September 2006
293 Pages
US$ 1,800 (electronic)

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 2005, projections are made to the years 2010 and 2015. 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 64 companies involved in drug delivery for CNS disorders are presented along with their technologies, products and 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 350 publications that are cited in the report. The report is supplemented with 47 tables and 7 figures.

T A B L E O F C O N T E N T S
0. Executive Summary .............................................................................. 12
1. Basics of Drug Delivery to the Central Nervous System........................ 14
Introduction..................................................................................................................14
Historical evolution of drug delivery for CNS disorders ....................................................14
Neuroanatomical and neurophysiological basis of drug delivery ......................................15
The cerebrospinal fluid .................................................................................................. 15
The extracellular space in the brain................................................................................. 16
Neurotransmitters ........................................................................................................ 16
Neuropharmacology relevant to drug delivery ................................................................18
Introduction to neuropharmacology................................................................................. 18
Pharmacokinetics......................................................................................................... 18
Absorption and distribution of drugs ........................................................................... 18
Drug metabolism and elimination ............................................................................... 19
Pharmacodynamics ...................................................................................................... 19
Receptors .............................................................................................................. 19
Sites of drug action in the CNS ....................................................................................... 19
Receptors coupled to guanine nucleotide binding proteins .............................................. 20
Acetylcholine receptor channels ................................................................................. 20
Dopamine receptors ................................................................................................ 20
GABA receptor channels ........................................................................................... 21
Glutamate receptor channels ..................................................................................... 21
Non-competitive NMDA antagonists............................................................................ 21
Serotonin receptors................................................................................................. 22
G-protein coupled receptors...................................................................................... 22
In vivo study of drug action in the CNS in human patients................................................... 22
Electroencephalography ........................................................................................... 22
Brain imaging ......................................................................................................... 23
Chronopharmacology as applied to the CNS ...................................................................... 23
2. Blood Brain Barrier ............................................................................... 26
Introduction..................................................................................................................26
Features of the blood-brain barrier relevant to CNS drug delivery....................................26
Functions of the BBB .................................................................................................... 26
BBB as an anatomical as well as physiological barrier .................................................... 26
BBB as a biochemical barrier ..................................................................................... 27
Other neural barriers .................................................................................................... 27
Blood-cerebrospinal fluid barrier ................................................................................ 27
Blood nerve barrier.................................................................................................. 27
Blood-retinal barrier ................................................................................................ 28
Blood-labyrinth barrier ............................................................................................. 28
Passage of substances across the blood-brain barrier .....................................................28
Transporters localized in the BBB.................................................................................... 29
Glucose transporter ................................................................................................. 30
Amino acid transporters ........................................................................................... 31
Ionic transporter..................................................................................................... 31
Efflux transport systems........................................................................................... 31
BBB-specific enzymes ................................................................................................... 32
Receptor-mediated peptide and protein transcytosis........................................................... 33
Folate transport system ................................................................................................ 34
Molecular biology of the BBB.......................................................................................... 34
Transport of peptides and proteins across the BBB............................................................. 34
Passage of leptin across the BBB................................................................................ 34
Passage of cytokines across the BBB .......................................................................... 35
Passage of hormones across the BBB.......................................................................... 35
Drugs that cross the BBB by binding to plasma proteins................................................. 36
Factors that increase the permeability of the BBB .............................................................. 36
CNS disorders that affect the permeability of BBB.............................................................. 37
Neurodegenerative disorders..................................................................................... 37
Mitochondrial encephalopathies ................................................................................. 38
Multiple sclerosis ..................................................................................................... 38
Central nervous system injuries ................................................................................. 39
