中枢神经疾病给药技术：技术・市场・企业

Abstract

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 2007, projections are made to the years 2012 and 2017. 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 68 companies involved in drug delivery for CNS disorders are presented along with their technologies, products and 63 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 50 tables and 8 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 45
• Autoimmune disorders 46
• Brain tumors 46
• Testing permeability of the BBB 46
• In vitro models of BBB 47
• In vivo study of BBB 47
• Brain imaging 48
• In silico prediction of BBB 48
• Relevance of the BBB penetration to pharmacological action 49
• BBB penetration and CNS drug screening 50
• CERENSESM 50
• Transthyretin monomer as a marker of blood-CSF barrier disruption 50
• Evaluation of BBB permeability by brain imaging 51
• Biomarkers of disruption of blood-brain barrier 51
• Future directions for research on the BBB 51
• Application of genomics and proteomics to the study of BBB 52
• Use of neural stem cells to construct the blood brain barrier 53
• Strategies to cross the BBB 53

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
• Transdermal drug delivery for neurological disorders 59
• Drug delivery to the brain via inner ear 59
• 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 61
• 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 64
• Osmotic opening of the BBB 64
• Focal disruption of BBB by ultrasound 65
• Chemical opening of the BBB 65
• Cerebral vasodilatation to open the BBB 65
• Use of nitric oxide donors to open the BBB 66
• Manipulation of the sphingosine 1-phosphate receptor system 66
• Pharmacological strategies to facilitate transport across the BBB 66
• 2B-Trans"! technology with specific carrier protein 67
• ABC afflux transporters and penetration of the BBB 67
• Carrier-mediated drug delivery across the BBB 68
• Glutathione transporters for drug delivery across the BBB 68
• Glycosylation Independent Lysosomal Targeting 68
• Inhibition of P-glycoprotein to enhance drug delivery across the BBB 69
• Modification of the drug to enhance its lipid solubility 69
• Monoclonal antibody fusion proteins 70
• Neuroimmunophilins 70
• Peptide-mediated transport across the BBB 70
• Prodrug bioconversion strategies and their CNS selectivity 72
• Role of the transferrin-receptor system in CNS drug delivery 73
• Transport of small molecules across the BBB 73
• Transport across the BBB by short chain oligoglycerolipids 73
• Transvascular delivery across the BBB 73
• Trojan horse approach 74
• Use of receptor-mediated transocytosis to cross the BBB 75
• Cell-based drug delivery to the CNS 76
• Activated T lymphocytes 76
• Microglial cells 76
• Neural stem cells 76
• Drug delivery to the CNS by using novel formulations 77
• Crystalline formulations 77
• Liposomes 77
• Monoclonal antibodies 78
• Microspheres 79
• Microbeads 79
• Lipid-coated microbubbles 80
• Brain-targeted chemical delivery systems 80
• Nanotechnology-based drug delivery to CNS 81
• Nanoparticles for drug delivery to CNS 81
• Nanovesicles for transport across BBB 82
• Nanotechnology-based devices and implants for CNS 82
• Biochip implants for drug delivery to the CNS 83
• Controlled-release microchip 83
• Retinal implant chip 83
• Convection-enhanced delivery to the CNS 84
• Systemic administration of drugs for CNS effects 85
• Sustained and controlled release drug delivery to the CNS 85
• Fast dissolving oral selegiline 86
• Choice of the route of systemic delivery for effect on the CNS disorders 87
• Methods of delivery of biopharmaceuticals to the CNS 87
• Delivery of biopharmaceuticals across the BBB 87
• Methods of delivery of peptides for CNS disorders 88
• Challenges for delivery of peptides across the BBB 88
• Transnasal administration of neuropeptides 88
• Direct delivery of neuropeptides into the brain 89
• Alteration of properties of the BBB for delivery of peptides 89
• Molecular manipulations of peptides to facilitate transport into CNS 89
• CNS delivery of peptides via conjugation to biological carriers 90
• Delivery of conopeptides to the brain 90
• Delivery of neurotrophic factors to the nervous system 91
• Systemic administration of NTFs 92
• Delivery systems to facilitate crossing of the BBB by NTFs 93
• Use of microspheres for delivery of neurotrophic factors 94
• Intracerebroventricular injection 94
• Direct application of NTFs to the CNS 95
• Intrathecal administration 95
• Implants for delivery of neurotrophic factors 95
• Use of neurotrophic factor mimics 96
• Use of microorganisms for therapeutic entry into the brain 97
• Bacteriophages as CNS therapeutics 97
• Intracellular drug delivery in the brain 98
• Local factors in the brain affecting drug action 98
• Methods for testing drug delivery to the CNS 98
• Animal models for testing drug delivery 98
• Screening for drug-P-gp interaction at BBB 99

