Reportlinker Adds Drug Delivery in Central Nervous System Diseases - technologies,markets and companies
NEW YORK, Sept. 7 /PRNewswire/ -- Reportlinker.com announces that a new market research report is available in its catalogue:
Drug Delivery in Central Nervous System Diseases - technologies,markets and companies
Summary
The delivery of drugs to central nervous system (CNS) is a challenge in the treatment of neurological disorders. Drugs may be administered directly into the CNS or administered systematically (e.g., by intravenous injection) for targeted action in the CNS. The major challenge to CNS drug delivery is the blood-brain barrier (BBB), which limits the access of drugs to the brain substance.
Advances in understanding of the cell biology of the BBB have opened new avenues and possibilities for improved drug delivery to the CNS. Several carrier or transport systems, enzymes, and receptors that control the penetration of molecules have been identified in the BBB endothelium. Receptor-mediated transcytosis can transport peptides and proteins across the BBB. Methods are available to assess the BBB permeability of drugs at the discovery stage to avoid development of drugs that fail to reach their target site of action in the CNS.
Various strategies that have been used for manipulating the blood-brain barrier for drug delivery to the brain include osmotic and chemical opening of the blood-brain barrier as well as the use of transport/carrier systems. Other strategies for drug delivery to the brain involve bypassing the BBB. Various pharmacological agents have been used to open the BBB and direct invasive methods can introduce therapeutic agents into the brain substance. It is important to consider not only the net delivery of the agent to the CNS, but also the ability of the agent to access the relevant target site within the CNS. Various routes of administration as well as conjugations of drugs, e.g., with liposomes and nanoparticles, are considered. Some routes of direct administration to the brain are non-invasive such as transnasal route whereas others involve entry into the CNS by devices and needles such as in case of intrathecal and intracerebroventricular delivery. Systemic therapy by oral and parenteral routes is considered along with sustained and controlled release to optimize the CNS action of drugs. Among the three main approaches to drug delivery to the CNS - systemic administration, injection into CSF pathways, and direct injection into the brain - the greatest developments is anticipated to occur in the area of targeted delivery by systemic administration.
Many of the new developments in the treatment of neurological disorders will be biological therapies and these will require innovative methods for delivery. Cell, gene and antisense therapies are not only innovative treatments for CNS disorders but also involve sophisticated delivery methods. RNA interference (RNAi) as a form of antisense therapy is also described.
The role of drug delivery is depicted in the background of various therapies for neurological diseases including drugs in development and the role of special delivery preparations. Pain is included as it is considered to be a neurological disorder. Cell and gene therapies will play an important role in the treatment of neurological disorders in the future.
The method of delivery of a drug to the CNS has an impact on the drug's commercial potential. The market for CNS drug delivery technologies is directly linked to the CNS drug market. Values are calculated for the total CNS market and the share of drug delivery technologies. Starting with the market values for the year 2009, projections are made to the years 2014 and 2019. The markets values are tabulated according to therapeutic areas, technologies and geographical areas. Unmet needs for further development in CNS drug delivery technologies are identified according to the important methods of delivery of therapeutic substances to the CNS. Finally suggestions are made for strategies to expand CNS delivery markets. Besides development of new products, these include application of innovative methods of delivery to older drugs to improve their action and extend their patent life.
Profiles of 71 companies involved in drug delivery for CNS disorders are presented along with their technologies, products and 69 collaborations. These include pharmaceutical companies that develop CNS drugs and biotechnology companies that provide technologies for drug delivery. A number of cell and gene therapy companies with products in development for CNS disorders are included. References contains over 400 publications that are cited in the report. The report is supplemented with 51 tables and 9 figures.
