Abstract
Summary
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 2007 to 2017 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 87 companies that either develop technologies for drug delivery to the cardiovascular system or products using these technologies are profiled and 68 collaborations between companies are tabulated. The bibliography includes 200 selected references from recent literature on this topic. The report is supplemented with 27 tables and 6 figures .
Table of Contents
0. Executive Summary 11
1. Cardiovascular Diseases 13
- Introduction 13
- History of cardiovascular drug delivery 13
- Overview of cardiovascular disease 14
- Coronary artery disease 14
- Angina pectoris 14
- Limitations of current therapies for myocardial ischemic disease 14
- Cardiomyopathies 14
- Cardiac arrhythmias 15
- Congestive heart failure 15
- Peripheral arterial disease 15
- Current management 16
- Atherosclerosis 16
- The endothelium as a target for cardiovascular therapeutics 16
- Molecular cardiology 17
- Cardiogenomics 17
- Cardioproteomics 17
- Personalized cardiology 18
- Pharmacogenomics of cardiovascular disorders 18
- Modifying the genetic risk for myocardial infarction 19
- Management of heart failure 19
- Management of hypertension 20
- Pharmacogenomics of diuretic drugs 20
- Pharmacogenomics of ACE inhibitors 20
- Management of hypertension by personalized approach 21
- Pharmacogenetics of lipid-lowering therapies 21
- Polymorphisms in genes involved in cholesterol metabolism 21
- Role of eNOS gene polymorphisms 22
- Important advances in cardiovascular therapeutics 22
- Drug delivery, biotechnology and the cardiovascular system 23
2. Methods for Drug Delivery to the Cardiovascular System 25
- Introduction 25
- Routes of drug delivery to the cardiovascular system 25
- Local administration of drugs to the cardiovascular system 25
- Intramyocardial drug delivery 25
- Drug delivery via coronary venous system 26
- Intrapericardial drug delivery 26
- Formulations for drug delivery to the cardiovascular system 26
- Sustained and controlled release 27
- Programming the release at a defined time 27
- Dosage formulation of calcium channel blockers 28
- Sustained and controlled release verapamil 28
- Methods of administration of proteins and peptides 28
- Delivery of peptides by subcutaneous injection 29
- Depot formulations and implants 29
- Poly(ethylene glycol) technology 29
- Microencapsulation for protein delivery 30
- Localized delivery of biomaterials for tissue engineering 30
- Oral delivery of proteins and peptides 30
- DDS to improve systemic delivery of cardiovascular drugs 31
- Nanotechnology-based drug delivery 32
- Targeted drug delivery to the cardiovascular system 33
- Immunotargeting of liposomes to activated vascular endothelial cells 34
- PEGylated biodegradable particles targeted to inflamed endothelium 34
- Devices for cardiovascular drug delivery 35
- Local drug delivery by catheters 35
- Microneedle for periarterial injection 36
- Nanotechnology-based devices for the cardiovascular system 37
- Liposomal nanodevices for targeted cardiovascular drug delivery 37
- Nanotechnology approach to the problem of "vulnerable plaque" 38
- Role of cardiovascular imaging in cardiovascular therapeutics 38
- Chronopharmacotherapy of cardiovascular diseases 39
- Drug delivery in the management of cardiovascular disease 40
- Drug delivery in the management of hypertension 40
- Transnasal drug delivery for hypertension 40
- Transdermal drug delivery for hypertension 41
- Oral extended and controlled release preparations for hypertension 41
- Long-acting hypertensives for 24 h blood pressure control 42
- Drug delivery to control early morning blood pressure peak 42
- Role of drug delivery in improving compliance with antihypertensive therapy 43
- Drug delivery for congestive heart failure 43
- Oral human brain-type natriuretic peptide 43
- Nitric oxide-based therapies for congestive heart failure 43
- Automated drug delivery system for cardiac failure 44
- DDS in the management of ischemic heart disease 44
- Intravenous emulsified formulations of halogenated anesthetics 45
- Injectable peptide nanofibers for myocardial ischemia 45
- Delivery of angiogenesis-inducing agents for myocardial ischemia 45
- Drug delivery for cardioprotection 46
- Drug delivery for cardiac rhythm disorders 47
