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Cardiovascular Drug Delivery - technologies,markets and companies

Drug delivery to the cardiovascular system is different from delivery to other systems because of the anatomy and physiology of the vascular system; it supplies blood and nutrients to all organs of the body. Drugs can be introduced into the vascular system for systemic effects or targeted to an organ via the regional blood supply. In addition to the usual formulations of drugs such as controlled release, devices are used as well. This report starts with an introduction to molecular cardiology and discusses its relationship to biotechnology and drug delivery systems.

Drug delivery to the cardiovascular system is approached at three levels: (1) routes of drug delivery; (2) formulations; and finally (3) applications to various diseases. Formulations for drug delivery to the cardiovascular system range from controlled release preparations to delivery of proteins and peptides. Cell and gene therapies, including antisense and RNA interference, are described in full chapters as they are the most innovative methods of delivery of therapeutics. Various methods of improving systemic administration of drugs for cardiovascular disorders are described including use of nanotechnology.

Cell-selective targeted drug delivery has emerged as one of the most significant areas of biomedical engineering research, to optimize the therapeutic efficacy of a drug by strictly localizing its pharmacological activity to a pathophysiologically relevant tissue system. These concepts have been applied to targeted drug delivery to the cardiovascular system. Devices for drug delivery to the cardiovascular system are also described.

Role of drug delivery in various cardiovascular disorders such as myocardial ischemia, hypertension and hypercholesterolemia is discussed. Cardioprotection is also discussed. Some of the preparations and technologies are also applicable to peripheral arterial diseases. Controlled release systems are based on chronopharmacology, which deals with the effects of circadian biological rhythms on drug actions.A full chapter is devoted to drug-eluting stents as treatment for restenosis following stenting of coronary arteries.Fifteen companies are involved in drug-eluting stents.

New cell-based therapeutic strategies are being developed in response to the shortcomings of available treatments for heart disease. Potential repair by cell grafting or mobilizing endogenous cells holds particular attraction in heart disease, where the meager capacity for cardiomyocyte proliferation likely contributes to the irreversibility of heart failure. Cell therapy approaches include attempts to reinitiate cardiomyocyte proliferation in the adult, conversion of fibroblasts to contractile myocytes, conversion of bone marrow stem cells into cardiomyocytes, and transplantation of myocytes or other cells into injured myocardium.

Advances in molecular pathophysiology of cardiovascular diseases have brought gene therapy within the realm of possibility as a novel approach to treatment of these diseases. It is hoped that gene therapy will be less expensive and affordable because the techniques involved are simpler than those involved in cardiac bypass surgery, heart transplantation and stent implantation. Gene therapy would be a more physiologic approach to deliver vasoprotective molecules to the site of vascular lesion. Gene therapy is not only a sophisticated method of drug delivery; it may at time need drug delivery devices such as catheters for transfer of genes to various parts of the cardiovascular system.

The cardiovascular drug delivery markets are estimated for the years 2013 to 2023 on the basis of epidemiology and total markets for cardiovascular therapeutics. The estimates take into consideration the anticipated advances and availability of various technologies, particularly drug delivery devices in the future. Markets for drug-eluting stents are calculated separately. Role of drug delivery in developing cardiovascular markets is defined and unmet needs in cardiovascular drug delivery technologies are identified.

Selected 82 companies that either develop technologies for drug delivery to the cardiovascular system or products using these technologies are profiled and 80 collaborations between companies are tabulated. The bibliography includes 200 selected references from recent literature on this topic. The report is supplemented with 29 tables and 7 figures

Table of Contents

0. Executive Summary

1. Cardiovascular Diseases

  • Introduction
  • History of cardiovascular drug delivery
  • Overview of cardiovascular disease
    • Coronary artery disease
      • Angina pectoris
      • Limitations of current therapies for myocardial ischemic disease
    • Cardiomyopathies
    • Cardiac arrhythmias
    • Congestive heart failure
    • Peripheral arterial disease
      • Current management
    • Atherosclerosis
    • The endothelium as a target for cardiovascular therapeutics
  • Molecular cardiology
    • Cardiogenomics
    • Cardioproteomics
  • Personalized cardiology
    • Pharmacogenomics of cardiovascular disorders
    • Modifying the genetic risk for myocardial infarction
    • Management of heart failure
    • Management of hypertension
      • Pharmacogenomics of diuretic drugs
      • Pharmacogenomics of ACE inhibitors
      • Management of hypertension by personalized approach
    • Pharmacogenetics of lipid-lowering therapies
      • Polymorphisms in genes involved in cholesterol metabolism
      • Role of eNOS gene polymorphisms
  • Important advances in cardiovascular therapeutics
  • Drug delivery, biotechnology and the cardiovascular system
  • Role of cardiovascular imaging in cardiovascular therapeutics
  • Chronopharmacotherapy of cardiovascular diseases

