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Drug Delivery in Central Nervous System Diseases - Technologies, Markets & Companies

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  • 392 Pages
  • November 2021
  • Region: Global
  • Jain PharmaBiotech
  • ID: 4748176

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 the 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 the 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 2020, projections are made to the years 2025 and 2030. The market 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 the development of new products, these include the application of innovative methods of delivery to older drugs to improve their action and extend their patent life.

Profiles of 77 companies involved in drug delivery for CNS disorders are presented along with their technologies, products and 101 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 420 publications that are cited in the report. The report is supplemented with 52 tables and 17 figures.

The report contains information on the following:

  • Basics of drug delivery to the CNS
  • Blood-brain barrier
  • Methods of drug delivery to the CNS
  • Delivery of cell, gene and antisense therapies to the CNS
  • Drug delivery in the treatment of CNS disorders
  • Drug delivery for brain tumors
  • Markets for drug delivery in CNS disorders
  • Companies

Table of Contents

0. Executive Summary
1. Basics of Drug Delivery to the Central Nervous System
  • Introduction
  • Historical evolution of drug delivery for CNS disorders
  • Neuroanatomical and neurophysiological basis of drug delivery
  • The cerebrospinal fluid
  • The lymphatic drainage system of the brain
  • The extracellular space in the brain
  • Neurotransmitters
  • Extracellular vesicles as drug delivery vehicles
  • Neuropharmacology relevant to drug delivery
  • Introduction to neuropharmacology
  • Pharmacokinetics
  • Absorption and distribution of drugs
  • Drug metabolism and elimination
  • Pharmacodynamics
  • Receptors
  • Sites of drug action in the CNS
  • Receptors coupled to guanine nucleotide binding proteins
  • Acetylcholine receptor channels
  • Dopamine receptors
  • GABA receptor channels
  • Glutamate receptor channels
  • Non-competitive NMDA antagonists
  • Serotonin receptors
  • G-protein coupled receptors
  • In vivo study of drug action in the CNS in human patients
  • Electroencephalography
  • Brain imaging
  • Chronopharmacology as applied to the CNS
  • Role of drug delivery in personalized therapy of CNS disorders
2. Blood Brain Barrier
  • Introduction
  • Features of the blood-brain barrier relevant to CNS drug delivery
  • The neurovascular unit
  • Functions of the BBB
  • BBB as an anatomical as well as physiological barrier
  • BBB as a biochemical barrier
  • Glucose transporters at the BBB
  • Role of shear stress on development of BBB
  • Genomics of BBB
  • Proteomics of BBB
  • Other neural barriers
  • Blood-cerebrospinal fluid barrier
  • Blood nerve barrier
  • Blood-retinal barrier
  • Blood-labyrinth barrier
  • Passage of substances across the blood-brain barrier
  • Transporters localized in the BBB
  • Adenosine carrier
  • Amino acid transporters
  • Efflux transport systems
  • Glucose transporter
  • Ionic transporter
  • BBB-specific enzymes
  • Receptor-mediated transcytosis
  • Lysophosphatidic acid-mediated increase in BBB permeability
  • Folate transport system
  • Transferrin receptor
  • Molecular biology of the BBB
  • Transport of peptides and proteins across the BBB
  • Passage of leptin across the BBB
  • Passage of cytokines across the BBB
  • Passage of hormones across the BBB
  • Passage of enzymes across the BBB
  • Passage of omega-3 fatty acids across the BBB
  • Drugs that cross the BBB by binding to plasma proteins
  • Current concepts of the permeability of the BBB
