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Video:

Hello everyone. Welcome to another lecture for Drug Delivery Engineering and
Principles. We are on the module where we are discussing different routes of
administration. We have discussed quite a lot in this course already and at this point let
us quickly recap what we learned in the last class and we are going to continue our
discussion on different routes of administration as we go along in this class as well ok.
(Refer Slide Time: 00:55)

So, we looked at transdermal administration in a little more detail. So, remember we are
saying that stratum corneum is a major lipid mortar layer, that is responsible for causing
a very tight skin barrier and this is the major challenge when you are looking to deliver
things trans-dermally.
Because most of the drugs is not able to penetrate through this barrier. Then we talked
about some of the strategies to overcome this barrier and enhance the delivery. So, one
was permeation enhancers. In this we discussed several cases; we talked about chemical
enhancers, using things like DMSO, ethanol etcetera. We talked about product approach.

So, rather than mixing them together we can actually conjugate them together and you
can have D enhancers conjugated together. We talked about actually physical damages.
So, this could be electrical waste, so high voltage, high voltage pulse or could be low
voltage, long duration and then apart on that we also discussed several other methods
such as laser-based damage to the stratum corneum, ultrasound-based damage to the
stratum corneum.
But with all that all of this there is a risk that we may expose the skin to several
pathogens it should be done in sterile environment and should be very transient and there
is always some risk involved in these cases. We also talked about bombardment as well
when we talked about permeation. And then towards the end we discussed microneedles:
it is one of the approaches where you make these needles in a very small dimension.
(Refer Slide Time: 03:03)

So, anywhere between 100 to 500 microns and what is seen when you make these
needles of this size range, is you if let us say, this is the skin surface you are able to
penetrate through the skin, through this barrier of lipid and mortar layer and but you are
still further above, the blood vessels and the nerves.
So, in that way you can bypass the barrier increase the permeability, but quite high
amount because this is what was causing, decrease in the permeability but still not be
able to cause pain. And then we also talked about making biodegradable micro needles.
So, we talked about making this biodegradable and what that gives an advantage is first

of all we can use all kinds of polymers and all kinds of materials rather than being
limited to metals and then secondly, there is no problems of no sharp waste disposal
required. And that helps quite a lot in terms of decreasing the cost of these sharp waste
disposal and is very environmentally compliant.
(Refer Slide Time: 04:35)

So, let us continue further with a microneedle. we are going to go into much more
financial systems in the microneedles in this class and so, there as here are some of the
examples. So, they have taken Calcein and BSA which typically have low permeability,
through the skin and what you are seeing is here are various examples of micro needles
first of all in terms of the Calcein and BSA also.
We see that quite a bit of the Calcein is getting released immediately into the system
almost 100 percent and BSA being a larger molecule has a much slower release from the
drug, whereas you can use other kinds of polymers as well. So, if we look here what we
see is micro (Refer Time: 05:20) knows a different dimension, this is how by the way the
chip will actually look like. So, you have some kind of a mold and very tiny micro
needles this is to the scale if you can see this is a finger human finger.
So, this is actually zoomed in a bit and what you what you will find is these
microneedles is so, tiny that you cannot even see them even if you poke through them
you cannot even feel them because they do not touch the nerves and you can have these
hollow micro needles and you can even deliver PLGA micro particles of fairly big size

or even if you look at the scale bar here, you are talking about 1 to 10 micron size
particles can also be delivered and they can act as a deeper under your skin as well. So,
just some examples of how these micro needles are being used. So, if let us say the drug
is coming out so, quickly you can then encapsulate that into micro spheres which has
been done here. So, you can see the free drug was coming out very rapidly.
So, what they did is they started adding some polymers to it or they encapsulated into
microparticles and now you can have release happening over a period of quite a long
duration.
(Refer Slide Time: 06:29)

So, let us take an example of another research paper which was published in 2014 and
they came out with another system which they called ionic liquids.
So, what are ionic liquids? Here is an example of an ionic liquid. Ionic liquid is nothing,
but that as the name suggests they are ionic, but in this case, they are organic salts. So,
when we talk about traditional ions we are looking at let us say salts like NaCl and when
these salts are in the aqueous phase they are nothing, but Na positive and Cl minus and
they are just floating around and interacting with other Cl and other Na ions as they
move around, but in cases of ionic liquids we are talking about organic salts.
So, as you can see this is an organic molecule, carbon based and this in general has a
positive charge, because of the presence of these amines and then these corresponding

