Drug Delivery Technology: Revolutionizing CNS Therapies
Revolutionizing CNS Therapies
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| “The World Health Organization has indicated that CNS disorders are the major medical challenge of the 21st Century, yet treatments for most CNS disorders are either inadequate or absent. The CNS is the most challenging frontier for drug discovery largely because of the complexity of the brain and the existence of the BBB” Alan Palmer, Chief Executive of Pharmidex, UK The revenue derived from Central Nervous System (CNS) drugs is vast, in that such a large number of diseases and disease processes are grouped under the CNS “umbrella”. These include acute organic conditions, such as infection, pain (both acute and chronic); chronic organic conditions such as neoplasms, seizure disorders; chronic degenerative disorders such as multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and other dementias, as well as the range of functional disorders classified as mental illnesses: schizophrenia, affective and anxiety spectrum disorders, attention deficit hyperactivity disorder (ADHD), sleep disorders and addictions. The CNS has always posed problems in terms of drug delivery, drug efficacy and safety/ tolerability because of the presence of the blood brain barrier (BBB). The BBB is composed of a layer of extremely tightly packed epithelial cells, saturated with enzymes designed to protect the brain by disallowing the entry of noxious substances via the bloodstream. The unfortunate by-product of this has been the problem of delivering beneficial drugs to the CNS in sufficient quantities to effectively treat the targeted condition without causing unacceptable systemic adverse reactions. Administering drugs directly into the CNS e.g. intrathecally or intracerebrally, is an effective method of delivery but carries significant risks in terms of infection as well as being invasive and unpleasant for the patient. In recent years, methods of by-passing the BBB have been proposed, trialed and are now available, such as osmotic permeability, the use of nanoparticles small enough to penetrate the BBB, ultrasonic adjunctive drug treatment, and stem-cell and gene therapy, which effectively provide a “self-cure” by promoting neuroplasticity and cell regeneration within the central nervous system itself. Newer delivery methods such as transdermal drug delivery which can employ nanotechnology to increase absorption and bioavailability, as well as being non-invasive and simple to use are on the rise, and seem set to be used for a wide range of CNS disorders, including psychoses, pain and neurodegenerative disorders. |
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| Keywords: blood brain barrier, buccal, convection enhanced delivery, intracerebral, intranasal, intrathecal, nanotechnology, needle free delivery, non-invasive, oral, pulmonary, transdermal, ultrasound | |
 
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By Ruth Ohlsen / Publication Date: 13th December 2007
Contents:
1 The CNS market: opportunities for novel delivery technologies 7
1.1 Introduction 7
1.2 Overview of the market 8
1.2.1 Current market size 9
1.2.2 Patient population 10
1.2 Current CNS therapies 12
1.2.1 Product drivers and dampeners 12
1.3 CNS players & product pipeline 14
1.3.1 Key pharma players 14
1.3.2 Product pipeline 14
1.3.3 Product pipelines: neurodegenerative diseases, chronic organic conditions 22
1.3.4 Product pipeline: mental disorders, pain 23