  • BBB permeability in relation to disease
  • BBB permeability in relation to drug delivery
  • Factors that increase the permeability of the BBB
  • BBB disruption as an adverse effect of pharmaceuticals
  • BBB disruption as adverse effect of vaccines for CNS disorders
  • CNS disorders and BBB
  • Autoimmune disorders
  • Brain tumors
  • Primary brain tumors
  • Cerebral metastases
  • Central nervous system injuries
  • Cerebrovascular disease
  • Cerebral ischemia
  • Intracerebral hemorrhage
  • Epilepsy
  • Infections
  • Inflammation
  • Mitochondrial encephalopathies
  • Multiple sclerosis
  • Neurodegenerative disorders
  • BBB in Alzheimer disease
  • BBB in Parkinson disease
  • BBB in amyotrophic lateral sclerosis
  • West Nile virus infection
  • Testing permeability of the BBB
  • In vitro models of BBB
  • In vivo study of BBB
  • Brain imaging
  • In silico prediction of BBB
  • Relevance of the BBB penetration to pharmacological action
  • BBB penetration and CNS drug screening
  • BBB models for testing drug delivery
  • In vivo brain distribution of P-glycoprotein
  • Transthyretin monomer as a marker of blood-CSF barrier disruption
  • Evaluation of BBB permeability by brain imaging
  • Biomarkers of disruption of blood-brain barrier
  • Future directions for research on the BBB
  • Use of neural stem cells to construct the blood brain barrier
  • Strategies to cross the BBB
3. Methods of Drug Delivery to the CNS
  • Introduction
  • Routes of drug delivery to the brain
  • Drug delivery to the brain via the nasal route
  • Devices for nasal administration of drugs for CNS
  • Role of nanobiotechnology in nasal drug drug delivery
  • Nasal mucosal patch to facilitate drug delivery across the BBB
  • Passage of viruses to the brain via the nasal route
  • Potential and limitations of nasal drug delivery to the brain
  • Drugs that can be delivered to the brain via the nasal route
  • Erythropoietin
  • Esketamine
  • Hypocretin
  • IFN beta-1b
  • Levetiracetam
  • Lysosomal enzymes
  • Midazolam
  • Neurotrophic factors
  • Thyrotropin-releasing hormone
  • Neuroprotective drugs for stroke
  • Transdermal drug delivery for neurological disorders
  • Drug delivery to the brain via inner ear
  • Drug delivery for disorders of the spinal cord
  • Intrathecal drug delivery
  • Anatomical & physiological aspects of intrathecal drug delivery
  • Advantages of intrathecal drug delivery
  • Drugs that can be delivered by intrathecal route
  • Pharmacokinetics of intrathecal drug delivery
  • Retrograde delivery to the brain via the epidural venous system
  • Devices for drug delivery to the CNS
  • Catheters for drug delivery to the CNS
  • Reservoirs and pumps for drug delivery to the CNS
  • Invasive neurosurgical approaches
  • Intraarterial drug delivery to the brain
  • Direct injection into the CNS substance or CNS lesions
  • Targeted delivery of biologicals to the spinal cord by microinjection
  • Intraventricular injection of drugs
  • Strategies for drug delivery to the CNS across the BBB
  • Increasing the permeability (opening) of the BBB
  • Osmotic opening of the BBB
  • Chemical opening of the BBB
  • Cerebral vasodilatation to open the BBB
  • Modulation of vascular permeability by laser irradiation
  • Neurostimulation for opening BBB
  • Ultrasound-induced focal disruption of BBB
  • Ultrasound-induced delivery across BBB without focal disruption
  • Use of nitric oxide donors to open the BBB
  • Manipulation of the sphingosine 1-phosphate receptor system
  • Pharmacological strategies to facilitate transport across the BBB
  • 2B-Trans™ technology
  • ABC afflux transporters and penetration of the BBB
  • Adenosine agonist-mediated drug delivery across the BBB
  • Carrier-mediated drug delivery across the BBB
  • Fusion of receptor-binding peptide from apoE with therapeutic protein
  • G-Technology®