4. Delivery of Cell, Gene and Antisense Therapies to the CNS 101

• Introduction 101
• Cell therapy of neurological disorders 101
• Methods for delivering cell therapies in CNS disorders 101
• Encapsulated cells 102
• Genetically modified stem cells for metachromatic leukodystrophy 103
• CNS neotissue implant 103
• CNS delivery of cells by catheters 103
• Subarachnoid delivery of stem cells 104
• Intravascular administration 104
• Gene therapy techniques for the nervous system 105
• Introduction 105
• Methods of gene transfer to the nervous system 106
• AAV vector mediated gene therapy for neurogenetic disorders 107
• Ideal vector for gene therapy of neurological disorders 107
• Promoters of gene transfer 107
• Routes of delivery of genes to the CNS 108
• Cell-mediated gene therapy of neurological disorders 109
• Neuronal cells 109
• Implantation of genetically modified encapsulated cells into the brain 110
• Genetically modified bone marrow cells 110
• Nanoparticles as non-viral vectors for CNS gene therapy 111
• Companies involved in cell/gene therapy of neurological disorders 111
• Antisense therapy of CNS disorders 112
• Delivery of antisense oligonucleotides to the CNS 113
• Delivery of oligonucleotides cross the BBB 114
• Cellular delivery systems for oligonucleotides 114
• High-flow microinfusion into the brain parenchyma 115
• Systemic administration of peptide nucleic acids 115
• Introduction of antisense compounds into the CSF Pathways 115
• Intrathecal administration of antisense compounds 116
• Intracerebroventricular administration of antisense oligonucleotides 116
• Nanoparticle-based delivery of antisense therapy to the CNS 117
• Methods of delivery of ribozymes 117
• Delivery aspects of RNAi therapy of CNS disorders 118
• Delivery of siRNA to the CNS 118
• Future drug delivery strategies applicable to the CNS 118