2. Methods for Drug Delivery to the Cardiovascular System

  • Introduction
  • Routes of drug delivery to the cardiovascular system
  • Local administration of drugs to the cardiovascular system
    • Intramyocardial drug delivery
    • Drug delivery via coronary venous system
    • Intrapericardial drug delivery
  • Formulations for drug delivery to the cardiovascular system
    • Sustained and controlled release
      • Programming the release at a defined time
      • Dosage formulation of calcium channel blockers
      • Sustained and controlled release verapamil
    • Methods of administration of proteins and peptides
      • Delivery of peptides by subcutaneous injection
      • Depot formulations and implants
      • Poly(ethylene glycol) technology
      • Liposomes for cardiovascular drug delivery
      • Microencapsulation for protein delivery
      • Localized delivery of biomaterials for tissue engineering
      • Oral delivery of proteins and peptides
  • DDS to improve systemic delivery of cardiovascular drugs
    • Nanotechnology-based drug delivery
    • Controlled delivery of nanoparticles to injured vasculature
    • Nanoparticles for cardiovascular imaging and targeted drug delivery
    • Nanofiber-based scaffolds with drug-release properties
  • Targeted drug delivery to the cardiovascular system
    • Immunotargeting of liposomes to activated vascular endothelial cells
    • PEGylated biodegradable particles targeted to inflamed endothelium
  • Devices for cardiovascular drug delivery
    • Local drug delivery by catheters
    • Microneedle for periarterial injection
    • Nanotechnology-based devices for the cardiovascular system
      • Liposomal nanodevices for targeted cardiovascular drug delivery
      • Nanotechnology approach to the problem of "vulnerable plaque"
  • Drug delivery in the management of cardiovascular disease
    • Drug delivery in the management of hypertension
      • Transnasal drug delivery for hypertension
      • Transdermal drug delivery for hypertension
      • Oral extended and controlled release preparations for hypertension
      • Long-acting hypertensives for 24 h blood pressure control
      • Drug delivery to control early morning blood pressure peak
      • Role of drug delivery in improving compliance with antihypertensive therapy
    • Drug delivery for congestive heart failure
      • Oral human brain-type natriuretic peptide
      • Nitric oxide-based therapies for congestive heart failure
      • Automated drug delivery system for cardiac failure
    • DDS in the management of ischemic heart disease
      • Intravenous emulsified formulations of halogenated anesthetics
      • Injectable peptide nanofibers for myocardial ischemia
      • Delivery of angiogenesis-inducing agents for myocardial ischemia
    • Drug delivery for cardioprotection
      • Cardioprotection during reperfusion
    • Drug delivery for cardiac rhythm disorders
    • Drug delivery in the treatment of angina pectoris
      • Sustained and controlled-release nitrate for angina pectoris
      • Transdermal nitrate therapy
      • Controlled release calcium blockers for angina pectoris
      • Sustained-release formulation of ranolazine
    • Vaccines for hypertension
    • Drug delivery in the management of pulmonary hypertension
      • Prostacyclin by inhalation
      • Endothelin receptor antagonist treatment of PAH
    • Anticoagulation in cardiovascular disease
      • Oral heparin
      • Low molecular weight heparin-loaded polymeric nanoparticles
      • Transdermal anticoagulants
    • Thrombolysis for cardiovascular disorders
      • Use of ultrasound to facilitate thrombolysis
      • Delivery of alteplase through the AngioJet rheolytic catheter
    • Drug delivery for peripheral arterial disease
      • Delivery of thrombolytic agent to the clot through a catheter
      • Delivery of growth factors to promote angiogenesis in ischemic limbs
      • Immune modulation therapy for PAD
      • NO-based therapies for peripheral arterial disease
    • Drug delivery in the management of hypercholesterolemia
      • Controlled/sustained release formulations of statins
      • Combinations of statins with other drugs to increase efficacy
      • Controlled release fenofibrate
      • Extended release nicotinic acid
      • Intravenous infusion of lipoprotein preparations to raise HDL
      • Innovative approaches to hypercholesterolemia
    • Single dose therapy for more than one cardiovascular disorder

