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Intranasal delivery: An approach to bypass the blood brain barrier

Blowmonkey

Blowmonkey

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Intranasal delivery: An approach to bypass the BBB

Talegaonkar S, Mishra PR
Department of Pharmaceutics, Jamia Hamdard, New Delhi -110062, India

Correspondence Address:
Department of Pharmaceutics, Jamia Hamdard, New Delhi -110062, India
[email protected]

Abstract

The blood brain barrier (BBB) represents one of the strictest barriers of in vivo therapeutic drug delivery. The barrier is defined by restricted exchange of hydrophilic compounds, small proteins and charged molecules between the plasma and central nervous system (CNS). For decades, the BBB has prevented the use of many therapeutic agents for treating Alzheimer's disease, stroke, brain tumor, head injury, spinal cord injury, depression, anxiety and other CNS disorders. Different attempts were made to deliver the drug across the BBB such as modification of therapeutic agents, altering the barrier integrity, carrier-mediated transport, invasive techniques, etc. However, opening the barrier by such means allows entry of toxins and undesirable molecules to the CNS, resulting in potentially significant damage. An attempt to overcome the barrier in vivo has focused on bypassing the BBB by using a novel, practical, simple and non-invasive approach i.e. intranasal delivery. This method works because of the unique connection which the olfactory and trigeminal nerves (involved in sensing odors and chemicals) provide between the brain and external environments. The olfactory epithelium acting as a gateway for substances entering the CNS and peripheral circulation is well known. Also, it is common knowledge that viral infections such as common cold, smallpox, measles, and chicken pox take place through the nasopharynx. The neural connections between the nasal mucosa and the brain provide a unique pathway for the non-invasive delivery of therapeutic agents to the CNS. This pathway also allows drugs which do not cross the BBB to enter the CNS and it eliminates the need for systemic delivery and thereby reducing unwanted systemic side effects. Intranasal delivery does not require any modification of therapeutic agents and does not require that drugs be coupled with any carrier. A wide variety of therapeutic agents, including both small molecules and macromolecules can be rapidly delivered to the CNS using this method. The present review discusses the various applications, advantages and limitations of this novel approach.
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http://www.ijp-online.com/article.a...ssue=3;spage=140;epage=147;aulast=Talegaonkar

Your doctor wants you to snort your medicine! :D

Nah, but really, pretty weird article. They make some wild claims.
 
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Didn't work cause there is a <br> stuck in the middle of it... Try this link instead...

I suppose in the rodent, it would be a reasonable way to bypass the BBB as their olfactory tubercle is fucking massive in comparison to the size of their brain/body, relative to ours... *shrug*
 
if this article is indeed true, than one could hypothosize that loperamide (immodium) could cross the BBB through internasal use. im half tempted to try it.
 
I don't think snorting that tiny immodium pill will be dangerous, though I doubt anything will happen other than getting instant constipation ;).
 
You could also theorize why some phenetylamines might be dangerous through intranasal use (take the thiols for example). With oral use enzymes alter the substances before entering the BBB, intranasally it directly enters the BBB what should give it a different character. Not my theory, but it does seem logical to me.
 
Could just be that the drugs are so damn potent.. if they're good substrates for gastic CYPs, the plasma concentration difference between oral and insufflated usage could be massive.
 
You could also theorize why some phenetylamines might be dangerous through intranasal use (take the thiols for example). With oral use enzymes alter the substances before entering the BBB
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Are you sure about that? How would orally consumed phenethylamines be altered before crossing the BBB and by what enzymes? If the phenethylamines are altered before crossing the BBB, then wouldn't all in-vitro tests that scientists do on receptor affinities be pointless unless they do the same alterations, making it a different molecule?

Now I could see that with intranasal absorbtion, esp along olfactory nerve, you'd get a different distribution of the phenethylamine across different parts of the brain. That could lead to a different profile of effects. The olfactory nerves enter the brain at the limbic system, which affects mood and emotion, and which is also somewhat near the autonomic nervous system, which would give you more physiological effects.
 
As I say, couldn't it just be bypasssing metabolism, and hence causing a higher plasma concentration?
 
BilZ0r said:
Could just be that the drugs are so damn potent.. if they're good substrates for gastic CYPs, the plasma concentration difference between oral and insufflated usage could be massive.
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I think you pretty much hit the nail on the head w/ that one, BilZ0r... :\
 
Certainly that lack of first pass metabolism in the gut can make many drugs an order of magnitide more potent when insufflated as compared to oral. I don't think anyone was questioning that. However even when people snort small fractions of oral doses of some of the phenethylamines, people often report a different profile of effects, with generally more physical effects during the come up. I don't see why that might not be due to some absorption into the lower parts of the brain from the nasal areas. Of course, its just a hypothesis. It may also just be one's reaction the pain in the sinuses and resulting placebo effects.
 
It might also be related to the rate of increase of plama concentrations. Although it's the same drug, there is a world of difference between oral and IV use of amphetamine - the only difference is the rate at which plasma concn. rises (it also works for things like opiates & other psychostimulants). Given that nasal doses of a psychedelic phenethylamine are going to cause a much more rapid rise in plama concn. than oral use (even if the nasal dose is a fraction of the oral dose), and that, as a rule, the rapid onset of psychedelics can cause much more distress, expressed through psychosomatic symptoms (nausea etc), it's only the speed of onset that is responsible for all of the perceived toxic symptoms
 
Very Interesting Thread

This could open up the door for the O-Desmethylation of various drugs.
 
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