- Drug delivery in the treatment of angina pectoris 47
- Sustained and controlled-release nitrate for angina pectoris 48
- Transdermal nitrate therapy 48
- Controlled release calcium blockers for angina pectoris 49
- Drug delivery in the management of pulmonary hypertension 49
- Anticoagulation in cardiovascular disease 50
- Oral heparin 50
- Low molecular weight heparin-loaded polymeric nanoparticles 50
- Transdermal anticoagulants 51
- Thrombolysis for cardiovascular disorders 51
- Use of ultrasound to facilitate thrombolysis 51
- Delivery of alteplase through the AngioJet rheolytic catheter 51
- Drug delivery for peripheral arterial disease 52
- Delivery of thrombolytic agent to the clot through a catheter 52
- Immune modulation therapy for PAD 52
- NO-based therapies for peripheral arterial disease 53
- Drug delivery in the management of hypercholesterolemia 53
- Controlled/sustained release formulations of statins 53
- Combinations of statins with other drugs to increase efficacy 54
- Controlled release fenofibrate 55
- Extended release nicotinic acid 55
- Intravenous infusion of lipoprotein preparations to raise HDL 56
- Innovative approaches to hypercholesterolemia 56
- Single dose therapy for more than one cardiovascular disorder 57
3. Cell Therapy for Cardiovascular Disorders 59
- Introduction 59
- Inducing the proliferation of cardiomyocytes 59
- Role of stem cells in repair of the heart 59
- Cell-mediated immune modulation for chronic heart disease 59
- Cell therapy for atherosclerotic coronary artery disease 60
- Transplantation of myoblasts for myocardial infarction 60
- MyoCell"! (Bioheart) 61
- Transplantation of cardiac progenitor cells for revascularization of myocardium 62
- Methods of delivery of cells to the heart 62
- Cellular cardiomyoplasty 62
- IGF-1 delivery by nanofibers to improve cell therapy for MI 62
- Intracoronary infusion of bone marrow-derived cells for AMI 63
- Non-invasive delivery of cells to the heart by MorphRguide catheter 63
- Transplantation of stem cells for myocardial infarction 63
- Transplantation of embryonic stem cells 63
- Transplantation of hematopoietic stem cells 64
- Transplantation of cord blood stem cells for myocardial infarction 64
- Intracoronary infusion of mobilized peripheral blood stem cells 64
- Human mesenchymal stem cells for cardiac regeneration 65
- Cytokine preconditioning of human fetal liver CD133+ SCs 65
- Transplantation of expanded adult SCs derived from the heart 66
- Transplantation of endothelial cells 66
- Transplantation of genetically modified cells 66
- Transplantation of cells secreting vascular endothelial growth factor 66
- Transplantation of genetically modified bone marrow stem cells 67
- Cell transplantation for congestive heart failure 67
- Myoblasts for treatment of congestive heart failure 67
- Injection of adult stem cells for congestive heart failure 67
- Role of cell therapy in cardiac arrhythmias 68
- Atrioventricular conduction block 68
- Ventricular tachycardia 69
- ESCs for correction of congenital heart defects 69
- Cardiac progenitors cells for treatment of heart disease in children 70
- Stem cell therapy for peripheral arterial disease 70
- Clinical trials of cell therapy in cardiovascular disease 71
- A critical evaluation of cell therapy for heart disease 73
- Publications of clinical trials of cell therapy for CVD 73
- Future directions for cell therapy of CVD 73
4. Gene Therapy for Cardiovascular Disorders 75
- Introduction 75
- Techniques of gene transfer to the cardiovascular system 76
- Direct plasmid injection into the myocardium 76
- Catheter-based systems for vector delivery 76
- Ultrasound microbubbles for cardiovascular gene delivery 77
- Vectors for cardiovascular gene therapy 77
- Adenoviral vectors for cardiovascular diseases 77
- Plasmid DNA-based delivery in cardiovascular disorders 78
- Intravenous rAAV vectors for targeted delivery to the heart 78
- Hypoxia-regulated gene therapy for myocardial ischemia 78
- Angiogenesis and gene therapy of ischemic disorders 79
- Therapeutic angiogenesis vs. vascular growth factor therapy 79
- Gene painting for delivery of targeted gene therapy to the heart 80
- Gene delivery to vascular endothelium 80
- Targeted plasmid DNA delivery to the cardiovascular system with nanoparticles 80
- Gene delivery by vascular stents 81
