Recent Patents on Drug Delivery & Formulation 2009, 3, 71-89 71 1872-2113/09 $100.00+.00 © 2009 Bentham Science Publishers Ltd. CNS Drug Delivery Systems: Novel Approaches Shadab A. Pathan 1 , Zeenat Iqbal 1 , Syed M. A. Zaidi 3 , Sushma Talegaonkar 1 , Divya Vohra 2 , Gaurav K. Jain 1 , Adnan Azeem 1 , Nitin Jain 1 , Jigar R. Lalani 4 , Roop K. Khar 1 and Farhan J. Ahmad 1,3 * 1 Department of Pharmaceutics, Faculty of Pharmacy, 2 Department of Pharmacology, Faculty of Pharmacy, 3 Faculty of Interdisciplinary Studies, Hamdard University, New Delhi-110062, India, 4 Department of Pharmacy, Faculty of Technology & Engineering, The M.S. University of Baroda, Vadodara-390001, Gujarat, India Received: May 16, 2008; Accepted: November 22, 2008; Revised: November 28, 2008 Abstract: The brain is a delicate organ, and nature has very efficiently protected it. The brain is shielded against potentially toxic substances by the presence of two barrier systems: the blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB). Unfortunately, the same mechanisms that protect it against intrusive chemicals can also frustrate therapeutic interventions. Despite aggressive research, patients suffering from fatal and/or debilitating central nervous system (CNS) diseases, such as brain tumours, HIV encephalopathy, epilepsy, cerebrovascular diseases and neurodegenerative disorders, far outnumber those dying of all types of systemic cancers or heart diseases. The abysmally low number of potential therapeutics reaching commercial success is primarily due to the complexity of the CNS drug development. The clinical failure of many probable candidates is often, ascribable to poor delivery methods which do not pervade the unyielding BBB. It restricts the passive diffusion of many drugs into the brain and constitutes a significant obstacle in the pharmacological treatment of central nervous system (CNS) disorders. General methods that can enhance drug delivery to the brain are, therefore, of great pharmaceutical interest. Various strategies like non-invasive methods, including drug manipulation encompassing transformation into lipophilic analogues, prodrugs, chemical drug delivery, carrier-mediated drug delivery, receptor/vector mediated drug delivery and intranasal drug delivery, which exploits the olfactory and trigeminal neuronal pathways to deliver drugs to the brain, are widely used. On the other hand the invasive methods which primarily rely on disruption of the BBB integrity by osmotic or biochemical means, or direct intracranial drug delivery by intracerebroventricular, intracerebral or intrathecal administration after creating reversible openings in the head, are recognised. Extensive review pertaining specifically, to the patents relating to drug delivery across the CNS is currently available. However, many patents e.g. US63722506, US2002183683 etc., have been mentioned in a few articles. It is the objective of this article to expansively review drug delivery systems for CNS by discussing the recent patents available. Keywords: Patents, drug targeting, CNS, BBB, nanoparticles, liposomes, polymers. 1. INTRODUCTION In 1998, the global market for CNS drugs was US $33 billion, which was roughly, half that of the global market for cardiovascular drugs. This was when the global burden of CNS affictions had risen remarkably and an expected US $1.5 billion people around the world were likely to suffer from one or the other brain diseases. The recent advances in understanding the causes as well as treatment approaches to CNS disorders have governed the pharmaceutical interest in this field, which is evident from the rapid growth in the global CNS drugs. Market which reached a US $55.5 billion in 2005, and is further forecasted to expand to US $63.9 billion in 2010 [1]. In spite of an impressive increase in CNS drug discovery leading to numerous molecules indicated in neurological disorders the biggest impediment remains the effective delivery of these agents across the BBB. Despite aggressive research, patients suffering from fatal or debilitating CNS diseases, such as brain tumours, HIV encephalopathy, epilepsy, cerebrovascular diseases and neurodegenerative disorders, far outnumber those dying of *Address Correspondence to this author at the Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi-110062, India; Tel: +91-09810720387; Fax: +91-11-26059663; E-mail: farhanja_2000@yahoo.com all types of systemic cancers or heart diseases [2]. The blood brain barrier (BBB) represents an insurmountable barrier for the majority of drugs including anticancer agents, antibiotics, peptides and other oligo- and macromolecular drugs [3-6]. The presence of BBB often turns out to be the sole reason for the clinical failure of even a highly potent neurotherapeutic agent. 2. BLOOD BRAIN BARRIER (BBB) The brain is shielded against potentially toxic substances by the presence of two barrier systems: the blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB) [7]. The term “blood brain barrier” was first coined in 1900 by Lewandowsky, while studying the limited penetration of potassium ferrocyanate into the brain [8]. The structure of the BBB is subdivided into two components: the endothelial or capillary barrier and the ependymal barrier. The BBB is considered to be the major route for the uptake of serum ligands since its surface area is approximately 5000-fold greater than that of BCSFB. The BBB is formed by a complex cellular system of endothelial cells, astroglia, pericytes, perivascular macrophages, and a basal lamina. Compared to other tissues, brain endothelia have the most intimate cell-to-cell connections: endothelial cells adhere strongly to each other, forming structures specific to the CNS called "tight junctions" or zonula occludens.