Drug Delivery in Central Nervous System Diseases - Technologies, Markets and Companies
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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. A special chapter is devoted to drug delivery for brain tumors. 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 2011, projections are made to the years 2016 and 2021. 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 72 companies involved in drug delivery for CNS disorders are presented along with their technologies, products and 74 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 CONTENTS1. 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
Role of shear stress on development of BBB 31
Genomics of BBB 32
Proteomics of BBB 32
Other neural barriers 33
Blood-cerebrospinal fluid barrier 33
Blood nerve barrier 33
Blood-retinal barrier 34
Blood-labyrinth barrier 34
Passage of substances across the blood-brain barrier 34
Transporters localized in the BBB 34
Glucose transporter 35
Amino acid transporters 36
Ionic transporter 36
Efflux transport systems 36
BBB-specific enzymes 37
Receptor-mediated transcytosis 38
Lysophosphatidic acid-mediated increade in BBB permeability 38
Folate transport system 39
Molecular biology of the BBB 39
Transport of peptides and proteins across the BBB 39
Passage of leptin across the BBB 39
Passage of cytokines across the BBB 40
Passage of hormones across the BBB 40
Passage of enzymes across the BBB 41
Drugs that cross the BBB by binding to plasma proteins 41
Current concepts of the permeability of the BBB 41
Factors that increase the permeability of the BBB 42
BBB disruption as an adverse effect of pharmaceuticals 42
BBB disruption as adverse effect of vaccines for CNS disorders 43
Effect of CNS disorders on BBB 43
Autoimmune disorders 44
Brain tumors 44
Primary brain tumors 44
Cerebral metastases 44
Central nervous system injuries 45
Cerebrovascular disease 45
Epilepsy 46
Infections 46
Mitochondrial encephalopathies 47
Multiple sclerosis 47
Neurodegenerative disorders 47
Testing permeability of the BBB 48
In vitro models of BBB 49
In vivo study of BBB 50
Brain imaging 50
In silico prediction of BBB 50
Relevance of the BBB penetration to pharmacological action 52
BBB penetration and CNS drug screening 52
CERENSESM 52
Transthyretin monomer as a marker of blood-CSF barrier disruption 53
Evaluation of BBB permeability by brain imaging 53
Biomarkers of disruption of blood-brain barrier 53
Future directions for research on the BBB 54
Use of neural stem cells to construct the blood brain barrier 55
Strategies to cross the BBB 55
3. Methods of Drug Delivery to the CNS 57
Introduction 57
Routes of drug delivery to the brain 58
Delivery of drugs to the brain via the nasal route 58
Passage of viruses to the brain via the nasal route 59
Potential and limitations of nasal drug delivery to the brain 59
Nasal delivery of insulin-like growth factor-I 60
Nasal delivery of midazolam 60
Nasal delivery of hypocretin 60
Nasal administration of IFN beta-1b 61
Nasal administration of erythropoietin 61
Nasal delivery of thyrotropin-releasing hormone by nanoconstructs 61
Nasal delivery of neuroprotective drugs for stroke 62
Transdermal drug delivery for neurological disorders 62
Drug delivery to the brain via inner ear 62
Invasive neurosurgical approaches 63
Intraarterial drug delivery to the brain 63
Direct injection into the CNS substance or CNS lesions 64
Targeted delivery of biologicals to the spinal cord by microinjection 64
Intraventricular injection of drugs 64
Intrathecal drug delivery 65
Retrograde delivery to the brain via the epidural venous system 66
Devices for drug delivery to the CNS 67
Strategies for drug delivery to the CNS across the BBB 68
Increasing the permeability (opening) of the BBB 68
Osmotic opening of the BBB 68
Focal disruption of BBB by ultrasound 69
Chemical opening of the BBB 69
Cerebral vasodilatation to open the BBB 69
Modulation of vascular permeability by laser irradiation 70
Use of nitric oxide donors to open the BBB 70
Manipulation of the sphingosine 1-phosphate receptor system 70
Pharmacological strategies to facilitate transport across the BBB 71
2B-Trans™ technology 71
ABC afflux transporters and penetration of the BBB 71
Carrier-mediated drug delivery across the BBB 72
G-Technology® 73
Glycosylation Independent Lysosomal Targeting 73
Inhibition of P-glycoprotein to enhance drug delivery across the BBB 73
Modification of the drug to enhance its lipid solubility 74
Monoclonal antibody fusion proteins 75
Neuroimmunophilins 75
Peptide-mediated transport across the BBB 75
Prodrug bioconversion strategies and their CNS selectivity 77
Role of the transferrin-receptor system in CNS drug delivery 78