- Gene therapy for genetic cardiovascular disorders 81
- Genetic disorders predisposing to atherosclerosis 81
- Familial hypercholesterolemia 82
- Apolipoprotein E deficiency 83
- Hypertension 84
- Genetic factors for myocardial infarction 84
- Acquired cardiovascular diseases 84
- Coronary artery disease with angina pectoris 85
- Ad5FGF-4 85
- Ischemic heart disease with myocardial infarction 85
- Myocardial repair with IGF-1 therapy 86
- Congestive heart failure 86
- Rationale of gene therapy in CHF 87
- Genetic manipulation of β adrenergic receptor system in CHF 87
- Intracoronary adenovirus-mediated gene therapy for CHF 87
- AAV-mediated gene transfer for CHF 87
- AngioCell gene therapy for CHF 88
- nNOS gene transfer in CHF 88
- Gene therapy for cardiac arrhythmias 88
- Gene therapy and heart transplantation 90
- Gene therapy for peripheral arterial disease 90
- Angiogenesis by gene therapy 90
- HIF-1αgene therapy for peripheral arterial disease 91
- HGF gene therapy for peripheral arterial disease 91
- Ischemic neuropathy secondary to peripheral arterial disease 91
- Maintaining vascular patency after surgery 92
- Antisense therapy for cardiovascular disorders 92
- Antisense therapy for hypertension 93
- Antisense therapy for hypercholesterolemia 93
- RNAi for cardiovascular disorders 94
- RNAi for hypercholesterolemia 94
- microRNA and the cardiovascular system 95
- Role of miRNAs in angiogenesis 95
- Role of miRNAs in cardiac hypertrophy and failure 96
- Role of miRNAs in conduction and rhythm disorders of the heart 96
- miRNA-based approach for reduction of hypercholesterolemia 96
- miRNAs as therapeutic targets for cardiovascular diseases 97
- Future prospects of miRNA in the cardiovascular therapeutics 97
- Future prospects of gene therapy of cardiovascular disorders 98
- Companies involved in gene therapy of cardiovascular disorders 98
5. Drug-Eluting Stents 101
- Introduction 101
- Percutaneous transluminal coronary angioplasty 101
- Stents 101
- Restenosis 101
- Pathomechanism 101
- Treatment 102
- Nitric oxide-based therapies for restenosis 102
- Carbon monoxide inhalation for preventing restenosis 103
- Antisense approaches for prevention of restenosis after angioplasty 103
- Gene therapy to prevent restenosis after angioplasty 104
- Techniques of gene therapy for restenosis 106
- NOS gene therapy for restenosis 106
- Non-viral gene therapy to prevent intimal hyperplasia 107
- HSV-1 gene therapy to prevent intimal hyperplasia 107
- Drug delivery devices for restenosis 107
- Local drug delivery by catheter 108
- Absorbable metal stents 108
- Drug-eluting stents 108
- Various types of DES 109
- CYPHERR sirolimus-eluting coronary stent 109
- Sirolimus-eluting vs paclitaxel-eluting stents 110
- Paclitaxel-eluting stents 110
- Dexamethasone-eluting stents 110
- NO-generating stents 111
- Dexamethasone-eluting stents 111
- Novel technologies for DES 111
- Stents for delivery of gene therapy 111
- Stem cell-based stents 112
- Drug-eluting stents coated with polymer surfaces 113
- Absorbable DES 113
- Endeavour DES 113
- Bio-absorbable low-dose DES 114
- VAN 10-4 DES 114
- Nanotechnology-based stents 115
- Drugs encapsulated in biodegradable nanoparticles 115
- Magnetic nanoparticle-coated DES 115
- Nanocoated DES 116
- Nanopores to enhance compatibility of DES 117
- The ideal DES 117
- Companies developing drug-eluting stents 117
- Clinical trials of drug-eluting stents 118
- Measurements used in clinical trials of DES 118
- TAXUS paclitaxel-eluting stents 119
- Everolimus-eluting coronary stents 120
- XIENCE"! V Everolimus-Eluting coronary stent system 120
- COSTAR II clinical trial 121
- Endeavor RESOLUTE zotarolimus-eluting stent system 121
- CUSTOM I clinical trial 122
- NOBORI CORE Trial 122
- LEADERS trial 122
- Comparison of DES in clinical trials 123
- Comparison of DES with competing technologies 123
- DES versus coronary artery bypass graft 123
- DES versus bare metal stents 124
- Guidelines for DES vs BMS 126
- DES vs BMS for off-label indications 126
- Role of DES in cases of bare-metal in-stent restenosis 126
- DES versus balloon catheter coated with paclitaxel 127
- DES versus intracoronary radiation therapy for recurrent stenosis 127
- Cost-effectiveness of DES 127
- Safety issues of DES 128
- Adverse reactions to DES 128