negative charge is being provided by these fluoride based compounds and so, very
similar to what we have in cases of our normal salt, these also when you put them in a
solution they are also floating around; however, they are organic in this case. So, they are
quite amphiphilic in fact, they are quite lipid liking ions that are there. So essentially,
they are liquid at room temperature. These are again large asymmetric organic cations
and when I say asymmetric, you can see here the charge is equal although you can have
charges which are not equal as well.
So, if I have calcium chloride, you are talking about something of this configuration, but
in this case, there is a large asymmetry in the organic cations and the inorganic or so,
there could be organic cations, there could be inorganic cations and vice versa for the
anions as well, but it has to be at least, one part should be organic and they have
negligible vapor pressure. So, they do not really evaporate, but they have a very high
ability to dissolve organic, inorganic and polymeric materials, plus they are actually very
stable at high temperatures. I mean most of these salts they are not really very stable at
high temperature, but some of these organic salts are actually very stable at high
temperature and not only that they can actually dissolve organic, inorganic and
polymeric materials, which is what you will find in the skin layer. Right? I mean we
have talked about having a high lipid molder layer and then we have cell cytoplasm and
some fluid around as well. So, all of that is something that these ionic liquids can handle.
They are actually very useful in solubilization of some poorly soluble drugs in water.
So, if there are some drugs that are not getting solubilized in water, these ionic liquids,
can be used to solubilize them. So, if they are extremely lipophilic or they have some
property that causes the insolubility in water, you can use these ionic liquids to dissolve
them. So, now, what is done here? So, these authors then went ahead and tested these
ionic liquids for their enhancement ratio for a molecule called mannitol which is nothing,
but a sugar.
So, they have tested various different kinds of ionic liquids. So, these numbers just
suggest different kinds that they had and then they looked at how much they are
enhancing with respect to control. So, some of them like ionic liquids 4 and 7 identity
enhance any transport of mannitol from the skin surface to the inner part of the skin, but
some of the others such as, look at this 11 quite a lot of enhancement, almost 5 to 6 fold
enhancement, in the permeation of this mannitol. And again, the concept here is same

that these ionic liquids are extremely good solvents and they can disrupt this lipid mortar
layer and cause the enhancement to happen.
And then they looked at a skin biofilm, which is actually very difficult to treat because as
we have discussed in the previous classes the antibiotics are not able to kill the bacteria
in the biofilms. The amount of antibiotic that you actually need to kill a bacteria in a
biofilm is almost 1000 fold higher and then what it is for bacteria which is not in the
biofilm.
So, here you can see, here if you treat the biofilm with just antibiotic and saline you find
that there is almost no reduction. So, it is almost 100 percent surviving whereas, if you
treat just with the ionic liquids itself, they are actually acting as such a good solvent and
such a good disrupter of these biofilms, that almost more than an order of magnitude has
got disrupted. And now if you add antibiotic with these ionic liquids, there is further
enhancement of the efficacy.
Remember this is on the log scale so, it is quite a bit reduction that you are looking at
with these ionic liquids. So, one application is here.
(Refer Slide Time: 11:37)

And then they have looked at whether these ionic liquids can actually transport drugs
across the skin layer. So, what they are looking here is they have porcine skin model. So,

they have collected pig skin which is quite thick similar to humans. So, this is the skin
surface, of this porcine skin.
So, what they first done is they have labeled insulin, which is which is a molecule
required for treatment of diabetes and they have put it on the skin and looked at it after
some time. So, what they find is if they are just putting insulin, what you can appreciate
from this figure is all nearly 90, 95 percent of it is on the skin very little amount is
actually going and penetrating inside the skin.
However, if they use their cage which was one of the molecules, again the ionic liquid,
the geranic acid and choline ionic liquid and if they use this 1 is to 2 with the insulin,
then you can see you can appreciate how much the permeation is increased. is actually
very uniformly distributed throughout the skin and it will continue to permeate inside.
So, you can actually deliver quite a lot of your insulin through this method ok.
(Refer Slide Time: 13:01)

So, we will stop there for the skin-based methods we will now switch gear and we are
going to go for inhalation-based drug delivery. So, inhalation based drug delivery is not
new, again it has been used for quite a bit of time in fact, all the way back to 15000 BC
where some of the Egyptians were using vapors to deliver drugs and obviously, this
progress has increased in the last few years as you can see not much development, but
towards the last you can start to see quite a lot of products starting to come out in the
market and we will discuss some of these nebulizers and MDI and DPI as we go along in

this class, but that is just this is just to point out that it is actually being used quite a lot in
humans.
(Refer Slide Time: 13:53)