  • Glycosylation Independent Lysosomal Targeting
  • Inhibition of P-glycoprotein to enhance drug delivery across the BBB
  • LipoBridge technology
  • Modification of the drug to enhance its lipid solubility
  • Monoclonal antibody fusion proteins
  • Neuroimmunophilins
  • Peptide-mediated transport across the BBB
  • Prodrug bioconversion strategies and their CNS selectivity
  • Transport of small molecules across the BBB
  • Transport across the BBB by short chain oligoglycerolipids
  • Transvascular delivery across the BBB
  • Trojan horse approach
  • Role of the transferrin-receptor system in CNS drug delivery
  • Use of receptor-mediated transocytosis to cross the BBB
  • Cell-based drug delivery to the CNS
  • Activated T lymphocytes
  • Microglial cells
  • Neural stem cells
  • Drug delivery to the CNS by using novel formulations
  • Crystalline formulations
  • Liposomes
  • Monoclonal antibodies
  • Microspheres
  • Microbeads
  • Brain-targeted chemical delivery systems
  • Nanotechnology-based drug delivery to CNS
  • Nanoparticles for drug delivery across the BBB
  • Nanovesicles for transport across BBB
  • Nanoparticle-based reservatrol delivery to the brain
  • Penetration of BBB by nanoparticles coated with polysorbate 80
  • Targeting nicotinic acetylcholine receptor
  • Transcytosis of transferrin-containing nanoparticles across the BBB
  • V-SMART® drug delivery platform
  • Nanotechnology-based devices and implants for CNS
  • Biochip implants for drug delivery to the CNS
  • Controlled-release microchip
  • Nanoscaffold for delivering antiinflammatory molecules to the brain
  • Retinal implant chip
  • Convection-enhanced delivery to the CNS
  • Systemic administration of drugs for CNS effects
  • Sustained and controlled release drug delivery to the CNS
  • Fast dissolving oral selegiline
  • Choice of the route of systemic delivery for effect on the CNS disorders
  • Methods of delivery of biopharmaceuticals to the CNS
  • Delivery of biopharmaceuticals across the BBB
  • Methods of delivery of peptides for CNS disorders
  • Alteration of properties of the BBB for delivery of peptides
  • Challenges for delivery of peptides across the BBB
  • CNS delivery of peptides via conjugation to biological carriers
  • Delivery of conopeptides to the brain
  • Direct delivery of neuropeptides into the brain
  • Molecular manipulations of peptides to facilitate transport into CNS
  • Transport to spinal cord motor neurons after peripheral injection
  • Transnasal administration of neuropeptides
  • Delivery of neurotrophic factors to the nervous system
  • Systemic administration of NTFs
  • Delivery systems to facilitate crossing of the BBB by NTFs
  • Direct application of NTFs to the CNS
  • Intracerebroventricular injection
  • Intrathecal administration
  • Implants for delivery of neurotrophic factors
  • Use of neurotrophic factor mimics
  • Use of microspheres for delivery of neurotrophic factors
  • Use of nanobiotechnology for delivery of neurotrophic factors
  • Use of microorganisms for therapeutic entry into the brain
  • Bacteriophages as CNS therapeutics
  • Intracellular drug delivery in the brain
  • Local factors in the brain affecting drug action
  • Methods for testing drug delivery to the CNS
  • Animal models for testing drug delivery
  • Conducting preclinical studies of CNS drug delivery
  • Screening for drug-P-gp interaction at BBB
  • Translating from preclinical to clinical application
4. Delivery of Cell, Gene and Antisense Therapies to the CNS
  • Introduction
  • Cell therapy of neurological disorders
  • Methods for delivering cell therapies in CNS disorders
  • Cerebrospinal fluid-stem cell interactions for therapy of CNS disorders
  • Engineered stem cells for drug delivery to the brain
  • Encapsulated cells
  • Intrathecal delivery of stem cells
  • Intraparenchymal delivery of stem cells to the spinal cord