1.4 Growth areas for CNS drug delivery 24
1.4.1 Penetrating the blood brain barrier 24
1.4.2 Transdermal delivery 24
2 Market drivers and opportunities for drug delivery technologies 25
3 Key drug delivery companies and academic researchers in CNS drug delivery 27
4 Current CNS drug delivery issues and opportunities 33
4.1 Delivery across the BBB 34
4.2 Improving patients compliance 34
4.3 Harnessing neuroplasticity 34
5 Invasive delivery technologies 35
5.1 Small molecule nano-enabled delivery 35
5.1.1 Case study: Paliperidone palmitate (Johnson & Johnson/Elan) 35
5.1.2 Case study: DNA nanoparticles (Copernicus Therapeutics) 35
5.1.3 Case study: Nanocells (Midatech) 36
5.1.4 Case study: nab technology/Protosphere (Cenomed BioSciences) 37
5.2 Vaccine delivery 38
5.2.1 Case study: ProSavin (Oxford BioMedica) 38
5.2.2 Case study: DCVax (Northwest Biotherapeutics) 39
5.2.3 Case study: NicVax (Nabi Pharmaceuticals) 39
5.3 Gene therapy delivery 40
5.3.1 Case study: non-viral delivery (ArmaGen Technologies) 40
5.3.2 Case study: viral vectors (Neurologix/ Cornell Medical College) 41
5.3.3 Case study: Intracerebral delivery (Genzyme Corporation) 43
5.4 Stem cell delivery 43
5.4.1 Transplantation 45
5.4.2 Drug delivery of stem cells 45
5.4.3 Case study: NeuroGeneration 45
5.4.4 Case study: Neural stem cells (Institute of Cellular Medicine) 46
5.4.5 Case study: Neural repair cells (Aastrom / Tissue Repair Cell Technology) 46
5.5 Peptide delivery 47
5.5.1 Case study: Lipobridge technology (Genzyme Corporation / Pharmidex UK) 48
5.5.2 Case study: “Design for Peptides” (Genzyme Corporation/ Brookwood Pharmaceuticals/SurModics) 49
5.5.3 Case study: Nanobodies (Ablynx) 50
5.6 Implants, pumps and electrical delivery systems 51
5.6.1 Case study: Duros implant (ALZA/NiTi Medical Technologies) 51
5.6.2 Case study: Intrathecal delivery devices (Medtronics) 53
5.6.3 Case study: “Brain Gate” implants (Cybernetics Inc) 54
5.7 Our opinion on invasive drug delivery technologies 55
6 Minimally invasive delivery technologies 56
6.1 Ultrasound 56
6.1.1 Case study: Catheter for stroke & ischemic stroke (EKOS / NeuroWave 56
6.1.2 Case study: Ultrasonic delivery device (Perfusion Technology 58
6.2 Convection enhanced delivery 58
6.2.1 Case study: CED Research (University of California/National Cancer Institute 59
6.2.2 Case study: Cintredekin besudotox (NeoPharm) 60
6.3 Our opinion on minimally invasive delivery 61
7 Non-invasive delivery technologies 62
7.1 Needle free delivery 62
7.1.1 Case study: Intraject delivery (Zogenix Inc) 62
7.1.2 Case study: Glide solid dose injector (Glide Pharma) 63
7.2 Transdermal delivery 65
7.2.1 Case study: PassPort system (Altea Therapeutics) 65
7.2.2 Case study: Transdur patch (Durect / Endo Pharmaceuticals) 66
7.2.3 Case study: Viaderm technology (Transpharma Medical) 67
7.2.4 Case study: Exelon patch (Novartis) 68
7.2.5 Case study: Antipsychotic patch (Dermatrends / Teikoku Pharma 69
7.2.6 Case study: Zingo (Anesiva) 70
7.3 Intranasal/pulmonary delivery 72
7.3.1 Case study: Vianase - Controlled Particle Dispersion (Kurve Technology 72
7.3.2 Case study: Tempo inhaler (MAP Pharmaceuticals) 73
7.3.3 Case study: Intranasal midazolam (Intranasal Therapeutics 73
7.4 Novel oral formulations 75
7.4.1 Case study: Remoxy (Pain Therapeutics / King Pharmaceuticals) 75
7.4.2 Case study: Spheromers (Spherics/Takeda) 75
7.4.3 Case study: Oros implant (ALZA Corporation) 76
7.5 Buccal melt 77
7.5.1 Case study: Rapidmist (Generex) 77