TABLE OF CONTENTS
0.Executive Summary 15
1.Basics of Drug Delivery to the Central Nervous System 17
Introduction 17
Historical evolution of drug delivery for CNS disorders 17
Neuroanatomical and neurophysiological basis of drug delivery 18
The cerebrospinal fluid 18
The extracellular space in the brain 19
Neurotransmitters 19
Neuropharmacology relevant to drug delivery 21
Introduction to neuropharmacology 21
Pharmacokinetics 21
Absorption and distribution of drugs 21
Drug metabolism and elimination 22
Pharmacodynamics 22
Receptors 22
Sites of drug action in the CNS 22
Receptors coupled to guanine nucleotide binding proteins 23
Acetylcholine receptor channels 23
Dopamine receptors 23
GABA receptor channels 24
Glutamate receptor channels 24
Non-competitive NMDA antagonists 24
Serotonin receptors 25
G-protein coupled receptors 25
In vivo study of drug action in the CNS in human patients 25
Electroencephalography 25
Brain imaging 26
Chronopharmacology as applied to the CNS 26
2.Blood Brain Barrier 29
Introduction 29
Features of the blood-brain barrier relevant to CNS drug delivery 29
The neurovascular unit 29
Functions of the BBB 30
BBB as an anatomical as well as physiological barrier 30
BBB as a biochemical barrier 31
Genomics and proteomics of BBB 31
Other neural barriers 32
Blood-cerebrospinal fluid barrier 32
Blood nerve barrier 32
Blood-retinal barrier 32
Blood-labyrinth barrier 32
Passage of substances across the blood-brain barrier 33
Transporters localized in the BBB 33
Glucose transporter 34
Amino acid transporters 35
Ionic transporter 35
Efflux transport systems 35
BBB-specific enzymes 36
Receptor-mediated transcytosis 37
Lysophosphatidic acid-mediated increade in BBB permeability 37
Folate transport system 38
Molecular biology of the BBB 38
Transport of peptides and proteins across the BBB 38
Passage of leptin across the BBB 38
Passage of cytokines across the BBB 39
Passage of hormones across the BBB 39
Passage of enzymes across the BBB 40
Drugs that cross the BBB by binding to plasma proteins 40
Current concepts of the permeability of the BBB 40
Factors that increase the permeability of the BBB 41
BBB disruption as adverse effect of vaccines for CNS disorders 41
CNS disorders that affect the permeability of BBB 42
Neurodegenerative disorders 43
Mitochondrial encephalopathies 44
Multiple sclerosis 44
Central nervous system injuries 44
Epilepsy 45
Cerebrovascular disease 45
Infections 46
Autoimmune disorders 46
BBB and primary brain tumors 46
BBB and cerebral metastases 47
Testing permeability of the BBB 47
In vitro models of BBB 47
In vivo study of BBB 48
Brain imaging 48
In silico prediction of BBB 49
Relevance of the BBB penetration to pharmacological action 50
BBB penetration and CNS drug screening 51
CERENSESM 51
Transthyretin monomer as a marker of blood-CSF barrier disruption 51
Evaluation of BBB permeability by brain imaging 51
Biomarkers of disruption of blood-brain barrier 52
Future directions for research on the BBB 52
Application of genomics and proteomics to the study of BBB 53
Use of neural stem cells to construct the blood brain barrier 53
Strategies to cross the BBB 54
3.Methods of Drug Delivery to the CNS 55
Introduction 55
Routes of drug delivery to the brain 56
Delivery of drugs to the brain via the nasal route 56
Nasal delivery of insulin-like growth factor-I 57
Nasal delivery of midazolam 57
Nasal delivery of hypocretin 58
Intranasal administration of IFN beta-1b 58
Nasal delivery of thyrotropin-releasing hormone by nanoconstructs 58
Nasal delivery of neuroprotective drugs for stroke 59
Transdermal drug delivery for neurological disorders 59
Drug delivery to the brain via inner ear 60
Invasive neurosurgical approaches 60
Intraarterial drug delivery to the brain 60
Direct injection into the CNS substance or CNS lesions 61
Intraventricular injection of drugs 61
Intrathecal drug delivery 62
Retrograde delivery to the brain via the epidural venous system 63
