The brain is a delicate organ, and evolution built very efficient ways to protect it. Unfortunately, the same mechanisms that protect it against intrusive chemicals can also frustrate therapeutic interventions. Many existing pharmaceuticals are rendered ineffective in the treatment of brain diseases due to our inability to effectively deliver and sustain them within the brain. Despite aggressive research, patients suffering from fatal and/or debilitating brain disorders, such as brain tumors, HIV encephalopathy, epilepsy, cerebrovascular diseases, neurodegenerative disorders, etc. far outnumber those dying of all types of systemic cancer or heart diseases. The clinical failure of much potentially effective therapeutics is often not due to a lack of drug potency but rather to shortcomings in the method by which the drug is delivered. The major problem in brain drug delivery is presence of the blood brain barrier (BBB), blood cerebrospinal fluid barrier (BCSFB), blood tumor barrier (BTB) and efflux pumps present on the cerebral capillary endothelial luminal membrane. It impedes the drug delivery of hydrophilic and large lipophillic and macromolecular drugs.
Why brain delivery?: Brain disorders as neurological, psychiatric, and developmental disorders account for a significant proportion of the global burden of diseases. Many of these diseases and disorders are progressive and their incidence and prevalence increases with age. Worldwide the prevalence of these neurological diseases has been found to be increasing. The high economic and social costs of ignoring neurological, psychiatric, and developmental disorders include lost work time, reduced productivity, and the increased cost and difficulty of treating conditions that have become more debilitating. Many times, it is curse to family life. Recent therapies for achieving the better-quality health by curing brain related diseases aims at targeted treatment at cellular level receptors and signaling mechanisms. It is of utmost importance that interdependence of most of the metabolic disorders may lead to neurological problems and it also underscores the important function of brain controlling involuntary functions of the body. Hence, it may be the store for curing many chronic metabolic diseases if not all. Treatment of various diseases including obesity, diabetes, contraception, enzyme deficiencies can be targeted cellularly at their specific receptors in brain. Diseases as Parkinson's disease, Alzheimer's disease, psychosis etc. caused by chemical imbalance in brain neurochemicals and neuropeptides may be treated by their delivery to the brain and the drugs mimicking these peptides. Better understanding of transportation of endogenous compounds and genomics has evolved more focused approaches to drug discovery and delivery to combat brain related disorders.
Mechanisms of transport across BBB
Global perspective
World wide research on identifying new molecular targets for brain disorders and new and novel drug delivery systems (NDDS) for selective and improved brain bioavailability of drugs is gaining importance. The delivery of drugs as modified lipophillic analogues, chemical drug delivery, drug enclosed in carriers as liposomes, nanoparticles, in conjugation with polymer, monoclonal antibody and molecular trojan horses, for better penetration across the BBB. Receptor mediated transport using viral and non-viral vectors is also gaining importance. The other routes for drug delivery to brain as interstitial route, intraventricular / intrathecal route and intranasal route for direct brain delivery has also been explored. The global pharmaceutical market and industries are in phase of continuous dynamic transition and growth and all the major pharmaceutical companies are targeting the brain research as a prime area of research and healthcare responsibility.
Indian scenario
The brain research in India has been hampered mainly by the available research facilities with the research organizations. National Brain Research Centre, Gurgaon, has established links with 47 centres throughout India and few of the research institutes of the world and has shown enormous potential for new developments in drug discovery / delivery to treat brain disorders. The Indian pharma industries have large share of their earning from psychotropic drugs but their contribution to brain drug delivery research is suboptimal. TIFAC CORE In NDDS , Pharmacy Department, M.S. University of Baroda is contributing in a small manner by creating better understanding of brain drug delivery research. Our contributions in brain drug delivery are to provide alternatives ways of drug delivery for treatment of alzheimer's disease, epilepsy, obesity, contraception, anxiety and sleep disorders, and brain glioma. Various delivery systems as nanoparticles, liposomes, intranasal microemulsions for direct brain delivery of the therapeutics have been successfully developed. Still, lot to be done to understand about brain functions and associated disorders to accelerate and achieve the goals of alleviating the problems of brain drug delivery research finally leading to not only to treat brain disorders more effectively but also targeting it as an organ responsible for controlling most of metabolic processes of human body,
Brain delivery research in context with future needs
Even after noteworthy achievements in brain delivery research, drug delivery across the blood brain barrier still poses significant problems. Selective delivery of the drugs to the specific site in the brain needs to be realized by R & D s of pharmaceutical industries and research & academic institutions to alleviate brain and metabolic disorders and also take leverage of early entry to this utmost area of brain research to capture large market of the future . Moreover, our understanding of newer diseases and disease mechanisms has led to the identification of many intracellular drug targets, which has set newer and more ambitious goals for brain delivery research. Two promising new drug delivery technologies hold the cue to revolutionizing the future of medicine are based on a fusion of ideas derived from nanoscience and molecular biology. Clinical evaluation of some of the nanocarrier systems for brain drug delivery has already begun or they are in advanced preclinical evaluation stage. Research in understanding molecular transport at the BBB has already opened avenues for site-directed brain delivery with these nanocarriers. With this approach, large payloads of a drug can be delivered to the brain and this might prove to be significant for delivery of cytotoxic agents, neurotropic peptides, genetic vectors, enzymes, and difficult-to-deliver biopharmaceuticals. With advances in understanding the biology of the BBB, development of newer materials for nanocarrier development, and the engineering design principles used for fabrication and surface modification of nanocarrier formulations, there is a great hope that effective therapies for the brain diseases will be developed and delivered to the specific sites in the brain. Network of institutions (research / acedamic / pharma R & D) across the country / globe will facilitate sharing of expertise and available infrastructure for brain drug delivery research. It has to be recognized that neuroscience as a discipline is still in its infancy, not just in India but across the globe. Causes of several age-related neuro-degenerative disorders such as Parkinson's disease or psychiatric disorders like Attention Deficit Disorder (ADHD) & Schizophrenia and many other ailments are still a mystery. It controls many metabolic process of human body and hence, associated diseases. Finding cures to these diseases is a major challenge facing humanity today. To unravel these mysteries and to overwhelm these challenges requires a concerted multidisciplinary effort involving professionals from the cutting edge of different fields of science. Indian pharma industries should concentrate in brain drug delivery research more aggressively not only alleviate miseries associated many brain related/controlled human disorders but also reap the benefit of future market for these disorders .
(The author is professor & head, Pharmacy Department, & Coordinator, TIFAC-CORE in NDDS, Faculty of Technology and Engineering, The Maharaja Sayajirao University of Baroda, Vadodara)