3. Cell Therapy for Cardiovascular Disorders

  • Introduction
    • Inducing the proliferation of cardiomyocytes
    • Role of stem cells in repair of the heart
    • Cell-mediated immune modulation for chronic heart disease
    • Cell therapy for atherosclerotic coronary artery disease
    • Transplantation of myoblasts for myocardial infarction
      • MyoCell™ (Bioheart)
    • Transplantation of cardiac progenitor cells for revascularization of myocardium
  • Methods of delivery of cells to the heart
    • Cellular cardiomyoplasty
    • IGF-1 delivery by nanofibers to improve cell therapy for MI
    • Intracoronary infusion of bone marrow-derived cells for AMI
    • Non-invasive delivery of cells to the heart by Morph®guide catheter
    • Transplantation of stem cells for myocardial infarction
      • Transplantation of embryonic stem cells
      • Transplantation of hematopoietic stem cells
      • Transplantation of cord blood stem cells for myocardial infarction
      • Intracoronary infusion of mobilized peripheral blood stem cells
      • Human mesenchymal stem cells for cardiac regeneration
      • Cytokine preconditioning of human fetal liver CD133+ SCs
      • Transplantation of expanded adult SCs derived from the heart
      • Transplantation of endothelial cells
    • Transplantation of genetically modified cells
      • Transplantation of cells secreting vascular endothelial growth factor
      • Transplantation of genetically modified bone marrow stem cells
    • Cell transplantation for congestive heart failure
      • Injection of adult stem cells for congestive heart failure
      • Intracoronary infusion of cardiac stem cells
      • Myoblasts for treatment of congestive heart failure
    • Role of cell therapy in cardiac arrhythmias
      • Atrioventricular conduction block
      • Ventricular tachycardia
      • ESCs for correction of congenital heart defects
    • Cardiac progenitors cells for treatment of heart disease in children
    • Stem cell therapy for peripheral arterial disease
    • Targeted delivery of endothelial progenitor cells labeled with nanoparticles
    • Clinical trials of cell therapy in cardiovascular disease
    • A critical evaluation of cell therapy for heart disease
    • Publications of clinical trials of cell therapy for CVD
  • Future directions for cell therapy of CVD
    • Prospects of adult stem cell therapy for repair of heart
    • Regeneration of cardiomyocytes without use of cardiac stem cells
    • Repair of the damaged heart

4. Gene Therapy for Cardiovascular Disorders

  • Introduction
  • Techniques of gene transfer to the cardiovascular system
    • Direct plasmid injection into the myocardium
    • Catheter-based systems for vector delivery
    • Ultrasound microbubbles for cardiovascular gene delivery
    • Vectors for cardiovascular gene therapy
      • AAV vectors for therapeutic delivery to the heart
      • Adenoviral vectors for cardiovascular diseases
      • Plasmid DNA-based delivery in cardiovascular disorders
    • Hypoxia-regulated gene therapy for myocardial ischemia
    • Angiogenesis and gene therapy of ischemic disorders
    • Therapeutic angiogenesis vs. vascular growth factor therapy
    • Gene painting for delivery of targeted gene therapy to the heart
    • Gene delivery to vascular endothelium
      • Overexpression of eNOS to improve vasodilation with Ad vectors
    • Targeted plasmid DNA delivery to the cardiovascular system with nanoparticles
  • Gene therapy for genetic cardiovascular disorders
    • Genetic disorders predisposing to atherosclerosis
    • Familial hypercholesterolemia
    • Apolipoprotein E deficiency
    • Hypertension
    • Genetic factors for myocardial infarction
  • Acquired cardiovascular diseases
    • Coronary artery disease with angina pectoris
      • Ad5FGF-4
    • Ischemic heart disease with myocardial infarction
      • Angiogenesis for cardiovascular disease
      • Myocardial repair with IGF-1 therapy
      • miRNA gene therapy for ischemic heart disease
    • Congestive heart failure
      • Rationale of gene therapy in CHF
      • AAV-mediated gene transfer for CHF
      • AngioCell gene therapy for CHF
      • β-ARKct gene therapy
      • Elevating cardiac dATP by gene therapy to improve cardiac function
      • Intracoronary adenovirus-mediated gene therapy for CHF
      • nNOS gene transfer in CHF
    • Gene therapy for cardiac arrhythmias
      • Gene transfer for biological pacemakers
      • Management of arrhythmias due to myoblast transplantation
      • Genetically engineered cells as biological pacemakers
    • Cholesterol reduction by genetic engineering of PCSK9 gene
    • Gene therapy and heart transplantation
    • Gene therapy for peripheral arterial disease
      • Angiogenesis by gene therapy
      • HIF-1gene therapy for peripheral arterial disease
      • HGF gene therapy for peripheral arterial disease
      • Ischemic neuropathy secondary to peripheral arterial disease
    • Maintaining vascular patency after surgery
  • Antisense therapy for cardiovascular disorders
    • Antisense therapy for hypertension
    • Antisense therapy for hypercholesterolemia
  • RNAi for cardiovascular disorders
    • RNAi for hypercholesterolemia
    • microRNA and the cardiovascular system
      • Role of miRNAs in angiogenesis
      • Role of miRNAs in cardiac hypertrophy and failure
      • Role of miRNAs in conduction and rhythm disorders of the heart
      • miRNA-based approach for reduction of hypercholesterolemia
      • miRNAs as therapeutic targets for cardiovascular diseases
      • Future prospects of miRNA in the cardiovascular therapeutics
  • Future prospects of gene therapy of cardiovascular disorders
  • Companies involved in gene therapy of cardiovascular disorders