And so, what are some advantages of using inhalation? So, first is of course, it bypasses
the first pass metabolism. So, anything which is not oral or not through your intestine is
going to bypass your first pass metabolism, it is extremely good for local delivery to
lungs. So, if you want local delivery and to lungs only, this is one of the best ways out
there because everything you take in it is first going to go to the lungs and then if it is
small enough it can distribute out to the rest of the body.
So, if let us say you are trying to treat lung cancer or you have asthma or some lung
disease that you are looking at cystic fibrosis this is maybe inhalation maybe the best
route to go about it rather than delivering the drug to all over the body and then the
amount of the drug that bridges the lung is much lower and then you may have some
associated toxicity in the rest of the body regions and it is fairly patient compliant you
may have seen people using inhalers for asthma and so, it is just fairly easy to use
rectally accepted very well there is no risk of injuring the person, which might be the
present in cases of needles. So, these are some of the advantages here. However, there
are few disadvantages the systemic absorption of these molecules can only occur once
the drug actually reaches deep lungs.

So, if I just inhale something and if it is just localizing in the upper respiratory tract, in
my nose, in my upper lung like trachea and all, these drugs are not going to go to the
systemic absorption they will be removed by the lung itself and obviously, the solids and
liquids will only be absorbed into the system if it is below 100 nanometer. Anything
which is greater than 100 nanometer it is going to localize to lung we won’t be able to
pass through the lung and again we will discuss some of these as to why this in next
upcoming slides. But these are some of the disadvantages, when you are looking at
inhalers. Okay!
(Refer Slide Time: 15:53)

So, let us look at our lung route. So, our airways which are nothing, but several small
branches which carry the air all throughout our lungs; roughly branch about 16 to 17
times, before they reach alveolar sacs and what are alveolar sacs I will come in a
moment.
So, as you can see these are the airways. So, this is trachea, which is in your neck region
and they actually continue to divide several times. So, you can you can appreciate. So,
this is first division, this is second division, this is the third division, this is a fourth
division this is fifth division. So, this is going to continue to happen about all the way up
to 17 to 23 times, before it actually reaches the final alveolar sac. So, let us say this is the
alveolar sac which is in the deepest part of our lung. So, and that is where you want most
of the time when you are trying to do inhalation that is why you are trying to deliver

things. So, I mean it is a very intricate network in our body we have got about 500
million of these structures per human lung and so, it is a quite a lot of surface area and
that is where the major lung function and then the major lung and dynamics is happening
and so, this is the area that you essentially want to target.
If you are trying to deliver something through inhalation problem and then what further
complexes is; obviously, the body has evolved over quite a few years and it has put in a
lot of surveillance in this area. So, all of these alveolar sacs, they carry macrophages or
immune cells, about 10 to 15 macrophages per sac. So, quite a lot of surveillance that is
going around so, these immune cells are ready to take up anything that you are trying to
deliver which these macrophages may identify is something for in and clear it away.
So, that is another challenge most of the time when you deliver drugs you do not want to
deliver to these alveolar macrophages, you want to deliver to maybe epithelial cells ,
maybe let it go to systemic circulation and these macrophages impede those processes
and one other challenge here is the mucous layer. So, we all know that our lung is lined
with mucous and so, here is an example.
So, if you are in the upper region of the lung and this is how it would typically look like,
you will have a thick mucus layer about 8 micron, you have these long goblet cells that
secrete this mucus and if anything gets stuck to these mucus layer, that will not be able to
move further and, but as you go further down. So, as you go down to smaller and smaller
vessels. So, let us say somewhere down here, you have a scenario where these goblet
cells are smaller as well as the mucus layer is also small.
So, it is 3 micron and then finally, when you go to the alveolar sacs, we are talking about
a very thin layer of cells, with a very thin layer almost about 70 nanometer, very fluidic
layer of mucus. So, if you want to deliver things, what happens is now our lung apart
from these immune cells, our lung also has a system in which this mucus layer continues
to go up, through these lungs and get eliminated. And this transport of this mucus is
much higher in the upper regions, then in the lower regions.
So, if let us say you deliver something and it gets stuck in the upper region, due to this
mucociliary clearance that is going to take this mucus away and along with that anything
that is stuck to it all of this will get eliminated from the lung and we will actually either
just go down back to the stomach or will get eliminated in some other fashion.