Devices for drug delivery to the CNS 63
Strategies for drug delivery to the CNS across the BBB 64
Increasing the permeability (opening) of the BBB 65
Osmotic opening of the BBB 65
Focal disruption of BBB by ultrasound 65
Chemical opening of the BBB 66
Cerebral vasodilatation to open the BBB 66
Use of nitric oxide donors to open the BBB 66
Manipulation of the sphingosine 1-phosphate receptor system 67
Pharmacological strategies to facilitate transport across the BBB 67
2B-Trans™ technology 67
ABC afflux transporters and penetration of the BBB 68
Carrier-mediated drug delivery across the BBB 68
G-Technology® 69
Glycosylation Independent Lysosomal Targeting 70
Inhibition of P-glycoprotein to enhance drug delivery across the BBB 70
Modification of the drug to enhance its lipid solubility 70
Monoclonal antibody fusion proteins 71
Neuroimmunophilins 72
Peptide-mediated transport across the BBB 72
Prodrug bioconversion strategies and their CNS selectivity 73
Role of the transferrin-receptor system in CNS drug delivery 74
Transport of small molecules across the BBB 74
Transport across the BBB by short chain oligoglycerolipids 74
Transvascular delivery across the BBB 75
Trojan horse approach 75
Use of receptor-mediated transocytosis to cross the BBB 76
Cell-based drug delivery to the CNS 77
Activated T lymphocytes 78
Microglial cells 78
Neural stem cells 78
Drug delivery to the CNS by using novel formulations 78
Crystalline formulations 78
Liposomes 79
Monoclonal antibodies 80
Microspheres 80
Microbeads 81
Brain-targeted chemical delivery systems 81
Nanotechnology-based drug delivery to CNS 82
Nanoparticles for drug delivery across the BBB 82
Penetration of BBB by nanoparticles coated with polysorbate 80 83
NanoDel? technology for crossing the BBB 83
Masking BBB-limiting characteristics by nanotechnology 83
Peptide-nanoparticle conjugates for crossing the BBB 84
Nanovesicles for transport across BBB 84
Nanotechnology-based devices and implants for CNS 84
Biochip implants for drug delivery to the CNS 85
Controlled-release microchip 85
Retinal implant chip 85
Convection-enhanced delivery to the CNS 86
Systemic administration of drugs for CNS effects 86
Sustained and controlled release drug delivery to the CNS 86
Fast dissolving oral selegiline 88
Choice of the route of systemic delivery for effect on the CNS disorders 88
Methods of delivery of biopharmaceuticals to the CNS 89
Delivery of biopharmaceuticals across the BBB 89
Methods of delivery of peptides for CNS disorders 89
Challenges for delivery of peptides across the BBB 90
Transnasal administration of neuropeptides 90
Direct delivery of neuropeptides into the brain 90
Alteration of properties of the BBB for delivery of peptides 91
Molecular manipulations of peptides to facilitate transport into CNS 91
CNS delivery of peptides via conjugation to biological carriers 92
Delivery of conopeptides to the brain 92
Delivery of neurotrophic factors to the nervous system 93
Systemic administration of NTFs 94
Delivery systems to facilitate crossing of the BBB by NTFs 95
Use of microspheres for delivery of neurotrophic factors 96
Intracerebroventricular injection 96
Direct application of NTFs to the CNS 97
Intrathecal administration 97
Implants for delivery of neurotrophic factors 97
Use of neurotrophic factor mimics 98
Use of microorganisms for therapeutic entry into the brain 99
Bacteriophages as CNS therapeutics 99
Intracellular drug delivery in the brain 100
Local factors in the brain affecting drug action 100
Methods for testing drug delivery to the CNS 100
Animal models for testing drug delivery 100
Screening for drug-P-gp interaction at BBB 101
4.Delivery of Cell, Gene and Antisense Therapies to the CNS 103
Introduction 103
Cell therapy of neurological disorders 103
Methods for delivering cell therapies in CNS disorders 103
Encapsulated cells 104
Genetically modified stem cells for metachromatic leukodystrophy 105
CNS neotissue implant 105
CNS delivery of cells by catheters 105