5. Drug-Eluting Stents

  • Introduction
    • Percutaneous transluminal coronary angioplasty
    • Stents
  • Restenosis
    • Pathomechanism
    • Treatment
    • Nitric oxide-based therapies for restenosis
    • Carbon monoxide inhalation for preventing restenosis
    • Antisense approaches for prevention of restenosis after angioplasty
    • Gene therapy to prevent restenosis after angioplasty
      • Delivery of gene therapy for restenosis
      • HSV-1 gene therapy to prevent intimal hyperplasia
      • miRNA-based gene therapy for restenosis following angioplasty
      • Nonviral gene therapy to prevent intimal hyperplasia
      • NOS gene therapy for restenosis
      • Targets for gene therapy of restenosis
      • Viral vector-mediated gene therapy for restenosis
    • Drug delivery devices for restenosis
    • Local drug delivery by catheter
    • Stenosis associated with stents
    • Absorbable metal stents
  • Drug-eluting stents
    • Various types of DES
      • CYPHER® sirolimus-eluting coronary stent
      • Dexamethasone-eluting stents
      • NO-generating stents
      • Paclitaxel-eluting stents
      • Sirolimus-eluting vs paclitaxel-eluting stents
    • Novel technologies for DES
      • Absorbable DES
      • Bio-absorbable low-dose DES
      • Drug-eluting stents coated with polymer surfaces
      • Endeavour DES
      • Stents for delivery of gene therapy
      • Stem cell-based stents
      • VAN 10-4 DES
    • Nanotechnology-based stents
      • Drugs encapsulated in biodegradable nanoparticles
      • Magnetic nanoparticle-coated DES
      • Magnetic nanoparticles encapsulating paclitaxel targeted to stents
      • Nanocoated DES
      • Nanopores to enhance compatibility of DES
      • Paclitaxel-encapsulated targeted lipid-polymeric nanoparticles
    • The ideal DES
    • Companies developing drug-eluting stents
    • Clinical trials of drug-eluting stents
      • Measurements used in clinical trials of DES
      • TAXUS paclitaxel-eluting stents
      • XIENCE™ V everolimus-eluting coronary stent
      • COSTAR II clinical trial
      • Endeavor RESOLUTE zotarolimus-eluting stent system
      • CUSTOM I clinical trial
      • NOBORI CORE Trial
      • LEADERS trial
      • Comparison of DES in clinical trials
    • Comparison of DES with competing technologies
      • DES versus coronary artery bypass graft
      • DES versus bare metal stents
      • Multi-Link Vision bare metal stent vs DES
      • Guidelines for DES vs BMS
      • DES vs BMS for off-label indications
      • Role of DES in cases of bare-metal in-stent restenosis
      • DES versus balloon catheter coated with paclitaxel
      • DES versus intracoronary radiation therapy for recurrent stenosis
      • PCI plus DES as the preferred method for treatment of MI
      • Cost-effectiveness of DES
      • Comparison of revascularization methods for stable coronary disease
    • Safety issues of DES
      • Adverse reactions to DES
      • Long-term safety studies of DES
      • Endothelial vascular dysfunction due to sirolismus
      • Risk of clotting with DES
      • Effect of blood clot on release of drug from DES
    • Measures to prevent clotting associated with DES
      • Clopidogrel use and long-term outcomes of patients receiving DES
      • Cangrelor for platelet inhibition to prevent stent thrombosis
      • Prasugrel as antiplatelet agent
      • Use of magnetized cell lining to prevent clotting of DES
  • Regulatory issues of DES
    • Approved drug-eluting stents
    • Safety issues of drug-eluting stents
    • Assesssment of efficacy of various drug-eluting stents
  • Future prospects for treatment of restenosis by DES
    • Future role of DES in management of cardiovascular diseases
    • Stent cost and marketing strategies
    • Improvements in stent technology
      • Bioabsorbale stent
    • DES vs drug-eluting balloons