- Endothelial vascular dysfunction due to sirolismus 128
- Risk of clotting with DES 129
- Clopidogrel use and long-term outcomes of patients receiving DES 130
- Effect of blood clot on release of drug from DES 130
- Use of magnetized cell lining to prevent clotting of DES 131
- Long-term safety studies of DES 131
- Regulatory issues of DES 132
- Future prospects for treatment of restenosis by DES 133
- Future role of DES in management of cardiovascular diseases 133
- Stent cost and marketing strategies 134
- Improvements in stent technology 134
- Bioabsorbale stent 135
6. Markets for Cardiovascular Drug Delivery 137
- Introduction 137
- Epidemiology of cardiovascular disease 137
- Cost of care of cardiovascular disorders 138
- Cardiovascular markets according to important diseases 139
- Antithrombotics 139
- Anticholesterol agents 139
- Antihypertensive agents 140
- Drugs for congestive heart failure 140
- Markets for innovative technologies for cardiovascular disorders 140
- Markets for cell therapy of cardiovascular disorders 140
- Markets for gene therapy of cardiovascular disorders 141
- Markets for drug-eluting stents 141
- Major players in DES market 141
- Impact of safety issues on future markets for DES 141
- DES market in Asia 142
- Patenting and legal issues of DES 143
- The financial impact of DES on cardiovascular markets 143
- Unmet needs for cardiovascular drug delivery 144
- Role of DDS in developing cardiovascular markets 145
- Markets for cardiovascular devices 145
- Marketing of innovative cardiovascular drug delivery devices 145
- Direct to consumer advertising of DES 146
- Future trends in the integration of drug delivery with therapeutics 146
- Future prospects of cardiovascular drug delivery 146
7. Companies involved in Cardiovascular Drug Delivery 149
- Profiles of companies 149
- Collaborations 242
8. References 245
Tables
- Table 1 1: Landmarks in the historical evolution of cardiovascular drug delivery 13
- Table 1 2: Gene polymorphisms that alter cardiovascular response to drugs 18
- Table 2 1: Routes of drug delivery used for treatment of cardiovascular disorders 25
- Table 2 2: Formulations for drug delivery to the cardiovascular system 26
- Table 2 3: Improved methods of systemic drug delivery of cardiovascular drugs 32
- Table 2 4: Targeted delivery of therapeutic substances to the cardiovascular system 33
- Table 2 5: Classification of devices for drug delivery to the cardiovascular system 35
- Table 2 6: Various methods of delivery of therapeutic agents for hypertension 40
- Table 2 7: Marketed controlled/ extended release preparation for hypertension 41
- Table 2 8: Drug delivery in ischemic heart disease 44
- Table 2 9: Methods of delivery of nitrate therapy in angina pectoris 47
- Table 2 10: Drug delivery for peripheral arterial disorders 52
- Table 3 1: Clinical trials of cell therapy in cardiovascular disease 71
- Table 4 1: Cardiovascular disorders for which gene therapy is being considered 75
- Table 4 2: Catheter-based systems for vector delivery to the cardiovascular system 76
- Table 4 3: Potential applications of antisense in cardiovascular disorders 93
- Table 4 4: Companies involved in gene therapy of cardiovascular diseases 98
- Table 5 1: Treatment of restenosis 102
- Table 5 2: Devices used for drug delivery in restenosis 107
- Table 5 3: Companies involved in drug-eluting stents 117
- Table 6 1: Prevalence of cardiovascular disorders in major markets: US 2007-2017 138
- Table 6 2: Prevalence of cardiovascular disorders in major markets: Europe 2007-2017 138
- Table 6 3: Prevalence of cardiovascular disorders in major markets: Japan 2007-2017 138
- Table 6 4: Values of cardiovascular DDS in major markets 2007-2017 139
- Table 6 5: Markets for innovative technologies for cardiovascular disorders 2007-2017 140
- Table 7 1: Top 5 companies in cardiovascular drug delivery 149
- Table 7 2: Collaborations in cardiovascular drug delivery 242
Figures
- Figure 1 1: Drug delivery, biotechnology and cardiovascular diseases 23
- Figure 2 1: Microneedle for periarterial injection 37
- Figure 5 1: Vicious circle of vascular occlusion following angioplasty and stenting 103
- Figure 5 2: Medtronic' s Endeavour drug-eluting stent 114
- Figure 5 3: Magnetic nanoparticle-coated stent 116
- Figure 6 1: Unmet needs for cardiovascular drug delivery 144