Subarachnoid delivery of stem cells 106
Intravascular administration 106
Gene therapy techniques for the nervous system 107
Introduction 107
Methods of gene transfer to the nervous system 108
AAV vector mediated gene therapy for neurogenetic disorders 109
Ideal vector for gene therapy of neurological disorders 109
Promoters of gene transfer 109
Routes of delivery of genes to the nervous system 110
Direct injection into CNS 110
Introduction of the genes into cerebral circulation 111
Introduction of genes into cerebrospinal fluid 111
Intravenous administration of vectors 111
Delivery of gene therapy to the peripheral nervous system 112
Cell-mediated gene therapy of neurological disorders 112
Neuronal cells 112
Neural stem cells and progenitor cells 112
Astrocytes 112
Cerebral endothelial cells 113
Implantation of genetically modified encapsulated cells into the brain 113
Genetically modified bone marrow cells 113
Nanoparticles as non-viral vectors for CNS gene therapy 114
Applications of gene therapy for neurological disorders 114
Companies involved in cell/gene therapy of neurological disorders 115
Antisense therapy of CNS disorders 116
Delivery of antisense oligonucleotides to the CNS 117
Delivery of oligonucleotides cross the BBB 118
Cellular delivery systems for oligonucleotides 118
High-flow microinfusion into the brain parenchyma 119
Systemic administration of peptide nucleic acids 119
Introduction of antisense compounds into the CSF Pathways 119
Intrathecal administration of antisense compounds 120
Intracerebroventricular administration of antisense oligonucleotides 120
Nanoparticle-based delivery of antisense therapy to the CNS 121
Methods of delivery of ribozymes 121
Delivery aspects of RNAi therapy of CNS disorders 122
Delivery of siRNA to the CNS 122
Future drug delivery strategies applicable to the CNS 122
5.Drug Delivery in the Treatment of CNS Disorders 125
Parkinson's disease 125
Drug delivery systems for Parkinson's disease 126
Duodenal levodopa infusion 128
Transdermal drug delivery for PD 128
Transdermal dopamine agonists for Parkinson's disease 128
Transdermal administration of other drugs for Parkinson's disease 130
Intracerebral administration of GDNF 130
Cell therapy for Parkinson's disease 130
Human dopaminergic neurons for PD 132
Graft survival-enhancing drugs 132
Xenografting porcine fetal neurons 132
Encapsulated cells for PD 133
Stem cells for PD 133
Engineered stem cells for drug delivery to the brain in PD 135
Human retinal pigment epithelium cells for PD 135
Delivery of cells for PD 136
Gene therapy for Parkinson disease 136
Rationale 136
Techniques of gene therapy for PD 137
Prospects of gene therapy for Parkinson's disease 140
Companies developing gene therapy for PD 141
RNAi therapy of Parkinson's disease 141
Alzheimer disease 142
Drug delivery for Alzheimer disease 142
Blood-brain partitioning of an AMPA receptor modulator 143
Clearing amyloid through the BBB 143
Delivery of the passive antibody directly to the brain 143
Delivery of thyrotropin-releasing hormone analogs by molecular packaging 144
Intranasal delivery of nerve growth factor to the brain 144
Nanoparticle-based drug delivery for Alzheimer's disease 144
Perispinal etanercept 145
Slow release implant of an AChE inhibitor 145
Transdermal drug delivery in Alzheimer's disease 145
Trojan-horse approach to prevent build-up of A? aggregates 146
Cell and gene therapy for Alzheimer disease 146
NGF gene therapy 146
Neprilysin gene therapy 147
RNAi therapy of Alzheimer's disease 148
Huntington's disease 148
Treatment of Huntington's disease 148
Drug delivery in Huntington's disease 149
Gene therapy of Huntington's disease 149
Encapsulated genetically engineered cellular implants 149
Viral vector mediated administration of neurotrophic factors 149
RNAi therapeutics for the treatment of HD 149
Amyotrophic lateral sclerosis 149
Treatment of ALS 150
Drug delivery in ALS 150