  • Intravascular administration
  • Neural stem cells as therapeutic delivery vehicles
  • Gene therapy techniques for the nervous system
  • Introduction
  • Methods of gene transfer to the nervous system
  • AAV vector mediated gene therapy for neurogenetic disorders
  • Ideal vector for gene therapy of neurological disorders
  • Promoters of gene transfer
  • Routes of delivery of genes to the nervous system
  • Direct injection into CNS
  • Introduction of the genes into cerebral circulation
  • Introduction of genes into cerebrospinal fluid
  • Intravenous administration of vectors
  • Delivery of gene therapy to the peripheral nervous system
  • Cell-mediated gene therapy of neurological disorders
  • Neuronal cells
  • Neural stem cells and progenitor cells
  • Astrocytes
  • Cerebral endothelial cells
  • Implantation of genetically modified encapsulated cells into the brain
  • Genetically modified bone marrow cells
  • Nanoparticles as nonviral vectors for CNS gene therapy
  • Applications of gene therapy for neurological disorders
  • Companies involved in cell/gene therapy of neurological disorders
  • Antisense therapy of CNS disorders
  • Delivery of antisense oligonucleotides to the CNS
  • Delivery of oligonucleotides cross the BBB
  • Cellular delivery systems for oligonucleotides
  • High-flow microinfusion into the brain parenchyma
  • Systemic administration of peptide nucleic acids
  • Introduction of antisense compounds into the CSF Pathways
  • Intrathecal administration of antisense compounds
  • Intracerebroventricular administration of antisense oligonucleotides
  • Nanoparticle-based delivery of antisense therapy to the CNS
  • Methods of delivery of ribozymes
  • Delivery aspects of RNAi therapy of CNS disorders
  • Delivery of siRNA to the CNS
  • Future drug delivery strategies applicable to the CNS
5. Drug Delivery for Treatment of Neurological Disorders
  • Introduction
  • Targeted drug delivery for neurological disorders
  • Parkinson's disease
  • Drug delivery systems for Parkinson's disease
  • Methods of delivery of levodopa in PD
  • Duodenal levodopa infusion
  • Inhaled levodopa
  • Sublingual apomorphine
  • Transdermal drug delivery for PD
  • Transdermal dopamine agonists for PD
  • Transdermal administration of other drugs for PD
  • Intracerebral administration of GDNF
  • Cell therapy for PD
  • Human dopaminergic neurons for PD
  • Graft survival-enhancing drugs
  • Xenografting porcine fetal neurons
  • Encapsulated cells for PD
  • Stem cells for PD
  • Engineered stem cells for drug delivery to the brain in PD
  • Human retinal pigment epithelium cells for PD
  • Delivery of cells for PD
  • Gene therapy for Parkinson disease
  • Rationale
  • Techniques of gene therapy for PD
  • Prospects of gene therapy for PD
  • Companies developing gene therapy for PD
  • RNAi therapy of Parkinson's disease
  • Alzheimer disease
  • Drug delivery for Alzheimer disease
  • Blood-brain partitioning of an AMPA receptor modulator
  • Clearing amyloid through the BBB
  • Delivery of the passive antibody directly to the brain
  • Delivery of thyrotropin-releasing hormone analogs by molecular packaging
  • Exosome-based drug delivery in AD
  • Nanoparticle-based drug delivery for Alzheimer’s disease
  • Perispinal etanercept
  • Slow release implant of an AChE inhibitor
  • Intranasal insulin in Alzheimer disease
  • Transdermal drug delivery in Alzheimer's disease
  • Trojan-horse approach to prevent build-up of Aß aggregates
  • Cell and gene therapy for Alzheimer disease
  • NGF gene therapy
  • Neprilysin gene therapy
  • RNAi therapy of Alzheimer's disease
  • Huntington's disease
  • Treatment of HD
  • Gene therapy of HD
  • Encapsulated genetically engineered cellular implants
  • Viral vector mediated administration of neurotrophic factors
