Blood-to-Brain Drug Delivery Using Nanocarriers
Brain and nervous system disorders represent a large, unmet medical need affecting two billion people worldwide; a number that is expected to grow with increasing life expectancy and the expanding global population. CNS drug development is hampered by the
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Blood-to-Brain Drug Delivery Using Nanocarriers Pieter J. Gaillard, Corine C. Visser, Marco de Boer, Chantal C.M. Appeldoorn, and Jaap Rip
Abstract Brain and nervous system disorders represent a large, unmet medical need affecting two billion people worldwide; a number that is expected to grow with increasing life expectancy and the expanding global population. CNS drug development is hampered by the restricted transport of drug candidates across the bloodbrain barrier (BBB). We will discuss blood-to-brain drug delivery strategies that make use of nanocarriers, like liposomes, albumin nanoparticles, and polymeric nanoparticles. The focus will be on the key pharmaceutical, pharmacological, and regulatory aspects towards the clinical development of nanocarriers. Clinical development of treatments employing nanocarriers is not as straightforward as for a single active moiety; therefore, we will highlight the issues that should be considered when translating basic research towards clinical development. Although it is still unrealistic to expect a magic bullet for exclusive CNS drug delivery, much progress has been made towards successful development of novel treatments for patients with devastating brain diseases.
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Introduction
Current strategies to enhance drug delivery to the brain are either focused on locally circumventing the blood-brain barrier (BBB) through direct injections or globally through the blood stream (using targeted delivery approaches or by opening the blood-brain barrier). Since techniques such as convection-enhanced delivery, intranasal delivery, and (transiently) opening the blood-brain barrier are discussed elsewhere in this section on strategies for improved CNS drug delivery (Thorne 2014; Bankiewicz 2014; Fortin 2014; Konofagou 2014), we will not elaborate on this. P.J. Gaillard (*) • C.C. Visser • M. de Boer • C.C.M. Appeldoorn • J. Rip to-BBB technologies BV, J.H. Oortweg 19, Leiden 2333 CH, The Netherlands e-mail: [email protected] M. Hammarlund-Udenaes et al. (eds.), Drug Delivery to the Brain, AAPS Advances in the Pharmaceutical Sciences Series 10, DOI 10.1007/978-1-4614-9105-7_15, © American Association of Pharmaceutical Scientists 2014
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P.J. Gaillard et al.
pharmaceuticals
pharmacology
safety
CMC nanocarrier
analytical sciences
toxicology drug delivery
bloodbrain barrier
CNS/ behaviour
route of admin
neuroscience
Fig. 15.1 Obtaining regulatory approval for clinical research using nanocarriers for drug delivery to the brain requires that many involved research areas connect with clockwork precision. Turning one wheel will influence the whole development process. CMC chemistry, manufacturing, and controls
Rather we will discuss drug delivery strategies that make use of nanocarriers, focusing on the carriers themselves. Although ligands are an essential part for targeting and delivery to the brain, this chapter’s focus will be on the pharmaceutical development of the nanocarriers and their pharmacokinetics and biodistribution and not, or to a lesser ext
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