5. Drug Delivery in the Treatment of CNS Disorders 119

• Parkinson' s disease 119
• Drug delivery systems for Parkinson' s disease 120
• Duodenal levodopa infusion 122
• Transdermal drug delivery for PD 122
• Transdermal dopamine agonists for Parkinson' s disease 122
• Transdermal administration of other drugs for Parkinson' s disease 124
• Intracerebral administration of GDNF 124
• Cell therapy for Parkinson' s disease 124
• Human dopaminergic neurons for PD 126
• Graft survival-enhancing drugs 126
• Xenografting porcine fetal neurons 126
• Encapsulated cells for PD 127
• Stem cells for PD 127
• Engineered stem cells for drug delivery to the brain in PD 129
• Human retinal pigment epithelium cells for PD 129
• Delivery of cells for PD 130
• Gene therapy for Parkinson disease 130
• Rationale 130
• Techniques of gene therapy for PD 131
• Prospects of gene therapy for Parkinson' s disease 134
• Companies developing gene therapy for PD 135
• RNAi therapy of Parkinson' s disease 135
• Alzheimer disease 136
• Drug delivery for Alzheimer disease 136
• Blood-brain partitioning of an AMPA receptor modulator 137
• Clearing amyloid through the BBB 137
• Delivery of the passive antibody directly to the brain 138
• Delivery of thyrotropin-releasing hormone analogs by molecular packaging 138
• Intranasal delivery of nerve growth factor to the brain 138
• Nanoparticle-based drug delivery for Alzheimer' s disease 139
• Perispinal etanercept 139
• Slow release implant of an AChE inhibitor 139
• Transdermal drug delivery in Alzheimer' s disease 140
• Trojan-horse approach to prevent build-up of Aβ aggregates 140
• Cell and gene therapy for Alzheimer disease 141
• NGF gene therapy 141
• Neprilysin gene therapy 142
• RNAi therapy of Alzheimer' s disease 142
• Huntington' s disease 142
• Treatment of Huntington' s disease 143
• Drug delivery in Huntington' s disease 143
• Gene therapy of Huntington' s disease 143
• Encapsulated genetically engineered cellular implants 143
• Viral vector mediated administration of neurotrophic factors 143
• RNAi therapeutics for the treatment of HD 144
• Amyotrophic lateral sclerosis 144
• Treatment of ALS 144
• Drug delivery in ALS 145
• Gene and antisense therapy of amyotrophic lateral sclerosis 146
• Neurotrophic factor gene therapies of ALS 146
• Antisense therapy of ALS 147
• RNAi therapy of amyotrophic lateral sclerosis 147
• Drug delivery for CNS involvement in Hunter syndrome 148
• Cerebrovascular disease 148
• Treatment of stroke 148
• Drug delivery in stroke 149
• Intraarterial administration of tissue plasminogen activator in stroke 150
• Drug delivery for prevention of restenosis of carotid arteries 150
• Modified NO donors 151
• In-stent restenosis 151
• Targeted local anti-restenotic drug delivery 152
• Catheter-based drug delivery for restenosis 152
• Stents for prevention of restenosis 153
• Drug-eluting stents 153
• Antisense approach to prevent restenosis 154
• Drug-eluting stents for the treatment of intracranial atherosclerosis 154
• Tissues transplants for stroke 155
• Transplant of encapsulated tissue secreting neurotrophic factors 155
• Cell therapy for stroke 155
• Stem cell transplant into the brain 155
• Immortalized cell grafts for stroke 156
• Intravenous infusion of marrow stromal cells 156
• Intravenous infusion of umbilical cord blood stem cells 157
• Future of cell therapy for stroke 157
• Gene therapy of cerebrovascular diseases 157
• Gene transfer to cerebral blood vessels 157
• NOS gene therapy for restenosis 159
• Gene therapy for cerebral ischemia 159
• Gene therapy of strokes with a genetic component 161
• Drug delivery to intracranial aneurysms 161
• Drug delivery for vasospasm following subarachnoid hemorrhage 161
• Intrathecal tissue plasminogen activator 163
• Gene therapy for vasospasm 163
• Drug delivery in multiple sclerosis 164
• Oral therapies for MS 164
• Antisense and RNAi approaches to MS 165
• Cell therapy for multiple sclerosis 165
• Hematopoietic stem cell transplantation for multiple sclerosis 165
• Embryonic stem cells and neural precursor cells for MS 166
• Gene therapy for multiple sclerosis 166
• Drug delivery in epilepsy 167
• Routes of administration of antiepileptic drugs 167
• Controlled-release preparations of carbamazepine 167