Epilepsy ................................................................................................................ 39
Cerebrovascular disease........................................................................................... 39
Infections .............................................................................................................. 39
Autoimmune disorders ............................................................................................. 40
Brain tumors .......................................................................................................... 40
Testing permeability of the BBB .....................................................................................40
In vivo study of BBB..................................................................................................... 41
In vitro models of BBB .................................................................................................. 41
In silico prediction of BBB.............................................................................................. 42
Relevance of the BBB penetration to pharmacological action................................................ 43
BBB penetration and CNS drug screening .................................................................... 43
Transthyretin monomer as a marker of blood-CSF barrier disruption ..................................... 44
Evaluation of BBB permeability by brain imaging ............................................................... 44
Biomarkers of disruption of blood-brain barrier.................................................................. 44
Future directions for research on the BBB.......................................................................45
Application of genomics and proteomics to the study of BBB................................................ 46
Strategies to cross the BBB ............................................................................................46
3. Methods of Drug Delivery to the CNS.................................................... 48
Introduction..................................................................................................................48
Routes of drug delivery to the brain ...............................................................................49
Delivery of drugs to the brain via the nasal route............................................................... 49
Nasal delivery of insulin-like growth factor-I ................................................................ 50
Nasal delivery of midazolam...................................................................................... 50
Nasal delivery of hypocretin ...................................................................................... 51
Intranasal administration of IFN beta-1b ..................................................................... 51
Nasal delivery of thyrotropin-releasing hormone by nanoconstructs.................................. 51
Invasive neurosurgical approaches.................................................................................. 52
Injection into the arterial circulation of the brain........................................................... 52
Direct injection into the CNS substance or CNS lesions .................................................. 52
Intraventricular injection of drugs .............................................................................. 53
Intrathecal drug delivery .......................................................................................... 53
Devices for drug delivery to the CNS .......................................................................... 54
Nanotechnology-based devices and implants for CNS .................................................... 55
Strategies for drug delivery to the CNS across the BBB ...................................................56
Increasing the permeability (opening) of the BBB .............................................................. 56
Osmotic opening of the BBB...................................................................................... 56
Chemical opening of the BBB .................................................................................... 57
Cerebral vasodilatation to open the BBB...................................................................... 57
Use of nitric oxide donors to open the BBB .................................................................. 58
Manipulation of the sphingosine 1-phosphate receptor system ........................................ 58
Pharmacological strategies to facilitate transport across the BBB .......................................... 58
Modification of the drug to enhance its lipid solubility .................................................... 59
Transvascular delivery across the BBB ........................................................................ 59
Use of transport or carrier systems ............................................................................ 59
Role of the transferrin-receptor system in CNS drug delivery .......................................... 60
Use of receptor-mediated transocytosis to cross the BBB ............................................... 60
2B-Trans™ technology with specific carrier protein........................................................ 61
ABC afflux transporters and penetration of the BBB....................................................... 61
Inhibition of efflux transporters that impede drug delivery.............................................. 62
Trojan horse approach............................................................................................. 63
Transport of small molecules across the BBB................................................................ 63
Peptide-mediated transport across the BBB ................................................................. 64
Transport across the BBB by short chain oligoglycerolipids ............................................. 65
Monoclonal antibody fusion proteins ........................................................................... 65
Prodrug bioconversion strategies and their CNS selectivity ............................................. 65
Activated T lymphocytes........................................................................................... 66
Neuroimmunophilins ................................................................................................ 66
Drug delivery to the CNS by using novel formulations......................................................... 66
Crystalline formulations............................................................................................ 66
Liposomes ............................................................................................................. 67
Monoclonal antibodies .............................................................................................. 68
Microspheres.......................................................................................................... 68
Microbeads ............................................................................................................ 69
Lipid-coated microbubbles ........................................................................................ 69
Nanoparticles ......................................................................................................... 69
