BRAIN TARGETING DRUG DELIVERY SYSTEM THROUGH NASAL CAVITY

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ABOUT AUTHORS:
Bhavesh B. Patel*1, Nilam A. Patel2
1Department of Industrial Pharmacy
2Department of Pharmaceutics and Pharmaceutical technology
Shree S. K. Patel college of pharmaceutical education and research,
Ganpat University, Kherva, Mehsana – 384012, Gujarat.
*pbhavesh11@gmail.com

ABSTRACT
Nasal drug delivery has always been an area of research for industries because of its benefit in both local as well as systemic delivery of various therapeutic and debatably a drug delivery route to the brain. To use this route several parameters are being considered like the nature of disease condition (acute or chronic) and intended effects (local, systemic or central nervous system (CNS)) of drug treatment. Which formulation is better to target brain through nose would also be considered, device for effective nasal to brain drug delivery is also a develop thrust area for device companies. By nasal route BBB can be avoided, rapid action can be given in diseases like migraine, brain tumor, Alzheimer, Parkinson’s disease and hormone replacement. Direct delivery of intranasal drugs to the brain has been proposed, but is not universally established.


REFERENCE ID: PHARMATUTOR-ART-1816

INTRODUCTION
Many nasally applied dosage forms are available in the market. Two third are locally acting decongestants, antihistamines or cortisones, and one third comprises a number of antimigrane drugs, peptide hormone analogs and nicotine nasal spray, all with systemic effects. Diseases of the Central Nervous System (CNS) that require drug treatments are numerous; schizophrenia, meningitis, migraine, obesity, Parkinson’s disease and Alzheimer’s disease and are all such examples. Drug delivery to the brain, however, remains problematic because of poor bioavailability from the blood due to the impervious nature of the endothelial membrane separating the systemic circulation and central interstitial fluid, termed the Blood Brain Barrier (BBB).[1] This is a major impeding factor to progress in the field. Hence, many potent therapeutic agents may have been abandoned because sufficient drug levels in the brain can not be achieved via the blood. A well described strategy to promote BBB penetration is to derivatise small molecular weight drugs into pro-drug analogues which are more lipophilic and so allow passive diffusion of the pro-drugs across the BBB. These are later converted by enzymes to the native form. [2] In recent years it has been shown in the literature from animal and human investigations that transport of exogenous materials directly from nose-to-brain is a potential route for by-passing the BBB. [3] This route, termed direct nasal cavity to brain drug delivery, involves the olfactory or trigeminal nerve systems which initiate in the brain and terminate at the olfactory neuroepithelium or respiratory epithelium (respectively) in the nasal cavity. If drugs could reach the CNS by this route then it would not only regenerate interest in previously abandoned drug compounds but also enable an entirely novel approach to CNS drug delivery. Recently, several nasal formulations, such as ergotamine (Novartis), sumatriptan (GlaxoSmithKline), and zolmitriptan (AstraZeneca) have been marketed to treat migraine. Scientists have also focused their research toward intranasal administration for drug delivery to the brain especially for the treatment of diseases, such as epilepsy[15,20-24] [4-9], migraine[13,14,18,25-27] [10-15], emesis, depression[28] [16], angina pectoris[29] [17] and erectile dysfunction[30] [18].. This system is a part of nasal drug delivery system which have-


ADVANTAGES

  • Non-invasive, rapid and comfortable
  • Bypasses the BBB and targets the CNS, reducing systemic exposure and thus systemic side effects
  • Rich vasculature and highly permeable structure of the nasal mucosa greatly enhance drug absorption
  • Does not require any modification of the therapeutic agent being delivered
  • Works for a wide range of drugs. It facilitates the treatment of many neurologic and psychiatric disorders
  • Problem of degradation of peptide drugs is minimized up to a certain extent
  • Easy accessibility to blood capillaries
  • Avoids destruction in the gastrointestinal tract, hepatic “first pass” elimination and gut wall metabolism, allowing increased, reliable bioavailability.

LIMITATIONS

  • Concentration achievable in different regions of the brain and spinal cord, varies with each agent
  • Delivery is expected to decrease with increasing molecular weight of drug Some therapeutic agents may be susceptible to partial degradation in the nasal mucosa or may cause irritation to the mucosa
  • Nasal congestion due to cold or allergies may interfere with this method of delivery
  • Frequent use of this route results in mucosal damage (e.g. infection, anosmia).

HOW CAN BE BRAIN TARGETED BY NASAL ROUTE


The respiratory region of the nose is considered to be the major site for drug absorption into the systemic circulation, where the compounds can be absorbed by transcellular pathways or paracellular passive absorption, carrier-mediated transport, and absorption through transcytosis pathways. The olfactory region, next to respiratory region, is the foremost site from where drug can be absorbed directly into the brain by different mechanisms including transcellular, paracellular, olfactory and trigeminal neural pathways.[19][20] The olfactory region of nasal mucosa contains olfactory cells which extend up into cranial cavity. When the drug formulation on nasal installation, comes in contact with the mucosa they are rapidly transported directly into the brain, skipping the BBB, and achieving very rapid cerebrospinal fluid levels.[24][21] Most of the lipid soluble molecules can readily enter the blood stream from the nasal mucosa and subsequently reach the CNS by crossing the BBB. [22] But majority of the pharmaceutical drug molecules are hydrophilic, which becomes another rate limiting barrier for drug targeting, as highly lipid soluble drug molecules show easier and better targeting ability due to higher partition coefficient. It has been reported that the drugs other than lipid soluble molecule can cross nasal mucosa if there is a local injury as that can lead to breakdown of the nasal mucosal barrier. [23]

In the recent years several drugs as well as peptides have been delivered effectively using intranasal route. Administration of NAD+ greatly decreased brain injury in a rat model of transient focal ischemia and profoundly decreased oxidative cell death. [24] Similarly intranasal administration of gallotannin, a poly (ADP-ribose) glycohydrolase (PARG) inhibitor showed a marked reduction in the frequency of ischemic brain injury in rats. [25] Olanzapine when delivered intranasally as mucoadhesive microemulsion formulation showed better effectiveness of the route of drug delivery into brain.[26][27] The delivery of buspirone hydrochloride as mucoadhesive formulation using chitosan and hydroxylpropyl beta cyclodextrin showed better brain concentration after intranasal administration in mice. [28] Similarly intranasal mucoadhesive microemulsion of sumatriptan showed better cerebral concentration and reduction in migraine headache. [29]

DIRECT BRAIN DELIVERY
Various newer approaches have been presented for the direct delivery of drug molecules to the CNS. These approaches have the advantage of delivering much higher concentration of neurotherapeutics by directly injecting the drug into CSF or parenchymal space subsequently reducing the drug concentration in the peripheral environment. [30] Several factors that monitors the CSF concentration includes drug volume distribution, site of puncture, rate of clearance, drug diffusion, transport pathways and CSF production rate.[31] Several approaches that have been developed for direct delivery of drug molecules and peptides into CNS include intracerebral, intraventricular, transcranial, intrathecal, intraparenchymal (intra CSF) delivery, polymer depot formation and BBB disruption.

To understand the mechanism, pathways, distribution and absorption of therapeutic agents administered to the CNS by the intranasal route, a brief description of the nasal physiology is considered necessary.

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