  • RNAi therapeutics for the treatment of HD
  • Amyotrophic lateral sclerosis
  • Treatment of ALS
  • Drug delivery in ALS
  • Delivery of stem cell therapy for ALS
  • Gene and antisense therapy of ALS
  • Neurotrophic factor gene therapies of ALS
  • Antisense therapy of ALS
  • RNAi therapy of amyotrophic lateral sclerosis
  • Cerebrovascular disease
  • Treatment of stroke
  • Drug delivery in stroke
  • Intraarterial administration of thrombolytic agents in stroke
  • Drug delivery for prevention of restenosis of carotid arteries
  • In-stent restenosis
  • Targeted local anti-restenotic drug delivery
  • Catheter-based drug delivery for restenosis
  • Stents for prevention of restenosis
  • Drug-eluting stents
  • Antisense approach to prevent restenosis
  • Drug-eluting stents for the treatment of intracranial atherosclerosis
  • Tissues transplants for stroke
  • Transplant of encapsulated tissue secreting neurotrophic factors
  • Methods for delivery of neurotrophic factors in stroke
  • Cell therapy for stroke
  • Stem cell transplant into the brain
  • Immortalized cell grafts for stroke
  • Intravenous infusion of marrow stromal cells
  • Intravenous infusion of umbilical cord blood stem cells
  • Future of cell therapy for stroke
  • Gene therapy of cerebrovascular diseases
  • Gene transfer to cerebral blood vessels
  • NOS gene therapy for restenosis
  • Gene therapy for cerebral ischemia
  • Gene therapy of strokes with a genetic component
  • Drug delivery to intracranial aneurysms
  • Drug delivery for vasospasm following subarachnoid hemorrhage
  • Intrathecal tissue plasminogen activator
  • Gene therapy for vasospasm
  • Drug delivery in multiple sclerosis
  • An electronic device for self injection of interferon beta-1a
  • Oral therapies for MS
  • Drug delivery for MS across the BBB
  • Delivery of methylprednisolone across the BBB
  • Monoclonal antibodies for MS and the BBB
  • Antisense and RNAi approaches to MS
  • Cell therapy for multiple sclerosis
  • Hematopoietic stem cell transplantation for multiple sclerosis
  • Embryonic stem cells and neural precursor cells for MS
  • Gene therapy for multiple sclerosis
  • Drug delivery in epilepsy
  • Routes of administration of antiepileptic drugs
  • Controlled-release preparations of carbamazepine
  • Intravenous carbamazepine
  • Various routes of administration of benzodiazepines
  • Methods of delivery of novel antiepileptic therapies
  • Use of neuronal membrane transporter
  • Delivery of the antiepileptic conopeptides to the brain
  • Nasal administration of AEDs
  • Intracerebral administration of AEDs
  • The role of drug delivery in status epilepticus
  • Cell therapy of epilepsy
  • Gene therapy for epilepsy
  • Gene therapy for neuroprotection in epilepsy
  • Concluding remarks on drug delivery in epilepsy
  • Drug delivery for pain
  • Intranasal delivery of analgesics
  • Intranasal administration of morphine
  • Intranasal morphine derivatives
  • Intranasal fentanyl
  • Intranasal buprenorphine
  • Intranasal ketamine
  • Intranasal ketorolac
  • Delivery of analgesics by inhalation
  • Delivery of analgesics to peripheral nerves
  • Spinal delivery of analgesics
  • Epidural dexamethasone
  • Epidural morphine
  • Relief of pain by intrathecal ziconotide
  • Intrathecal neostigmine
  • Intrathecal prostaglandin antagonists
  • Intrathecal fadolmidine
  • Intrathecal siRNA for relief of neuropathic pain
  • Concluding remarks on intrathecal delivery of analgesic agents
  • Intracerebroventricular drug delivery for pain
  • Delivery of analgesics to the CNS across the BBB
  • Drug delivery for migraine
  • Management of migraine
  • Novel drug delivery methods for migraine
  • Nasal formulations for migraine
  • Sublingual spray for migraine
  • Needle-free drug delivery for migraine
  • Drug delivery for traumatic brain injury
  • Cell therapy of traumatic brain injury