Brain-targeted chemical delivery systems ......................................................................... 70
Biochip implants for drug delivery to the CNS .................................................................71
Controlled-release microchip .......................................................................................... 71
Retinal implant chip...................................................................................................... 72
Systemic administration of drugs for CNS effects ............................................................72
Sustained and controlled release drug delivery to the CNS .................................................. 72
Fast dissolving oral selegiline .................................................................................... 74
Choice of the route of systemic delivery for effect on the CNS disorders ................................ 74
Methods of delivery of biopharmaceuticals to the CNS .....................................................75
Methods of delivery of peptides for CNS disorders .............................................................. 75
Challenges for delivery of peptides across the BBB........................................................ 75
Transnasal administration of neuropeptides ................................................................. 76
Direct delivery of neuropeptides into the brain ............................................................. 76
Alteration of properties of the BBB for delivery of peptides ............................................. 77
Molecular manipulations of peptides to facilitate transport into CNS ................................. 77
CNS delivery of peptides via conjugation to biological carriers......................................... 77
Delivery of conopeptides to the brain.......................................................................... 77
Delivery of neurotrophic factors to the nervous system....................................................... 78
Systemic administration of NTFs ................................................................................ 80
Delivery systems to facilitate crossing of the BBB by NTFs.............................................. 80
Use of microspheres for delivery of neurotrophic factors................................................. 81
Convection-enhanced delivery to the CNS ................................................................... 81
Intracerebroventricular injection ................................................................................ 82
Direct application of NTFs to the CNS.......................................................................... 83
Intrathecal administration......................................................................................... 83
Implants for delivery of neurotrophic factors................................................................ 83
Use of neurotrophic factor mimics.............................................................................. 84
Use of microorganisms for therapeutic entry into the brain .............................................85
Bacteriophages as CNS therapeutics................................................................................ 85
Intracellular drug delivery in the brain ...........................................................................85
Local factors in the brain affecting drug action ...............................................................86
Methods for testing drug delivery to the CNS ..................................................................86
Animal models for testing drug delivery ........................................................................... 86
4. Delivery of Cell, Gene and Antisense Therapies to the CNS................... 88
Introduction..................................................................................................................88
Cell therapy of neurological disorders .............................................................................88
Methods for delivering cell therapies in CNS disorders ........................................................ 88
Encapsulated cells ................................................................................................... 89
CNS neotissue implant ............................................................................................. 90
CNS delivery of cells by catheters .............................................................................. 90
Intravascular administration ..................................................................................... 90
Gene transfer techniques for the nervous system ...........................................................91
Introduction................................................................................................................ 91
Methods of gene transfer to the nervous system................................................................ 92
Ideal vector for gene therapy of neurological disorders ....................................................... 93
Promoters of gene transfer ............................................................................................ 93
Routes of delivery of genes to the CNS ............................................................................ 94
Cell- mediated gene therapy of neurological disorders ......................................................... 95
Neuronal cells ......................................................................................................... 95
Implantation of genetically modified encapsulated cells into the brain............................... 96
Genetically modified bone marrow cells ....................................................................... 96
Nanoparticles as non-viral vectors for CNS gene therapy..................................................... 97
Companies involved in cell/gene therapy of neurological disorders ........................................ 97
Antisense therapy of CNS disorders ................................................................................98
Delivery of antisense oligonucleotides to the CNS .............................................................. 99
Delivery of oligonucleotides cross the BBB.......................................................................100
Cellular delivery systems for oligonucleotides...................................................................100
High-flow microinfusion into the brain parenchyma ...........................................................101
Systemic administration of peptide nucleic acids...............................................................101
Introduction of antisense compounds into the CSF Pathways ..............................................101
Intrathecal administration of antisense compounds ...........................................................102
Intracerebroventricular administration of antisense oligonucleotides ....................................102
Nanoparticle-based delivery of antisense therapy to the CNS ..............................................103
Methods of delivery of ribozymes ...................................................................................103
Delivery aspects of RNAi therapy of CNS disorders ............................................................103