Transport of small molecules across the BBB 78
Transport across the BBB by short chain oligoglycerolipids 78
Transvascular delivery across the BBB 78
Trojan horse approach 79
Use of receptor-mediated transocytosis to cross the BBB 80
Cell-based drug delivery to the CNS 81
Activated T lymphocytes 81
Microglial cells 82
Neural stem cells 82
Drug delivery to the CNS by using novel formulations 82
Crystalline formulations 82
Liposomes 82
Monoclonal antibodies 84
Microspheres 84
Microbeads 85
Brain-targeted chemical delivery systems 85
Nanotechnology-based drug delivery to CNS 86
Nanoparticles for drug delivery across the BBB 86
Penetration of BBB by nanoparticles coated with polysorbate 80 87
NanoDel? technology for crossing the BBB 87
Masking BBB-limiting characteristics by nanotechnology 87
Peptide-nanoparticle conjugates for crossing the BBB 87
Nanovesicles for transport across BBB 88
Nanotechnology-based devices and implants for CNS 88
Biochip implants for drug delivery to the CNS 88
Controlled-release microchip 88
Retinal implant chip 89
Convection-enhanced delivery to the CNS 89
Systemic administration of drugs for CNS effects 90
Sustained and controlled release drug delivery to the CNS 90
Fast dissolving oral selegiline 92
Choice of the route of systemic delivery for effect on the CNS disorders 92
Methods of delivery of biopharmaceuticals to the CNS 93
Delivery of biopharmaceuticals across the BBB 93
Methods of delivery of peptides for CNS disorders 93
Challenges for delivery of peptides across the BBB 94
Transnasal administration of neuropeptides 94
Direct delivery of neuropeptides into the brain 94
Alteration of properties of the BBB for delivery of peptides 95
Molecular manipulations of peptides to facilitate transport into CNS 95
CNS delivery of peptides via conjugation to biological carriers 95
Delivery of conopeptides to the brain 96
Delivery of neurotrophic factors to the nervous system 96
Systemic administration of NTFs 98
Delivery systems to facilitate crossing of the BBB by NTFs 99
Use of microspheres for delivery of neurotrophic factors 99
Intracerebroventricular injection 99
Direct application of NTFs to the CNS 100
Intrathecal administration 101
Implants for delivery of neurotrophic factors 101
Use of neurotrophic factor mimics 101
Use of microorganisms for therapeutic entry into the brain 103
Bacteriophages as CNS therapeutics 103
Intracellular drug delivery in the brain 103
Local factors in the brain affecting drug action 103
Methods for testing drug delivery to the CNS 104
Animal models for testing drug delivery 104
Screening for drug-P-gp interaction at BBB 104
4. Delivery of Cell, Gene and Antisense Therapies to the CNS 105
Introduction 105
Cell therapy of neurological disorders 105
Methods for delivering cell therapies in CNS disorders 105
Encapsulated cells 106
Genetically modified stem cells for metachromatic leukodystrophy 107
CNS neotissue implant 107
CNS delivery of cells by catheters 107
Subarachnoid delivery of stem cells 108
Intravascular administration 108
Gene therapy techniques for the nervous system 109
Introduction 109
Methods of gene transfer to the nervous system 110
AAV vector mediated gene therapy for neurogenetic disorders 111
Ideal vector for gene therapy of neurological disorders 111
Promoters of gene transfer 111
Routes of delivery of genes to the nervous system 112
Direct injection into CNS 112
Introduction of the genes into cerebral circulation 113
Introduction of genes into cerebrospinal fluid 113
Intravenous administration of vectors 113
Delivery of gene therapy to the peripheral nervous system 114
Cell-mediated gene therapy of neurological disorders 114
Neuronal cells 114
Neural stem cells and progenitor cells 114
Astrocytes 114
Cerebral endothelial cells 115
Implantation of genetically modified encapsulated cells into the brain 115
Genetically modified bone marrow cells 115
Nanoparticles as non-viral vectors for CNS gene therapy 116
Applications of gene therapy for neurological disorders 116
Companies involved in cell/gene therapy of neurological disorders 117
Antisense therapy of CNS disorders 118
Delivery of antisense oligonucleotides to the CNS 119
Delivery of oligonucleotides cross the BBB 120
Cellular delivery systems for oligonucleotides 120
High-flow microinfusion into the brain parenchyma 121
Systemic administration of peptide nucleic acids 121
Introduction of antisense compounds into the CSF Pathways 121
Intrathecal administration of antisense compounds 122
Intracerebroventricular administration of antisense oligonucleotides 122
Nanoparticle-based delivery of antisense therapy to the CNS 123
Methods of delivery of ribozymes 123