So, that is what you want to avoid. So, the ideal way is to deliver it here, here the
transport of this mucus is very little this because the thickness is so, low and the
residence time of the drug that you are delivering here is much higher. So, it will have
more chance to act on whatever it wants to act on as well as get systemically absorbed
and we will come to how some of these processes happen.
(Refer Slide Time: 20:31)

So, this is basically. So, if I go back again, if I zoom in as to what happens at this
interface this is what it is. So, here is an SEM image which is false colored and what you
are seeing, is you have this is your alveolar sac. So, all of this is, alveolar sac zoomed in
and right next while we were saying you can see that there is a blood vessel going
through which has blood cells, flowing through it and this is then further zoomed in here.
So, again this is your alveolar sac, here is your cell layer with a very small thin layer of
mucus here and your blood vessel is right here. So, if you are able to deposit your drug
onto this surface, it is easy for this drug to then diffuse and go into the blood and once it
goes into the blood it is in the circulation. So, it can then travel very easily throughout
your body. So, that is what you are trying to achieve and that is the reason that we said
earlier that if your particles are greater than or if the drug is greater than 100 nanometers,
then this diffusion is going to be stopped, because these are too big to be able to diffuse
through this layer, but anything below 100 nanometers it just rapidly goes through here

and it is going to get absorbed into the systemic circulation. So, here is some of the lung
biology and that we need for designing some efficient delivery system.
(Refer Slide Time: 22:03)

So, now let us look at inhalation and what are the properties here. So, for free drug again
it is fine that we somehow need to deposit it in deep lung and once it gets deposited, it is
going be able to go in systemically absorb. What about the particles in general what
about the materials that you want to deliver? So, here is a deposition pattern. So, this
shows fractional deposition as to how much fraction deposits in the deep lung. So, this is
or in various regions basically. So, this is the alveolar region, which is this guy and this
is what we are most concerned with, although we can model for others as well and what
we find is the fractional deposition is very high, in the size range of about 1 to 3 microns.
So, if you have a drug or if you have a particle which is sized 1 to 3 micron and if you
inhale it, then the chances of this depositing in this layer, in the deep layer is much
higher and thereby the chances of it getting systemically absorbed and being efficient in
whatever it is trying to do. Because if you make it too low then the these size ranges are
actually exhaled out whereas, these size ranges as you can see from these graphs get
deposited in the upper lung, and why that is the case? That is the case because basically
there is an interplay of 3 major mechanism, which is the gravity, gravitational
sedimentation, the impaction and the Brownian diffusion and what does all of these
means? So, let us say this is what your trachea is and then it starts splitting into several

small capillaries and so, what happens is when you inhale things and if the, particles of
the drug are large molecule let us say 10 microns then they have a very high momentum
right?
So, the momentum is mass multiplied velocity and they have a very high momentum
because their mass is fairly high and so, what will happen is this is called impaction,
where they will just impact and rather than moving along with the airflow they just have
too much momentum and it is very difficult in the mass in the momentum conservation.
They will not be able to change the about that quickly and they will just hit the back wall
or some wall here at the time of bifurcation and trifurcations and once they hit the wall,
they will get stuck to the mucus. So, that is why the bigger particles get accumulated
right in their upper airways, what about the smaller particles let us say my particle is 100
nanometers.
Now, these particles are so, tiny compared to 10 microns. So, 10 microns is almost 100
times in diameter and since 100 times in diameter, the volume is actually even higher as
it is directly proportional to cube of R. So, we are talking about 10 to the power 6 times
heavier. So, if you have 100 nanometers particles, they are extremely light. So, their
momentum is actually very low and they can flow with the streamlines.
So, what happens is these particles will tend to go with the stream line all the way down
to alveolar sacs and then with the air flow itself they will come out. So, the air flow;
obviously, decreases as it goes down and then it further increases when it comes back.
So, as we inhale and exhale. So, that is why you do not see a much high deposition of
very small particles in the lung whereas, if you are between 1 to 3 microns, at that size
range what is been found is the momentum is not that high to impact the upper airways.
So, they continue to flow, but once they reach the deep lung because there is still heavier
than your 100 nm particles, the gravity takes over and the Brownian motion takes over
and they start moving and with the gravity start to fall as well. So, at that size range is
found that they have at enough momentum and enough gravitation that an alveolar sac
where the air velocity is fairly low, they can deposit and that is why the deposition in the
deep lung is very high, compared to any bigger size or a smaller size particle. So, that is
the major concept behind all this inhalation-based delivery. Ok! we will stop here and we
will discuss rest in the next class.

Thank you.