Future drug delivery strategies applicable to the CNS ................................................... 104
5. Drug Delivery in the Treatment of CNS Disorders ............................... 106
Parkinson's disease ..................................................................................................... 106
Drug delivery systems for Parkinson's disease..................................................................107
Transdermal drug delivery for PD..............................................................................109
Transdermal dopamine agonists for Parkinson's disease ................................................109
Transdermal administration of other drugs for Parkinson's disease ..................................110
Intracerebral administration of GDNF .........................................................................110
Cell therapy for Parkinson's disease ...............................................................................111
Human dopaminergic neurons for PD.........................................................................112
Graft survival-enhancing drugs .................................................................................113
Xenografting porcine fetal neurons ............................................................................113
Encapsulated cells for PD.........................................................................................113
Stem cells for PD ...................................................................................................114
Engineered stem cells for drug delivery to the brain in PD .............................................115
Human retinal pigment epithelium cells for PD ............................................................116
Delivery of cells for PD ............................................................................................116
Gene therapy for Parkinson disease................................................................................116
Rationale ..............................................................................................................116
Techniques of gene therapy for PD ............................................................................117
Prospects of gene therapy for Parkinson's disease ........................................................121
Companies developing gene therapy for PD ................................................................122
RNAi therapy of Parkinson's disease ...............................................................................122
Alzheimer disease........................................................................................................ 123
Drug delivery for Alzheimer disease ...............................................................................123
Blood-brain partitioning of an AMPA receptor modulator.....................................................124
Clearing amyloid through the BBB..................................................................................124
Trojan-horse approach to prevent build-up of Ab aggregates ..............................................124
Delivery of the passive antibody directly to the brain.........................................................125
Delivery of thyrotropin-releasing hormone analogs by molecular packaging ...........................125
Transdermal drug delivery in Alzheimer's disease .............................................................125
Intranasal delivery of nerve growth factor to the brain ......................................................126
Cell and gene therapy for Alzheimer disease ....................................................................126
NGF gene therapy ..................................................................................................126
Neprilysin gene therapy ..........................................................................................127
RNAi therapy of Alzheimer's disease ...............................................................................127
Huntington's disease ................................................................................................... 128
Treatment of Huntington's disease .................................................................................128
Drug delivery in Huntington's disease .............................................................................128
Gene therapy of Huntington’s disease .............................................................................128
Encapsulated genetically engineered cellular implants...................................................129
Viral vector mediated administration of neurotrophic factors..........................................129
Amyotrophic lateral sclerosis ....................................................................................... 129
Treatment of ALS........................................................................................................129
Drug delivery in ALS ....................................................................................................130
Gene and antisense therapy of amyotrophic lateral sclerosis ...............................................131
Neurotrophic factor gene therapies of ALS..................................................................131
Antisense therapy of ALS.........................................................................................132
RNAi therapy of amyotrophic lateral sclerosis ..............................................................132
Drug delivery for CNS involvement in Hunter syndrome ................................................ 133
Cerebrovascular disease .............................................................................................. 133
Treatment of stroke ....................................................................................................134
Drug delivery in stroke ................................................................................................134
Intraarterial administration of tissue plasminogen activator in stroke...............................135
Drug delivery for prevention of restenosis of carotid arteries ..............................................136
Modified NO donors ................................................................................................136
In-stent restenosis .................................................................................................137
Targeted local anti-restenotic drug delivery ................................................................138
Catheter-based drug delivery for restenosis ................................................................138
Stents for prevention of restenosis ............................................................................139
Drug-eluting stents ................................................................................................139
Antisense approach to prevent restenosis ...................................................................140
Drug-eluting stents for the treatment of intracranial atherosclerosis .....................................141
Tissues transplants for stroke ........................................................................................141
Transplant of encapsulated tissue secreting neurotrophic factors ....................................141