Gene and antisense therapy of amyotrophic lateral sclerosis 151
Neurotrophic factor gene therapies of ALS 151
Antisense therapy of ALS 153
RNAi therapy of amyotrophic lateral sclerosis 153
Drug delivery for CNS involvement in Hunter syndrome 153
Cerebrovascular disease 154
Treatment of stroke 154
Drug delivery in stroke 155
Intraarterial administration of tissue plasminogen activator in stroke 155
Drug delivery for prevention of restenosis of carotid arteries 156
Modified NO donors 157
In-stent restenosis 157
Targeted local anti-restenotic drug delivery 158
Catheter-based drug delivery for restenosis 158
Stents for prevention of restenosis 158
Drug-eluting stents 159
Antisense approach to prevent restenosis 160
Drug-eluting stents for the treatment of intracranial atherosclerosis 160
Tissues transplants for stroke 160
Transplant of encapsulated tissue secreting neurotrophic factors 161
Cell therapy for stroke 161
Stem cell transplant into the brain 161
Immortalized cell grafts for stroke 162
Intravenous infusion of marrow stromal cells 162
Intravenous infusion of umbilical cord blood stem cells 162
Future of cell therapy for stroke 163
Gene therapy of cerebrovascular diseases 163
Gene transfer to cerebral blood vessels 163
NOS gene therapy for restenosis 164
Gene therapy for cerebral ischemia 165
Gene therapy of strokes with a genetic component 166
Drug delivery to intracranial aneurysms 166
Drug delivery for vasospasm following subarachnoid hemorrhage 167
Intrathecal tissue plasminogen activator 168
Gene therapy for vasospasm 168
Drug delivery in multiple sclerosis 169
An electronic device for self injection of interferon beta-1a 170
Oral therapies for MS 170
Antisense and RNAi approaches to MS 170
Cell therapy for multiple sclerosis 171
Hematopoietic stem cell transplantation for multiple sclerosis 171
Embryonic stem cells and neural precursor cells for MS 171
Gene therapy for multiple sclerosis 172
Drug delivery in epilepsy 172
Routes of administration of antiepileptic drugs 173
Controlled-release preparations of carbamazepine 173
Intravenous carbamazepine 173
Various methods of delivery of diazepam 174
Methods of delivery of novel antiepileptic therapies 174
Regulated activation of prodrugs 174
Use of neuronal membrane transporter 174
Delivery of the antiepileptic conopeptides to the brain 174
Nasal administration of AEDs 175
Intracerebral administration of phenytoin 175
The role of drug delivery in status epilepticus 175
Cell therapy of epilepsy 176
Gene therapy for epilepsy 177
Gene therapy for neuroprotection in epilepsy 177
Concluding remarks on drug delivery in epilepsy 178
Drug delivery for pain 178
Intranasal delivery of analgesics 179
Intranasal administration of morphine 179
Intranasal morphine derivatives 180
Intranasal fentanyl 180
Intranasal buprenorphine 181
Intranasal ketamine 181
Intranasal ketorolac 181
Delivery of analgesics by inhalation 182
Spinal delivery of analgesics 183
Epidural dexamethasone 185
Epidural morphine 185
Relief of pain by intrathecal ziconotide 185
Intrathecal neostigmine 186
Intrathecal prostaglandin antagonists 186
Intrathecal fadolmidine 186
Intrathecal siRNA for relief of neuropathic pain 187
Concluding remarks on intrathecal delivery of analgesic agents 187
Intracerebroventricular drug delivery for pain 187
Delivery of analgesics to the CNS across the BBB 187
Drug delivery for migraine 188
Management of migraine 188
Novel drug delivery methods for migraine 189
Nasal formulations for migraine 190
Sublingual spray for migraine 191
Needle-free drug delivery for migraine 191
Relief of spasticity by intrathecal baclofen 191
Drug delivery for brain tumors 192
Methods for evaluation of anticancer drug penetration into brain tumor 192
Innovative methods of drug delivery for glioblastoma multiforme 192
Anticancer agents with increased penetration of BBB 193
Local delivery of chemotherapeutic agents into the tumor 194
Carmustine biodegradable polymer implants 194
