BRAIN TARGETING NOVAL APPROACHES: A COMPREHENSIVE REVIEW

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About Authors:
Sandhu Premjeet1, 2,Rathore Devashish2, Kataria Sahil1 , Middha Akanksh1
1Seth G. L. Bihani S.D. College of Technical Education,
Institute of Pharmaceutical Sciences and Drug Research,
Sri Ganganagar, Rajasthan, INDIA
2 School of Pharmaceutical Sciences, RGPV University campus,
Bhopal, M.P, INDIA

ABSTRACT
The blood – brain barrier (BBB) has always presented a challenge to scientists for brain drug targeting . the BBB evolved in such a way that it protects the brain from various foreign substance such as neurotoxins. This mechanism makes the BBB an insurmountable . This mechanism makes BBB an insurmountable barrier for numerous highly essential drugs , including antibiotics, cytostatics and other CNS active drug 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. 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.

Reference ID: PHARMATUTOR-ART-1188

INTRODUCTION
Most conventional dosage form deliver drug into the body that eventually reaches the site of action by distribution and passive  diffusion . The  drug also distribute to non targeted  site tissues because of nonselective distribution a much larger dose is given to the patient to achive therapeutic concentration into the desired tissue.  However drug action at the nontarget sites may result in toxicity or other adverse reaction. Delivery system that target the drug only to the desired site of drug action allow for more selective and targeted drug therapy could result in a significant reduction on dose and cost.
Targeted drug delivery is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. In traditional drug delivery systems such as oral ingestion or intravascular injection, the medication is distributed throughout the body through the systemic blood circulation. For most therapeutic agents, only a small portion of the medication reaches the organ to be affected. This improves efficacy of the while reducing side effects. There are two kinds of targeted drug delivery, active targeted drug delivery, such as some antibody medications; and passive targeted drug delivery, such as the Enhanced Permeability and Retention effect3.

BRAIN DRUG TARGETING
The brain is a delicate organ, and evolution built very efficient way to protect it .Unfortunately , the same mechanism that protect it against intrusive chemicals also frustrate therapeutic interventions. Many existing pharmaceutical are rendered ineffective in the treatment of cerebral diseases due to inability to effectively deliver and sustain them with them within brain. 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 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. 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.

INVASIVE STRATEGIES FOR BRAIN TARGETTING
Temporary physiological distruption of endothelial integrity of the brain is one of the invasive strategies for drug delivery to the brain . Hypertonic distruption with help of 25% mannitol or arabinose enhances the delivery of the small molecular weight cytostatic agent to the brain tumours. Osmotic distruption has been tested as a strategy for the drain delivery of macromolecular drugs such as monoclonal antibodies nanoparticle and viruses. BBB opening also achieved by the receptor mediated mechanism. Vasoactive compounds like prostaglandin, histamine, serotonine and leukotrine havs all been shown to induce BBB leakage12.

Disruption of the BBB
The thought behind this approach was to break down the barrier momentarily by injecting mannitol solution into arteries in the neck. The effect lasts for 20-30 minute, during which time drugs diffuse freely, that would not normally cross the BBB. This method permitted the delivery of chemotherapeutic agents in patients with cerebral lymphoma, malignant glioma and disseminated CNS germ cell tumors. Physiological stress, transient increase in intracranial pressure, and unwanted delivery of anticancer agents to normal brain tissues are the undesired side-effects of this approach in humans11.

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