Cell therapy for stroke .................................................................................................141
Stem cell transplant into the brain ............................................................................141
Immortalized cell grafts for stroke.............................................................................142
Intravenous infusion of marrow stromal cells ..............................................................142
Intravenous infusion of umbilical cord blood stem cells .................................................143
Future of cell therapy for stroke................................................................................143
Gene therapy of cerebrovascular diseases .......................................................................143
Gene transfer to cerebral blood vessels ......................................................................144
NOS gene therapy for restenosis...............................................................................145
Gene therapy for cerebral ischemia ................................................................................145
Gene therapy of strokes with a genetic component ......................................................147
Drug delivery to intracranial aneurysms ..........................................................................147
Drug delivery for vasospasm following subarachnoid hemorrhage ........................................148
Intrathecal tissue plasminogen activator ....................................................................149
Gene therapy for vasospasm....................................................................................149
Drug delivery in multiple sclerosis ................................................................................ 150
Oral therapies for MS...................................................................................................151
Antisense and RNAi approaches to MS ............................................................................151
Cell therapy for multiple sclerosis ..................................................................................151
Hematopoietic stem cell transplantation for multiple sclerosis ........................................152
Embryonic stem cells and neural precursor cells for MS.................................................152
Gene therapy for multiple sclerosis ................................................................................152
Drug delivery in epilepsy.............................................................................................. 153
Routes of administration of antiepileptic drugs .................................................................153
Controlled-release preparations of carbamazepine .......................................................153
Various methods of delivery of diazepam....................................................................154
Methods of delivery of novel antiepileptic therapies ...........................................................154
Regulated activation of prodrugs...............................................................................154
Use of neuronal membrane transporter......................................................................155
Delivery of the antiepileptic conopeptides to the brain ..................................................155
Nasal administration of nipecotic acid ........................................................................155
Intracerebral administration of phenytoin ...................................................................155
The role of drug delivery in status epilepticus...................................................................156
Cell therapy of epilepsy................................................................................................156
Gene therapy for epilepsy.............................................................................................157
Gene therapy for neuroprotection in epilepsy ..............................................................157
Concluding remarks on drug delivery in epilepsy ..............................................................158
Drug delivery for pain .................................................................................................. 158
Intranasal delivery of analgesics....................................................................................159
Intranasal administration of morphine .......................................................................159
Intranasal fentanyl .................................................................................................160
Intranasal ketamine ...............................................................................................160
Delivery of analgesics by inhalation ................................................................................161
Spinal delivery of analgesics .........................................................................................161
Epidural administration of encapsulated morphine........................................................163
Relief of pain by intrathecal ziconotide .......................................................................163
Intrathecal neostigmine ..........................................................................................164
Intrathecal prostaglandin antagonists ........................................................................164
Intrathecal non-NMDA antagonists ............................................................................164
Intracerebroventricular drug delivery for pain ..................................................................165
Delivery of analgesics to the CNS across the BBB.........................................................165
Drug delivery for migraine ........................................................................................... 165
Management of migraine ..............................................................................................166
Novel drug delivery methods for migraine .......................................................................166
Nasal formulations for migraine ................................................................................167
Sublingual spray for migraine ...................................................................................168
Needle-free drug delivery for migraine............................................................................168
Relief of spasticity by intrathecal baclofen.................................................................... 168
Drug delivery for brain tumors ..................................................................................... 169
Anticancer agents with increased penetration of BBB.........................................................170
Local delivery of chemotherapeutic agents into the tumor ..................................................170
Carmustine biodegradable polymer implants...............................................................170
Fibrin glue implants containing anticancer drugs..........................................................171
Biodegradable microspheres containing 5-FU ..............................................................171
Nanoparticles for delivery of drugs to brain tumors across BBB ......................................171