Fibrin glue implants containing anticancer drugs. 194
Biodegradable microspheres containing 5-FU 195
Nanoparticles for delivery of drugs to brain tumors across BBB 195
Convection-enhanced delivery 196
Delivery of antibody-based anticancer therapy by ultrasound BBB disruption 196
Targeted monoclonal antibodies conjugated with liposomes 197
Immunoliposomes 197
Lipid-coated microbubbles as a delivery vehicle for taxol 197
Thermoliposomes containing cytotoxic drugs 197
Introduction of the chemotherapeutic agent into the CSF pathways 197
Intrathecal chemotherapy 197
Intraventricular chemotherapy for meningeal cancer 198
Increasing the permeability of blood-tumor barrier to anticancer drugs 198
Disruption of BBB 198
Nanoparticle-based targeted delivery of chemotherapy across the BBB 199
Modulating efflux transporters to enhance chemotherapy penetration 200
PDE5 inhibitors for enhancing tumor permeability to chemotherapy 200
Intraarterial chemotherapy 201
Interstitial delivery of dexamethasone for reduction of peritumor edema 201
Photodynamic therapy for chemosensitization 201
Boron neutron capture therapy 202
Gene therapy for glioblastoma multiforme. 203
Single-chain antibody-targeted adenoviral vectors 204
Peptides targeted to glial tumor cells 204
Antiangiogenic gene therapy 204
RNAi gene therapy of brain cancer 205
Drug delivery for traumatic brain injury 205
Cell therapy of traumatic brain injury 205
Gene therapy for traumatic brain injury 206
Drug delivery for spinal cord injury 206
Administration of neurotrotrophic factors for spinal cord injury 207
Cell therapy for spinal cord injury 207
Transplantation of glial cells for SCI 207
Fetal neural grafts for SCI 207
Embryonic stem cells for SCI 208
Schwann cell transplants for SCI 208
Olfactory glial cells for SCI 208
Marrow stromal cells for SCI 209
Intravenous injection of stem cells for spinal cord repair 209
Combinatorial approach for regeneration in SCI 209
Cell therapy of syringomyelia 210
Gene therapy of spinal cord injury 210
Drug delivery for retinal disorders 210
Age-related macular degeneration 211
TheraSight ocular brachytherapy system for wet AMD 211
Combretastatin A4P for myopic macular degeneration 211
Gene therapy for AMD 212
Anti-VEGF approach to AMD 212
Delivery of aptamers for treatment of AMD 212
Stem cell therapy for retinitis pigmentosa 213
Proliferative retinopathies 213
Drug delivery in CNS infections 214
Drug delivery in neuroAIDS 214
6.Markets for Drug Delivery in CNS Disorders 215
Introduction 215
Methods of calculation of CNS drug delivery markets 215
Markets for CNS drug delivery technologies 215
Drug delivery share in selected CNS markets 216
CNS share of drug delivery technologies 216
Geographical distribution of CNS drug delivery markets 217
Impact of improved drug delivery on CNS drug markets 217
Neurodegenerative disorders 217
Alzheimer's disease 217
Parkinson's Disease 218
Huntington's disease 218
Amyotrophic lateral sclerosis 218
Epilepsy 219
Migraine and other headaches 219
Stroke 219
Spinal cord injury 220
Multiple sclerosis 220
Brain tumors 220
Limitations of the current drug delivery technologies for CNS 220
Unmet needs in CNS drug delivery technologies 221
Future strategies for expanding CNS drug delivery markets 222
Education of neurologists 222
Demonstration of the advantages of the newer methods of delivery 222
Rescue of old products by novel drug delivery methods 223
Facilitation of the approval process of new drugs 223
7. Companies 225
Introduction 225
Profiles 225
Collaborations 300
8.References 303
Tables
Table 1 1: Landmarks in the development of drug delivery to the CNS 17
Table 2 1: Proteins expressed at the neurovascular unit 30
Table 2 2: Transporters that control penetration of molecules across the BBB 34
Table 2 3: Enzymes that control the penetration of molecules across the BBB 36
Table 2 4: Factors that increase the permeability of the BBB 41
Table 2 5: Diseases that affect the BBB 42
