-12 University College Cork, National University Of Ireland, Cork Igf1 pour réparation myocardique
EP3047861A3 (fr) * 2008-12-01 2016-08-31 University College Cork-National University of Ireland, Cork Igf1 pour réparation du myocarde
US10279083B2 (en) 2008-12-01 2019-05-07 University College Cork, National University Of Ireland, Cork IGF-I for myocardial repair
US9669134B2 (en) 2008-12-01 2017-06-06 University College Cork, National University Of Ireland, Cork IGF-I for myocardial repair
US9644019B2 (en) 2010-12-02 2017-05-09 Carlos Zaragoza Sánchez Compounds for treating cardiac damage after ischaemia/reperfusion
WO2012072820A1 (fr) * 2010-12-03 2012-06-07 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement d'une insuffisance cardiaque
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WO2014049152A1 (fr) * 2012-09-28 2014-04-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques pour le traitement de la fibrose cardiovasculaire
US9594083B2 (en) 2012-09-28 2017-03-14 Inserm (Institut National De La Sante Et De La Recherche Medicale) Method for the treatment of cardiovascular fibrosis
CN114712385A (zh) * 2015-07-30 2022-07-08 Tx医生公司 硫酸葡聚糖的新用途
WO2017100597A1 (fr) * 2015-12-11 2017-06-15 Cyta Therapeutics, Inc. Administration de particules d'agonistes et d'antagonistes de récepteurs de prostaglandine
WO2020115095A3 (fr) * 2018-12-05 2020-07-23 Glycardial Diagnostics, S.L. Procédés et compositions pour la prévention et/ou le traitement de l'ischémie et de la lésion d'ischémie-reperfusion
US20210196864A1 (en) * 2021-01-13 2021-07-01 Adnan I. Qureshi Implantable sustained release device and a method of use therefor in the treatment of brain disorders
US11931485B2 (en) * 2021-01-13 2024-03-19 Adnan I. Qureshi Implantable sustained release device and a method of use therefor in the treatment of brain disorders

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