Convection-enhanced delivery ..................................................................................172
Delivery of antibody-based anticancer therapy by ultrasound BBB disruption .........................173
Targeted monoclonal antibodies conjugated with liposomes ................................................173
Immunoliposomes ..................................................................................................173
Lipid-coated microbubbles as a delivery vehicle for taxol...............................................173
Thermoliposomes containing cytotoxic drugs...............................................................174
Introduction of the chemotherapeutic agent into the CSF pathways .....................................174
Intrathecal chemotherapy........................................................................................174
Intraventricular chemotherapy for meningeal cancer ....................................................174
Increasing the permeability of blood-tumor barrier to anticancer drugs.................................175
Intra-arterial chemotherapy..........................................................................................176
Interstitial delivery of dexamethasone for reduction of peritumor edema ..............................176
Photodynamic therapy for chemosensitization ..................................................................176
Boron neutron capture therapy......................................................................................176
Gene therapy for glioblastoma multiforme. ......................................................................177
Single-chain antibody-targeted adenoviral vectors .......................................................178
Peptides targeted to glial tumor cells .........................................................................178
Antiangiogenic gene therapy ....................................................................................179
RNAi gene therapy of brain cancer ............................................................................179
Drug delivery for traumatic brain injury........................................................................ 180
Cell therapy of traumatic brain injury .............................................................................180
Gene therapy for traumatic brain injury .....................................................................180
Drug delivery for spinal cord injury .............................................................................. 181
Administration of neurotrotrophic factors for spinal cord injury ............................................181
Cell therapy for spinal cord injury ..................................................................................181
Transplantation of glial cells for SCI...........................................................................182
Fetal neural grafts for SCI .......................................................................................182
Embryonic stem cells for SCI....................................................................................182
Schwann cell transplants for SCI...............................................................................183
Olfactory glial cells for SCI .......................................................................................183
Marrow stromal cells for SCI ....................................................................................183
Intravenous injection of stem cells for spinal cord repair ...............................................183
Combinatorial approach for regeneration in SCI ...........................................................184
Cell therapy of syringomyelia ...................................................................................184
Gene therapy of spinal cord injury.............................................................................184
Drug delivery for retinal disorders ................................................................................ 185
Age-related macular degeneration.............................................................................185
TheraSight ocular brachytherapy system for wet AMD ..................................................185
Combretastatin A4P for myopic macular degeneration ..................................................186
Gene therapy for AMD.............................................................................................186
Anti-VEGF approach to AMD.....................................................................................187
Delivery of aptamers for treatment of AMD .................................................................187
Stem cell therapy for retinitis pigmentosa .......................................................................187
Proliferative retinopathies.............................................................................................188
Drug delivery in CNS infections .................................................................................... 188
Drug delivery in neuroAIDS ..........................................................................................188
6. Markets for Drug Delivery in CNS Disorders........................................ 190
Introduction................................................................................................................ 190
Methods of calculation of CNS drug delivery markets.........................................................190
Markets for CNS drug delivery technologies .................................................................. 190
Drug delivery share in selected CNS markets...................................................................191
CNS share of drug delivery technologies .........................................................................191
Geographical distribution of CNS drug delivery markets.....................................................192
Impact of improved drug delivery on CNS drug markets................................................ 192
Neurodegenerative disorders ........................................................................................192
Alzheimer’s disease ................................................................................................192
Parkinson’s Disease ................................................................................................193
Huntington's disease...............................................................................................193
Amyotrophic lateral sclerosis ....................................................................................193
Epilepsy ....................................................................................................................194
Migraine and other headaches.......................................................................................194
Stroke ......................................................................................................................194
Spinal cord injury ........................................................................................................195
Multiple sclerosis ........................................................................................................195
Unmet needs in CNS drug delivery technologies............................................................ 195