  • Gene therapy for traumatic brain injury
  • Drug delivery for spinal cord injury
  • Administration of neurotrotrophic factors for spinal cord injury
  • Cell therapy for spinal cord injury
  • Transplantation of glial cells for SCI
  • Fetal neural grafts for SCI
  • Embryonic stem cells for SCI
  • Schwann cell transplants for SCI
  • Olfactory glial cells for SCI
  • Marrow stromal cells for SCI
  • Intravenous injection of stem cells for spinal cord repair
  • Combinatorial approach for regeneration in SCI
  • Cell therapy of syringomyelia
  • Gene therapy of spinal cord injury
  • Drug delivery in CNS infections
  • Drug delivery in neuroAIDS
  • Drug delivery for miscellaneous neurological disorders
  • Drug delivery for CNS involvement in Hunter syndrome
  • Trojan horse therapeutics to treat mucopolysaccharidosis types I & II
  • Antisense therapy for spinal muscular atrophy
  • Antisense gene splicing for SMA
  • Intrathecal antisense delivery
  • Genetically modified stem cells for metachromatic leukodystrophy
  • Relief of spasticity by intrathecal baclofen
  • Drug delivery for retinal disorders
  • Age-related macular degeneration
  • Squalamine
  • Combretastatin A4P for myopic macular degeneration
  • Gene therapy for AMD
  • Anti-VEGF approach to AMD
  • Delivery of pegaptanib for treatment of AMD
  • Stem cell therapy for retinitis pigmentosa
  • Proliferative retinopathies
  • Retinoblastoma
  • Drug delivery for inner ear disorders
  • Delivery of stem cells for hearing loss
  • Auditory hair cell replacement by gene therapy
  • Future prospects of drug delivery to the inner ear
  • Drug delivery in psychiatric disorders
  • Delivery of antidepressants
  • Transdermal delivery of antidepressants
  • Nasal delivery of antidepressants
  • Delivery methods and formulations of antipsychotics
  • Long-acting injectable antipsychotics
  • Transdermal haloperidol
  • Transdermal risperidone for treatment of schizophrenia
  • Transdermal blonanserin for treatment of schizophrenia
  • Transnasal oxytocin for schizophrenia
  • Transdermal lithium for bipolar disorder
6. Drug delivery for brain tumors
  • Introduction
  • Methods for evaluation of anticancer drug penetration into brain tumor
  • Innovative methods of drug delivery for glioblastoma
  • Delivery of anticancer drugs across the blood-brain barrier
  • Anticancer agents with increased penetration of BBB
  • BBB disruption
  • Nanoparticle-based targeted delivery of chemotherapy across the BBB
  • Tyrosine kinase inhibitor increases topotecan penetration into CNS
  • Bypassing the BBB by alternative methods of drug delivery
  • Intranasal perillyl alcohol
  • Intraarterial chemotherapy
  • Enhancing tumor permeability to chemotherapy
  • PDE5 inhibitors for increasing BTB permeability
  • Local delivery of therapeutic agents into the brain
  • Biodegradable microspheres containing 5-FU
  • Carmustine biodegradable polymer implants
  • Fibrin glue implants containing anticancer drugs
  • Interstitial delivery of dexamethasone for reduction of peritumor edema
  • Magnetically controlled microspheres
  • Convection-enhanced delivery
  • CED for receptor-directed cytotoxin therapy
  • CED of topotecan
  • CED of a modified diphtheria toxin conjugated to transferrin
  • CED of nanoliposomal CPT-11
  • CED for delivery 131I-chTNT-1/B MAb
  • Anticancer drug formulations for targeted delivery to brain tumors
  • Intravenous delivery of anticancer agents bearing transferrin
  • Liposomes for drug delivery to brain tumors
  • MAbs targeted to brain tumors
  • Targeted delivery of drug-peptide conjugates to glioblastoma
  • Multiple targeted drugs for brain tumors
  • Nanoparticles for targeted drug delivery in glioblastoma
  • Targeted antiangiogenic/apoptotic/cytotoxic therapies
  • Targeted drug delivery to gliomas using cholera toxin subunit B