7.5.2 Case study: Sativex (GW Pharmaceutical) 78
7.6 Reformulations 79
7.6.1 Extended release 79
7.7 Our opinion on non-invasive drug delivery technologies 80
8 Market trends in drug delivery in CNS 81
8.1 Key drug delivery players in the CNS arena 81
8.2 Recent partnerships and acquisitions 86
8.2.1 Strategic partnerships & joint ventures 86
8.2.2 Acquisitions 88
8.2.3 Emerging specialty pharma companies 88
8.3 Market trends now 2006-2012 89
8.3.1 Global drug delivery market 2006-2012 89
8.3.2 Pharma drivers and drug delivery trends by 201290
8.4 Market by 2020 91
8.4.1 Pharma drivers and drug delivery trends by 2020 96
9 Summary & Conclusions 97
10 Bibliography 99
11 Acknowledgements 100
List of Tables:
Figure 1.1: Schematic of the blood brain barrier 7
Figure 1.2: US$100 billion global CNS market 2006 10
Figure 1.3: Half a billion people affected with CNS conditions globally 11
Figure 1.4: Classes of CNS drugs approved 12
Figure 1.5: Drugs in clinical development for mental illness 14
Figure 4.1: CNS delivery opportunities 33
Figure 5.1: Mechanism of uptake of compacted DNA nanoparticles 36
Figure 5.2: Gene therapy for Parkinson’s disease 38
Figure 5.3: ArmaGen’s molecular Trojan horse 41
Figure 5.4: New approaches to Parkinson’s disease 42
Figure 5.5: Sources of stem cells 44
Figure 5.6: Applications of stem cells 47
Figure 5.7: LipoBridge technology 49
Figure 5.8: Ablynx’s nanobodies 50
Figure 5.9: Duros once-yearly osmotic implant 51
Figure 5.10: Duros system for delivery of antineoplastic agents into the brainstem for brain tumour 52
Figure 5.11: Sagittal CTS of Duros implant 52
Figure 5.12: Medtronic Mattric SCS sytem, percutaneous leads and laminotomy leads 54
Figure 5.13: Cyberkinetics brain gate implant 54
Figure 6.1: EKOS® NeuroWaveTM Catheter in stroke 57
Figure 6.2: The NeuroWave catheter 57
Figure 6.3: Convection enhanced delivery image 59
Figure 6.4: CED imaging 59
Figure 6.5: Model of CED 60
Figure 7.1: Intraject delivery device 62
Figure 7.2: Application of interject device 63
Figure 7.3: Glide delivery technology 64
Figure 7.4: PassPort Delivery System – transdermal versus subcutaneous delivery of apomorphine in rats 66
Figure 7.5: Trasndur - transdermal patch 67
Figure 7.6: Viaderm transdermal delivery 68
Figure 7.7: Exelon patch 69
Figure 7.8: Dermatrend’s A) transdermal technology and B) HRA molecule 70
Figure 7.9: Anesiva’s Zingo 71
Figure 7.10: CPD delivery profile 72
Figure 7.11: Spherics drug delivery technologies 76
Figure 7.12: Oros drug delivery technologies 77
Figure 7.13: Rapidmist device 78
Figure 8.1: Total number of pharmaceutical and drug delivery deals (1997-2006 88
Figure 8.2: Drug delivery deals as a proportion of specialty pharma deals (2000-2007 89
Figure 8.3: Migration of CNS products from invasive to non-invasive delivery 91
Figure 8.4: CNS drug delivery landscape by 2020 96
List of Tables
Table 1.1: Table drug expenditure in 2006 9
Table 1.2: Summary of key CNS drugs in clinical development – by therapeutic category 15
Table 3.1: Leading CNS delivery companies 27
Table 5.1: Medtronic’s range of delivery technologies 52
Table 8.1: Summary of leading drug delivery companies and their delivery technologies 81
Table 8.2: Summary of recent alliances, agreements and acquisitions within CNS delivery 86
Table 8.3: Forecasts of approved CNS products 2006-2012 (US$ billion 89
Table 8.4: Forecasts of pipeline DD driven CNS products 2006-2012 (US$ million 90
Table 8.5: Leading CNS drug delivery specialist by 2020 94