Table 3 1: Various methods of drug delivery to the central nervous system 55
Table 3 2: Drugs available for intrathecal administration 62
Table 3 3: Strategies for drug delivery to the CNS across the BBB 65
Table 3 4: Specific inhibitors of P-glycoprotein in clinical development 70
Table 3 5: Molecules attached to Trojan horses injected intravenously for CNS effect 75
Table 3 6: Examples of controlled and sustained release drug delivery for CNS disorders 87
Table 3 7: Novel methods of delivery of drugs for CNS disorders 89
Table 3 8: Indications for the clinical applications of NTFs in neurologic disorders 93
Table 3 9: Methods for delivery of neurotrophic factors to the CNS 94
Table 4 1: Methods for delivering cell therapies in CNS disorders 104
Table 4 2: Classification of methods of gene therapy 107
Table 4 3: Methods of gene transfer as applied to neurologic disorders 108
Table 4 4: Potential indications for gene therapy of neurologic disorders 114
Table 4 5: Companies developing cell/gene therapies for CNS disorders 115
Table 4 6: Methods of antisense delivery as applied to the CNS 117
Table 5 1: Strategies for the treatment of Parkinson's disease 125
Table 5 2: Drug delivery systems for Parkinson's disease 127
Table 5 3: Types of cell used for investigative treatment of Parkinson's disease 131
Table 5 4: Status of cell therapies in development for Parkinson's disease 131
Table 5 5: Gene therapy techniques applicable to Parkinson disease 137
Table 5 6: Companies developing gene therapy for Parkinson's disease 141
Table 5 7: Classification of pharmacotherapy for Alzheimer disease 142
Table 5 8: Novel drug delivery methods for Alzheimer disease therapies 142
Table 5 9: Classification of neuroprotective agents for amyotrophic lateral sclerosis 150
Table 5 10: Methods of delivery of therapies in development for ALS 151
Table 5 11: Classification of treatments for stroke 154
Table 5 12: Treatments of stroke involving innovative drug delivery methods 155
Table 5 13: Drug delivery for prevention of carotid artery restenosis after angioplasty 157
Table 5 14: Gene transfer in animal models of carotid artery restenosis 164
Table 5 15: Neuroprotective gene transfer strategies in models of cerebral ischemia 165
Table 5 16: Gene Therapy for reducing cerebral infarction in animal stroke models 166
Table 5 17: Pharmacological agents for treatment of cerebral vasospasm 167
Table 5 18: Gene therapy strategies for vasospasm 168
Table 5 19: A classification of drug delivery methods used in management of pain 178
Table 5 20: Spinal administration of drugs for pain 183
Table 5 21: Investigational drugs for pain administered by intrathecal route 184
Table 5 22: Current management of migraine 189
Table 5 23: Novel drug delivery methods for migraine 190
Table 5 24: Innovative methods of drug delivery for glioblastoma multiforme 193
Table 5 25: Strategies for gene therapy of malignant brain tumors 203
Table 6 1: Share of drug delivery technologies in selected CNS markets: 2009-2019 216
Table 6 2: CNS market share of drug delivery technologies 2009-2019 216
Table 6 3: Value of CNS drug delivery in the major world markets from 2009-2019 217
Table 6 4: Limitations of the current drug delivery technologies for CNS 221
Table 7 1: Collaborations of companies in CNS drug delivery 300
Figures
Figure 1 1: Interaction of neurotransmitters with receptors 20
Figure 2 1: The neurovascular unit 29
Figure 2 2: Various forms of passage of substances across the blood brain barrier 33
Figure 3 1: Routes of drug delivery to the brain 56
Figure 3 2: Use of receptor-mediated transcytosis to cross the BBB 76
Figure 5 1: Oral versus transdermal administration of a drug in Parkinson's disease 129
Figure 5 2: Effect of tyrosine hydroxylase gene delivery on dopamine levels 138
Figure 5 3: A concept of targeted drug delivery to GBM across the BBB 199
Figure 6 1: Unmet needs in the CNS drug delivery technologies 221
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