  • Introduction of the chemotherapeutic agent into the CSF pathways
  • Intraventricular chemotherapy for meningeal cancer
  • Intrathecal chemotherapy
  • Photodynamic therapy for chemosensitization of brain tumors
  • Nanoparticles for photodynamic therapy of brain tumors
  • Innovative delivery of radiotherapy to brain tumors
  • GliaSite Radiation Therapy System
  • Boron neutron capture therapy for brain tumors
  • Cell therapy for malignant brain tumors
  • Chimeric antigen receptor T cells
  • Mesenchymal stem cells to deliver treatment for gliomas
  • Intra-cavity stem cell therapy for medulloblastoma
  • Gene therapy for glioblastoma
  • Antiangiogenic gene therapy
  • Anticancer drug delivery by genetically engineered MSCs
  • Intracerebroventricular delivery of gene therapy for gliomas by NSCs
  • Intravenous gene delivery with nanoparticles into brain tumors
  • Ligand-directed delivery of dsRNA molecules targeted to EGFR
  • MSC-based gene delivery
  • Neural stem cells for drug/gene delivery to brain tumors
  • Peptides targeted to glial tumor cells
  • RNAi gene therapy of brain cancer
  • Single-chain antibody-targeted adenoviral vectors
  • Targeting normal brain cells with an AAV vector encoding interferon-?
  • Poliovirus-based vaccine for glioblastoma
  • Treatment of medulloblastoma by suppressing genes in Shh pathway
  • Virus-mediated oncolytic therapy of brain cancer
  • HIV-mediated Oncolysis
  • Autophagy by conditionally replicating adenoviruses
  • Reovirus-mediated Oncolysis
  • Measles virus-mediated oncolysis
  • Oncolytic virus targeted to brain tumor stem cells
  • Oncolysis with vesicular stomatitis virus
  • Future of viral-mediated oncolysis
  • Vaccination for glioblastoma
7. Markets for Drug Delivery in CNS Disorders
  • Introduction
  • Methods of calculation of CNS drug delivery markets
  • Markets for CNS drug delivery technologies
  • Drug delivery share in selected CNS markets
  • CNS share of drug delivery technologies
  • Geographical distribution of CNS drug delivery markets
  • Impact of improved drug delivery on CNS drug markets
  • Neurodegenerative disorders
  • Alzheimer disease
  • Parkinson disease
  • Huntington disease
  • Amyotrophic lateral sclerosis
  • Epilepsy
  • Migraine and other headaches
  • Stroke
  • Central nervous system trauma
  • Multiple sclerosis
  • Brain tumors
  • Limitations of the current drug delivery technologies for CNS
  • Unmet needs in CNS drug delivery technologies
  • Regulatory considerations for drugs that cross the BBB
  • Public-private collaboration for transfer of research to the clinic
  • Future strategies for expanding CNS drug delivery markets
  • Education of neurologists
  • Demonstration of the advantages of the newer methods of delivery
  • Rescue of old products by novel drug delivery methods
  • Facilitation of the approval process of new drugs
8. Companies
  • Introduction
  • Profiles of companies
  • Collaborations
9. References
Table 1-1: Landmarks in the development of drug delivery to the CNS
Table 2-1: Proteins expressed at the neurovascular unit
Table 2-2: Transporters that control penetration of molecules across the BBB
Table 2-3: Enzymes that control the penetration of molecules across the BBB
Table 2-4: Factors that increase the permeability of the BBB
Table 2-5: Diseases with associated disturbances of BBB
Table 3-1: Various methods of drug delivery to the central nervous system
Table 3-2: Drugs available for intrathecal administration
Table 3-3: Investigational drugs administered by intrathecal route
Table 3-4: Strategies for drug delivery to the CNS across the BBB
Table 3-5: Specific inhibitors of P-glycoprotein in clinical development
Table 3-6: Molecules attached to Trojan horses injected intravenously for CNS effect
Table 3-7: Examples of controlled and sustained release drug delivery for CNS disorders