• Various methods of delivery of diazepam 168
• Methods of delivery of novel antiepileptic therapies 168
• Regulated activation of prodrugs 168
• Use of neuronal membrane transporter 168
• Delivery of the antiepileptic conopeptides to the brain 169
• Nasal administration of AEDs 169
• Intracerebral administration of phenytoin 169
• The role of drug delivery in status epilepticus 170
• Cell therapy of epilepsy 170
• Gene therapy for epilepsy 171
• Gene therapy for neuroprotection in epilepsy 171
• Concluding remarks on drug delivery in epilepsy 172
• Drug delivery for pain 172
• Intranasal delivery of analgesics 173
• Intranasal administration of morphine 173
• Intranasal fentanyl 174
• Intranasal ketamine 174
• Delivery of analgesics by inhalation 175
• Spinal delivery of analgesics 175
• Epidural administration of encapsulated morphine 177
• Relief of pain by intrathecal ziconotide 177
• Intrathecal neostigmine 178
• Intrathecal prostaglandin antagonists 178
• Intrathecal non-NMDA antagonists 179
• Intrathecal siRNA for relief of neuropathic pain 179
• Intracerebroventricular drug delivery for pain 179
• Delivery of analgesics to the CNS across the BBB 179
• Drug delivery for migraine 179
• Management of migraine 180
• Novel drug delivery methods for migraine 181
• Nasal formulations for migraine 182
• Sublingual spray for migraine 182
• Needle-free drug delivery for migraine 182
• Relief of spasticity by intrathecal baclofen 183
• Drug delivery for brain tumors 183
• Methods for evaluation of anticancer drug penetration into brain tumor 183
• Innovative methods of drug delivery for glioblastoma multiforme 184
• Anticancer agents with increased penetration of BBB 184
• Local delivery of chemotherapeutic agents into the tumor 185
• Carmustine biodegradable polymer implants 185
• Fibrin glue implants containing anticancer drugs 186
• Biodegradable microspheres containing 5-FU 186
• Nanoparticles for delivery of drugs to brain tumors across BBB 186
• Convection-enhanced delivery 187
• Delivery of antibody-based anticancer therapy by ultrasound BBB disruption 188
• Targeted monoclonal antibodies conjugated with liposomes 188
• Immunoliposomes 188
• Lipid-coated microbubbles as a delivery vehicle for taxol 188
• Thermoliposomes containing cytotoxic drugs 188
• Introduction of the chemotherapeutic agent into the CSF pathways 189
• Intrathecal chemotherapy 189
• Intraventricular chemotherapy for meningeal cancer 189
• Increasing the permeability of blood-tumor barrier to anticancer drugs 190
• Disruption of BBB 190
• Modulating efflux transporters to enhance chemotherapy penetration 190
• PDE5 inhibitors for enhancing tumor permeability to chemotherapy 191
• Intra-arterial chemotherapy 191
• Interstitial delivery of dexamethasone for reduction of peritumor edema 191
• Photodynamic therapy for chemosensitization 192
• Boron neutron capture therapy 192
• Gene therapy for glioblastoma multiforme 193
• Single-chain antibody-targeted adenoviral vectors 194
• Peptides targeted to glial tumor cells 194
• Antiangiogenic gene therapy 194
• RNAi gene therapy of brain cancer 195
• Drug delivery for traumatic brain injury 195
• Cell therapy of traumatic brain injury 195
• Gene therapy for traumatic brain injury 196
• Drug delivery for spinal cord injury 196
• Administration of neurotrotrophic factors for spinal cord injury 197
• Cell therapy for spinal cord injury 197
• Transplantation of glial cells for SCI 197
• Fetal neural grafts for SCI 198
• Embryonic stem cells for SCI 198
• Schwann cell transplants for SCI 198
• Olfactory glial cells for SCI 199
• Marrow stromal cells for SCI 199
• Intravenous injection of stem cells for spinal cord repair 199
• Combinatorial approach for regeneration in SCI 199
• Cell therapy of syringomyelia 200
• Gene therapy of spinal cord injury 200
• Drug delivery for retinal disorders 200
• Age-related macular degeneration 201
• TheraSight ocular brachytherapy system for wet AMD 201
• Combretastatin A4P for myopic macular degeneration 201
• Gene therapy for AMD 202
• Anti-VEGF approach to AMD 202
• Delivery of aptamers for treatment of AMD 203
• Stem cell therapy for retinitis pigmentosa 203
• Proliferative retinopathies 204
• Drug delivery in CNS infections 204
• Drug delivery in neuroAIDS 204

