Cardiovascular Drug Delivery - technologies,markets and companies

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

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
• 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
• 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”
• Role of cardiovascular imaging in cardiovascular therapeutics
• Chronopharmacotherapy of cardiovascular diseases
• 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
• 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
• 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
• 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 MorphRguide 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
• Myoblasts for treatment of congestive heart failure
• Injection of adult stem cells for 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

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
• Adenoviral vectors for cardiovascular diseases
• Plasmid DNA-based delivery in cardiovascular disorders
• Intravenous rAAV vectors for targeted delivery to the heart
• 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
• Targeted plasmid DNA delivery to the cardiovascular system with nanoparticles
• Gene delivery by vascular stents
• 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
• Congestive heart failure
• Rationale of gene therapy in CHF
• β-ARKct gene therapy
• Intracoronary adenovirus-mediated gene therapy for CHF
• AAV-mediated gene transfer for CHF
• AngioCell 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
• Gene therapy and heart transplantation
• Gene therapy for peripheral arterial disease
• Angiogenesis by gene therapy
• HIF-1α gene 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
• miRNA-based approach for restenosis following angioplasty
• Gene therapy to prevent restenosis after angioplasty
• Techniques of gene therapy for restenosis
• NOS gene therapy for restenosis
• Non-viral gene therapy to prevent intimal hyperplasia
• HSV-1 gene therapy to prevent intimal hyperplasia
• Drug delivery devices for restenosis
• Local drug delivery by catheter
• Absorbable metal stents
• Drug-eluting stents
• Various types of DES
• CYPHERR sirolimus-eluting coronary stent
• Sirolimus-eluting vs paclitaxel-eluting stents
• Paclitaxel-eluting stents
• Dexamethasone-eluting stents
• NO-generating stents
• Dexamethasone-eluting stents
• Novel technologies for DES
• Stents for delivery of gene therapy
• Stem cell-based stents
• Drug-eluting stents coated with polymer surfaces
• Absorbable DES
• Endeavour DES
• Bio-absorbable low-dose DES
• VAN 10-4 DES
• Nanotechnology-based stents
• Drugs encapsulated in biodegradable nanoparticles
• Magnetic nanoparticle-coated DES
• Nanocoated DES
• Nanopores to enhance compatibility of DES
• 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
• Everolimus-eluting coronary stents
• XIENCE"! V Everolimus-Eluting coronary stent system
• 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
• 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
• Cost-effectiveness of DES
• Safety issues of DES
• Adverse reactions to DES
• Endothelial vascular dysfunction due to sirolismus
• Risk of clotting with DES
• Clopidogrel use and long-term outcomes of patients receiving DES
• Effect of blood clot on release of drug from DES
• Use of magnetized cell lining to prevent clotting of DES
• Long-term safety studies of DES
• Regulatory issues of DES
• 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

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: Methods of delivery of nitrate therapy in angina pectoris
• Table 2 10: 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 6 1: Prevalence of cardiovascular disorders in major markets: US 2008-2018
• Table 6 2: Prevalence of cardiovascular disorders in major markets: Europe 2008-2018
• Table 6 3: Prevalence of cardiovascular disorders in major markets: Japan 2008-2018
• Table 6 4: Values of cardiovascular DDS in major markets 2008-2018
• Table 6 5: Markets for innovative technologies for cardiovascular disorders 2008-2018
• 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: Microneedle for periarterial injection
• Figure 5 1: Vicious circle of vascular occlusion following angioplasty and stenting
• Figure 5 2: Medtronic' s Endeavour drug-eluting stent
• Figure 5 3: Magnetic nanoparticle-coated stent
• Figure 6 1: Unmet needs for cardiovascular drug delivery