Table 3-8: Novel methods of delivery of drugs for CNS disorders
Table 3-9: Indications for the clinical applications of NTFs in neurologic disorders
Table 3-10: Methods for delivery of neurotrophic factors to the CNS
Table 4-1: Methods for delivering cell therapies in CNS disorders
Table 4-2: Classification of methods of gene therapy
Table 4-3: Methods of gene transfer as applied to neurologic disorders
Table 4-4: Potential indications for gene therapy of neurologic disorders
Table 4-5: Companies developing cell/gene therapies for CNS disorders
Table 4-6: Methods of antisense delivery as applied to the CNS
Table 5-1: Strategies for the treatment of Parkinson's disease
Table 5-2: Drug delivery systems for Parkinson's disease
Table 5-3: Types of cell used for investigative treatment of Parkinson's disease
Table 5-4: Status of cell therapies in development for Parkinson's disease
Table 5-5: Gene therapy techniques applicable to Parkinson disease
Table 5-6: Companies developing gene therapy for Parkinson's disease
Table 5-7: Classification of pharmacotherapy for Alzheimer disease
Table 5-8: Novel drug delivery methods for Alzheimer disease therapies
Table 5-9: Classification of neuroprotective agents for amyotrophic lateral sclerosis
Table 5-10: Methods of delivery of therapies in development for ALS
Table 5-11: Classification of treatments for stroke
Table 5-12: Treatments of stroke involving innovative drug delivery methods
Table 5-13: Drug delivery for prevention of carotid artery restenosis after angioplasty
Table 5-14: Gene transfer in animal models of carotid artery restenosis
Table 5-15: Neuroprotective gene transfer strategies in models of cerebral ischemia
Table 5-16: Gene Therapy for reducing cerebral infarction in animal stroke models
Table 5-17: Pharmacological agents for treatment of cerebral vasospasm
Table 5-18: Gene therapy strategies for vasospasm
Table 5-19: A classification of drug delivery methods used in management of pain
Table 5-20: Spinal administration of drugs for pain
Table 5-21: Investigational drugs for pain administered by intrathecal route
Table 5-22: Current management of migraine
Table 5-23: Novel drug delivery methods for migraine
Table 6-1: Innovative methods of drug delivery for glioblastoma
Table 6-2: Strategies for gene therapy of malignant brain tumors
Table 7-1: Share of drug delivery technologies in selected CNS markets: 2020-2030
Table 7-2: CNS market share of drug delivery technologies 2020-2030
Table 7-3: Value of CNS drug delivery in the major world markets from 2020-2030
Table 7-4: Limitations of the current drug delivery technologies for CNS
Table 8-1: Collaborations of companies in CNS drug delivery

Figure 1-1: Interaction of neurotransmitters with receptors
Figure 2-1: The neurovascular unit
Figure 2-2: Various forms of passage of substances across the blood brain barrier
Figure 2-3: Disruptive vs non-disruptive changes in BBB as response to disease
Figure 2-4: Role of BBB models for drug delivery in preclinical CNS drug development
Figure 3-1: Routes of drug delivery to the brain
Figure 3-2: Extracellular mechanism for drug transportation to the brain following intranasal administration
Figure 3-3: Penetration of CSF into spinal cord
Figure 3-4: Disposition of opioids after intrathecal administration
Figure 3-5: Use of receptor-mediated transcytosis to cross the BBB
Figure 3-6: Nanotechnology-based strategies for delivery of BDNF to the CNS
Figure 5-1: Oral versus transdermal administration of a drug in Parkinson's disease
Figure 5-2: Effect of tyrosine hydroxylase gene delivery on dopamine levels
Figure 5-3: Trojan horse approach for delivery of AGT-181 to the brain
Figure 6-1: A concept of targeted drug delivery to glioblastoma across the BBB
Figure 6-2: Mechanism of antitumor effects of poliovirus-based vaccine for glioblastoma
Figure 7-1: Unmet needs in the CNS drug delivery technologies