Delivery aspects of RNAi therapy of CNS disorders 124
Delivery of siRNA to the CNS 124
Future drug delivery strategies applicable to the CNS 124
5. Drug Delivery for Treatment of Neurological Disorders 127
Introduction 127
Parkinson's disease 127
Drug delivery systems for Parkinson's disease 128
Methods of delivery of levodopa in PD 130
Duodenal levodopa infusion 130
Sublingual apomorphine 130
Transdermal drug delivery for PD 130
Transdermal dopamine agonists for PD 131
Transdermal administration of other drugs for PD 132
Intracerebral administration of GDNF 132
Cell therapy for PD 133
Human dopaminergic neurons for PD 134
Graft survival-enhancing drugs 134
Xenografting porcine fetal neurons 135
Encapsulated cells for PD 135
Stem cells for PD 136
Engineered stem cells for drug delivery to the brain in PD 137
Human retinal pigment epithelium cells for PD 137
Delivery of cells for PD 138
Gene therapy for Parkinson disease 138
Rationale 138
Techniques of gene therapy for PD 139
Prospects of gene therapy for PD 143
Companies developing gene therapy for PD 143
RNAi therapy of Parkinson's disease 144
Alzheimer disease 144
Drug delivery for Alzheimer disease 144
Blood-brain partitioning of an AMPA receptor modulator 145
Clearing amyloid through the BBB 145
Delivery of the passive antibody directly to the brain 146
Delivery of thyrotropin-releasing hormone analogs by molecular packaging 146
Intranasal delivery of nerve growth factor to the brain 146
Nanoparticle-based drug delivery for Alzheimer's disease 147
Perispinal etanercept 147
Slow release implant of an AChE inhibitor 148
Transdermal drug delivery in Alzheimer's disease 148
Trojan-horse approach to prevent build-up of A? aggregates 148
Cell and gene therapy for Alzheimer disease 149
NGF gene therapy 149
Neprilysin gene therapy 150
RNAi therapy of Alzheimer's disease 150
Huntington's disease 151
Treatment of HD 151
Gene therapy of HD 151
Encapsulated genetically engineered cellular implants 151
Viral vector mediated administration of neurotrophic factors 152
RNAi therapeutics for the treatment of HD 152
Amyotrophic lateral sclerosis 152
Treatment of ALS 152
Drug delivery in ALS 153
Gene and antisense therapy of amyotrophic lateral sclerosis 154
Neurotrophic factor gene therapies of ALS 154
Antisense therapy of ALS 155
RNAi therapy of amyotrophic lateral sclerosis 155
Drug delivery for CNS involvement in Hunter syndrome 156
Cerebrovascular disease 156
Treatment of stroke 157
Drug delivery in stroke 157
Intraarterial administration of tissue plasminogen activator in stroke 158
Drug delivery for prevention of restenosis of carotid arteries 159
Modified NO donors 159
In-stent restenosis 160
Targeted local anti-restenotic drug delivery 160
Catheter-based drug delivery for restenosis 161
Stents for prevention of restenosis 161
Drug-eluting stents 162
Antisense approach to prevent restenosis 162
Drug-eluting stents for the treatment of intracranial atherosclerosis 163
Tissues transplants for stroke 163
Transplant of encapsulated tissue secreting neurotrophic factors 163
Cell therapy for stroke 163
Stem cell transplant into the brain 164
Immortalized cell grafts for stroke 164
Intravenous infusion of marrow stromal cells 165
Intravenous infusion of umbilical cord blood stem cells 165
Future of cell therapy for stroke 165
Gene therapy of cerebrovascular diseases 165
Gene transfer to cerebral blood vessels 166
NOS gene therapy for restenosis 167
Gene therapy for cerebral ischemia 167
Gene therapy of strokes with a genetic component 168
Drug delivery to intracranial aneurysms 169
Drug delivery for vasospasm following subarachnoid hemorrhage 169
Intrathecal tissue plasminogen activator 170
Gene therapy for vasospasm 171
Drug delivery in multiple sclerosis 172
An electronic device for self injection of interferon beta-1a 172
Oral therapies for MS 172
Antisense and RNAi approaches to MS 173
Cell therapy for multiple sclerosis 173
Hematopoietic stem cell transplantation for multiple sclerosis 173
Embryonic stem cells and neural precursor cells for MS 174
Gene therapy for multiple sclerosis 174
Drug delivery in epilepsy 175
Routes of administration of antiepileptic drugs 175
Controlled-release preparations of carbamazepine 175
Intravenous carbamazepine 176
Various methods of delivery of diazepam 176
Methods of delivery of novel antiepileptic therapies 176
Regulated activation of prodrugs 176
Use of neuronal membrane transporter 176
Delivery of the antiepileptic conopeptides to the brain 177
Nasal administration of AEDs 177
Intracerebral administration of AEDs 177
The role of drug delivery in status epilepticus 178
Cell therapy of epilepsy 179
Gene therapy for epilepsy 179