6. Markets for Cardiovascular Drug Delivery

  • Introduction
  • Epidemiology of cardiovascular disease
  • Cost of care of cardiovascular disorders
  • Cardiovascular markets according to important diseases
    • Antithrombotics
    • Anticholesterol agents
    • Antihypertensive agents
    • Drugs for congestive heart failure
  • Markets for innovative technologies for cardiovascular disorders
    • Markets for cell therapy of cardiovascular disorders
    • Markets for gene therapy of cardiovascular disorders
    • Markets for drug-eluting stents
      • Major players in DES market
      • Impact of safety issues on future markets for DES
      • DES market in Asia
      • Patenting and legal issues of DES
      • The financial impact of DES on cardiovascular markets
  • Unmet needs for cardiovascular drug delivery
  • Role of DDS in developing cardiovascular markets
    • Markets for cardiovascular devices
    • Marketing of innovative cardiovascular drug delivery devices
    • Direct to consumer advertising of DES
    • Future trends in the integration of drug delivery with therapeutics
    • Future prospects of cardiovascular drug delivery

7. Companies involved in Cardiovascular Drug Delivery

  • Profiles of companies
  • Collaborations

8. References

Tables

  • Table 1-1: Landmarks in the historical evolution of cardiovascular drug delivery
  • Table 1-2: Gene polymorphisms that alter cardiovascular response to drugs
  • Table 2-1: Routes of drug delivery used for treatment of cardiovascular disorders
  • Table 2-2: Formulations for drug delivery to the cardiovascular system
  • Table 2-3: Improved methods of systemic drug delivery of cardiovascular drugs
  • Table 2-4: Targeted delivery of therapeutic substances to the cardiovascular system
  • Table 2-5: Classification of devices for drug delivery to the cardiovascular system
  • Table 2-6: Various methods of delivery of therapeutic agents for hypertension
  • Table 2-7: Marketed controlled/ extended release preparation for hypertension
  • Table 2-8: Drug delivery in ischemic heart disease
  • Table 2-9: Strategies for cardioprotection
  • Table 2-10: Methods of delivery of nitrate therapy in angina pectoris
  • Table 2-11: Drug delivery for peripheral arterial disorders
  • Table 3-1: Clinical trials of cell therapy in cardiovascular disease
  • Table 4-1: Cardiovascular disorders for which gene therapy is being considered.
  • Table 4-2: Catheter-based systems for vector delivery to the cardiovascular system
  • Table 4-3: Potential applications of antisense in cardiovascular disorders
  • Table 4-4: Companies involved in gene therapy of cardiovascular diseases
  • Table 5-1: Treatment of restenosis
  • Table 5-2: Devices used for drug delivery in restenosis
  • Table 5-3: Companies involved in drug-eluting stents
  • Table 5-4: Drug-eluting stents approved by the FDA
  • Table 6-1: Prevalence of cardiovascular disorders in major markets: US 2013-2023
  • Table 6-2: Prevalence of cardiovascular disorders in major markets: Europe 2013-2023
  • Table 6-3: Prevalence of cardiovascular disorders in major markets: Japan 2013-2023
  • Table 6-4: Values of cardiovascular DDS in major markets 2013-2023
  • Table 6-5: Markets for innovative technologies for cardiovascular disorders 2013-2023
  • Table 7-1: Top 5 companies in cardiovascular drug delivery
  • Table 7-2: Collaborations in cardiovascular drug delivery

Figures

  • Figure 1-1: Drug delivery, biotechnology and cardiovascular diseases
  • Figure 2-1: MicroSyringe for periarterial injection
  • Figure 5-1: Vicious circle of vascular occlusion following angioplasty and stenting
  • Figure 5-2: Measurement of in-stent stenosis
  • Figure 5-3: Medtronic's Endeavour drug-eluting stent
  • Figure 5-4: Magnetic nanoparticle-coated stent
  • Figure 6-1: Unmet needs for cardiovascular drug delivery
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