Future strategies for expanding CNS drug delivery markets .......................................... 196
Education of neurologists .............................................................................................196
Demonstration of the advantages of the newer methods of delivery .....................................197
Rescue of old products by novel drug delivery methods .....................................................197
Facilitation of the approval process of new drugs ..............................................................197
7. Companies.......................................................................................... 198
Introduction................................................................................................................ 198
Profiles ....................................................................................................................... 198
Collaborations ............................................................................................................. 266
8. References.......................................................................................... 270

Tables
Table 1-1: Landmarks in the development of drug delivery to the CNS ........................................... 14
Table 2-1: Transporters that control penetration of molecules across the BBB .................................. 30
Table 2-2: Enzymes that control the penetration of molecules across the BBB.................................. 33
Table 2-3: Factors that increase the permeability of the BBB......................................................... 36
Table 2-4: Diseases that affect the BBB..................................................................................... 37
Table 3-1: Various methods of drug delivery to the central nervous system..................................... 48
Table 3-2: Drugs available for intrathecal administration .............................................................. 53
Table 3-3: Strategies for drug delivery to the CNS across the BBB ................................................. 56
Table 3-4: Specific inhibitors of P-glycoprotein in clinical development ............................................ 62
Table 3-5: Examples of controlled and sustained release drug delivery for CNS disorders ................... 73
Table 3-6: Novel methods of delivery of drugs for CNS disorders ................................................... 74
Table 3-7: Indications for the clinical applications of NTFs in neurologic disorders ............................. 78
Table 3-8: Methods for delivery of neurotrophic factors to the CNS ................................................ 79
Table 4-1: Methods for delivering cell therapies in CNS disorders ................................................... 89
Table 4-2: Classification of methods of gene therapy ................................................................... 91
Table 4-3: Methods of gene transfer as applied to neurologic disorders ........................................... 93
Table 4-4: Companies developing cell/gene therapies for CNS disorders.......................................... 97
Table 4-5: Methods of antisense delivery as applied to the CNS ..................................................... 99
Table 5-1: Strategies for the treatment of Parkinson's disease .....................................................106
Table 5-2: Drug delivery systems for Parkinson's disease ............................................................108
Table 5-3: Types of cell used for investigative treatment of Parkinson's disease ..............................111
Table 5-4: Cell therapies in development for Parkinson's disease ..................................................112
Table 5-5: Gene therapy techniques applicable to Parkinson disease .............................................118
Table 5-6: Companies developing gene therapy for Parkinson's disease .........................................122
Table 5-7: Classification of pharmacotherapy for Alzheimer disease ..............................................123
Table 5-8: Novel drug delivery methods for Alzheimer disease therapies ........................................123
Table 5-9: Classification of neuroprotective agents for amyotrophic lateral sclerosis .........................130
Table 5-10: Methods of delivery of therapies in development for ALS.............................................130
Table 5-11: Classification of treatments for stroke .....................................................................134
Table 5-12: Treatments of stroke involving innovative drug delivery methods .................................134
Table 5-13: Drug delivery for prevention of carotid artery restenosis after angioplasty .....................138
Table 5-14: Gene transfer in animal models of carotid artery restenosis .........................................144
Table 5-15: Neuroprotective gene transfer strategies in models of cerebral ischemia ........................146
Table 5-16: Gene Therapy for reducing cerebral infarction in animal stroke models ..........................146
Table 5-17: Pharmacological agents for treatment of cerebral vasospasm ......................................148
Table 5-18: Gene therapy strategies for vasospasm ...................................................................149
Table 5-19: A classification of drug delivery methods used in management of pain ..........................159
Table 5-20: Spinal/intrathecal administration of drugs for pain.....................................................161
Table 5-21: Investigational drugs for pain administered by intrathecal route...................................162
Table 5-22: Current management of migraine ...........................................................................166
Table 5-23: Novel drug delivery methods for migraine ................................................................167
Table 5-24: Innovative methods of drug delivery for glioblastoma multiforme .................................169
Table 5-25: Strategies for gene therapy of malignant brain tumors ...............................................177
Table 6-1: Share of drug delivery technologies in selected CNS markets: 2005-2015 .......................191
Table 6-2: CNS market share of drug delivery technologies 2005-2015..........................................191
Table 6-3: Value of CNS drug delivery in the major world markets from 2005-2015 .........................192
Table 7-1: Collaborations of companies in CNS drug delivery .......................................................266

Figures
Figure 1-1: Interaction of neurotransmitters with receptors .......................................................... 17
Figure 2-1: Various form of passage of substances across the blood brain barrier ............................. 29
Figure 3-1: Routes of drug delivery to the brain.......................................................................... 49
Figure 3-2: Use of receptor-mediated transcytosis to cross the BBB .............................................. 60
Figure 5-1: Oral versus transdermal administration of a drug in Parkinson's disease.........................110
Figure 5-2: Effect of tyrosine hydroxylase gene delivery on dopamine levels ...................................119
Figure 6-1: Unmet needs in the CNS drug delivery technologies ...................................................196