Gene therapy for neuroprotection in epilepsy 180
Concluding remarks on drug delivery in epilepsy 180
Drug delivery for pain 181
Intranasal delivery of analgesics 182
Intranasal administration of morphine 182
Intranasal morphine derivatives 182
Intranasal fentanyl 183
Intranasal buprenorphine 184
Intranasal ketamine 184
Intranasal ketorolac 184
Delivery of analgesics by inhalation 185
Spinal delivery of analgesics 185
Epidural dexamethasone 187
Epidural morphine 187
Relief of pain by intrathecal ziconotide 188
Intrathecal neostigmine 189
Intrathecal prostaglandin antagonists 189
Intrathecal fadolmidine 189
Intrathecal siRNA for relief of neuropathic pain 189
Concluding remarks on intrathecal delivery of analgesic agents 189
Intracerebroventricular drug delivery for pain 190
Delivery of analgesics to the CNS across the BBB 190
Drug delivery for migraine 191
Management of migraine 191
Novel drug delivery methods for migraine 192
Nasal formulations for migraine 193
Sublingual spray for migraine 193
Needle-free drug delivery for migraine 193
Relief of spasticity by intrathecal baclofen 194
Drug delivery for traumatic brain injury 194
Cell therapy of traumatic brain injury 194
Gene therapy for traumatic brain injury 195
Drug delivery for spinal cord injury 195
Administration of neurotrotrophic factors for spinal cord injury 195
Cell therapy for spinal cord injury 196
Transplantation of glial cells for SCI 196
Fetal neural grafts for SCI 196
Embryonic stem cells for SCI 196
Schwann cell transplants for SCI 197
Olfactory glial cells for SCI 197
Marrow stromal cells for SCI 198
Intravenous injection of stem cells for spinal cord repair 198
Combinatorial approach for regeneration in SCI 198
Cell therapy of syringomyelia 198
Gene therapy of spinal cord injury 199
Drug delivery in CNS infections 199
Drug delivery in neuroAIDS 199
Drug delivery for retinal disorders 200
Age-related macular degeneration 200
TheraSight ocular brachytherapy system for wet AMD 201
Combretastatin A4P for myopic macular degeneration 201
Gene therapy for AMD 201
Anti-VEGF approach to AMD 202
Delivery of aptamers for treatment of AMD 202
Stem cell therapy for retinitis pigmentosa 203
Proliferative retinopathies 203
Drug delivery for inner ear disorders 203
6. Drug delivery for brain tumors 205
Introduction 205
Methods for evaluation of anticancer drug penetration into brain tumor 205
Innovative methods of drug delivery for glioblastoma multiforme 205
Delivery of anticancer drugs across the blood-brain barrier 206
Anticancer agents with increased penetration of BBB 206
BBB disruption 207
Nanoparticle-based targeted delivery of chemotherapy across the BBB 208
Tyrosine kinase inhibitor increases topotecan penetration into CNS 209
Bypassing the BBB by alternative methods of drug delivery 210
Intranasal perillyl alcohol 210
Intraarterial chemotherapy 210
Enhancing tumor permeability to chemotherapy 211
PDE5 inhibitors for increasing BTB permeability 211
Local delivery of therapeutic agents into the brain 211
Biodegradable microspheres containing 5-FU 211
Carmustine biodegradable polymer implants 211
Fibrin glue implants containing anticancer drugs. 212
Interstitial delivery of dexamethasone for reduction of peritumor edema 212
Magnetically controlled microspheres 213
Convection-enhanced delivery 213
CED for receptor-directed cytotoxin therapy 213
CED of topotecan 213
CED of a modified diphtheria toxin conjugated to transferrin 214
CED of nanoliposomal CPT-11 214
CED for delivery 131I-chTNT-1/B MAb 214
Anticancer drug formulations for targeted delivery to brain tumors 214
Lipid-coated microbubbles as a delivery vehicle for taxol 214
Liposomes for drug delivery to brain tumors 215
MAbs targeted to brain tumors 215
Multiple targeted drugs for brain tumors 216
Nanoparticles for targeted drug delivery in glioblastoma multiforme 217
Targeted antiangiogenic/apoptotic/cytotoxic therapies 217
Introduction of the chemotherapeutic agent into the CSF pathways 218
Intraventricular chemotherapy for meningeal cancer 218
Intrathecal chemotherapy 219
Photodynamic therapy for chemosensitization of brain tumors 219
Nanoparticles for photodynamic therapy of brain tumors 220
Innovative delivery of radiotherapy to brain tumors 220
GliaSite Radiation Therapy System 220
Boron neutron capture therapy for brain tumors 220
Cell therapy for glioblastoma multiforme 221
Mesenchymal stem cells to deliver treatment for gliomas 221
Gene therapy for glioblastoma multiforme. 221
Antiangiogenic gene therapy 222
Anticancer drug delivery by genetically engineered MSCs 223
Intravenous gene delivery with nanoparticles into brain tumors
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