6. Markets for Drug Delivery in CNS Disorders 207

• Introduction 207
• Methods of calculation of CNS drug delivery markets 207
• Markets for CNS drug delivery technologies 207
• Drug delivery share in selected CNS markets 208
• CNS share of drug delivery technologies 208
• Geographical distribution of CNS drug delivery markets 209
• Impact of improved drug delivery on CNS drug markets 209
• Neurodegenerative disorders 209
• Alzheimer' s disease 209
• Parkinson' s Disease 210
• Huntington' s disease 210
• Amyotrophic lateral sclerosis 210
• Epilepsy 211
• Migraine and other headaches 211
• Stroke 211
• Spinal cord injury 212
• Multiple sclerosis 212
• Brain tumors 212
• Limitations of the current drug delivery technologies for CNS 212
• Unmet needs in CNS drug delivery technologies 213
• Future strategies for expanding CNS drug delivery markets 214
• Education of neurologists 214
• Demonstration of the advantages of the newer methods of delivery 214
• Rescue of old products by novel drug delivery methods 215
• Facilitation of the approval process of new drugs 215

7. Companies 217

• Introduction 217
• Profiles 217
• Collaborations 290

8. References 293

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 64
• Table 3 4: Specific inhibitors of P-glycoprotein in clinical development 69
• Table 3 5: Molecules attached to Trojan horses injected intravenously for CNS effect 74
• Table 3 6: Examples of controlled and sustained release drug delivery for CNS disorders 86
• Table 3 7: Novel methods of delivery of drugs for CNS disorders 87
• Table 3 8: Indications for the clinical applications of NTFs in neurologic disorders 91
• Table 3 9: Methods for delivery of neurotrophic factors to the CNS 92
• Table 4 1: Methods for delivering cell therapies in CNS disorders 102
• Table 4 2: Classification of methods of gene therapy 105
• Table 4 3: Methods of gene transfer as applied to neurologic disorders 106
• Table 4 4: Companies developing cell/gene therapies for CNS disorders 111
• Table 4 5: Methods of antisense delivery as applied to the CNS 113
• Table 5 1: Strategies for the treatment of Parkinson' s disease 119
• Table 5 2: Drug delivery systems for Parkinson' s disease 121
• Table 5 3: Types of cell used for investigative treatment of Parkinson' s disease 125
• Table 5 4: Status of cell therapies in development for Parkinson' s disease 125
• Table 5 5: Gene therapy techniques applicable to Parkinson disease 131
• Table 5 6: Companies developing gene therapy for Parkinson' s disease 135
• Table 5 7: Classification of pharmacotherapy for Alzheimer disease 136
• Table 5 8: Novel drug delivery methods for Alzheimer disease therapies 137
• Table 5 9: Classification of neuroprotective agents for amyotrophic lateral sclerosis 144
• Table 5 10: Methods of delivery of therapies in development for ALS 145
• Table 5 11: Classification of treatments for stroke 149
• Table 5 12: Treatments of stroke involving innovative drug delivery methods 149
• Table 5 13: Drug delivery for prevention of carotid artery restenosis after angioplasty 151
• Table 5 14: Gene transfer in animal models of carotid artery restenosis 158
• Table 5 15: Neuroprotective gene transfer strategies in models of cerebral ischemia 159
• Table 5 16: Gene Therapy for reducing cerebral infarction in animal stroke models 160
• Table 5 17: Pharmacological agents for treatment of cerebral vasospasm 162
• Table 5 18: Gene therapy strategies for vasospasm 163
• Table 5 19: A classification of drug delivery methods used in management of pain 173
• Table 5 20: Spinal/intrathecal administration of drugs for pain 176
• Table 5 21: Investigational drugs for pain administered by intrathecal route 176
• Table 5 22: Current management of migraine 180
• Table 5 23: Novel drug delivery methods for migraine 181
• Table 5 24: Innovative methods of drug delivery for glioblastoma multiforme 184
• Table 5 25: Strategies for gene therapy of malignant brain tumors 193
• Table 6 1: Share of drug delivery technologies in selected CNS markets: 2007-2017 208
• Table 6 2: CNS market share of drug delivery technologies 2007-2017 208
• Table 6 3: Value of CNS drug delivery in the major world markets from 2007-2017 209
• Table 6 4: Limitations of the current drug delivery technologies for CNS 213
• Table 7 1: Collaborations of companies in CNS drug delivery 290

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 75
• Figure 5 1: Oral versus transdermal administration of a drug in Parkinson' s disease 123
• Figure 5 2: Effect of tyrosine hydroxylase gene delivery on dopamine levels 132
• Figure 6 1: Unmet needs in the CNS drug delivery technologies 213