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Hello everyone, welcome to another lecture for Drug Delivery Engineering and
Principles. I am Rachit, I am going to talk to you about Route Specific Delivery that we
have been discussing in this course.
(Refer Slide Time: 00:39)

So, quick recap of what we learned in the last class; In the last class we learned about
inhalation continuing our discussion on inhalation. So, one thing we talked about is; what
is the right particle size for deposition in deep lungs. So, if I plot it on the x axis; let us
say if I say particle size and on the y axis if I talk about fraction that is depositing.
And this defined for deep lungs which is our major concern, when we are talking about
delivery. Then what do we get? We get, so we will get something of a curve like this;
where, we have a see that anywhere between 1 to 5 microns. So, this is micron we get
quite a high deposition and anything above that; we do not get much deposition deep
lung anything, below that we also do not get much deposition in the deep lung.

So, this is the optimal range for let us say polymeric particles and I will come to that
again in a moment. And we discussed why this is the case; it is the interplay of three
different forces the gravitational sedimentation, the inertial impaction and the Brownian
motion. And it just so happens that the velocity, that we deal with the lung this size range
helps in better deposition. So, the deposited sizes in this range are exhaled out and sizes
in this range are stopped at the upper tract.
So, that is what we discussed in particle deposition based on size; then we looked at
nebulizers as one of the methods for lung delivery. And this involves using some power
to generate mist and it works very well in the hospital setting. Again, you can generate
this mist in the size range of 1 to 5 microns and it works very well in the hospital setting.
But in the patient compliant department, this fails quite a bit just because the patients
will have to go to the hospital every time, they want to do this. And then we discussed
dry powder inhalation which causes first of all stability because these things are in dry
powder.
And then not only that; this is very patient compliant and which is fairly obvious right?
because the patients can actually inhale this themselves; it is not a very complicated
procedure; its well accepted by the society as well; so and there is no stigma attached to
it either; so, this is what we discussed. And then finally, we discussed how we can play
around with these dry powder particles; if we are using particles in those cases where we
can engineer the particles instead of having a solid matrix.
If let us say, if it was supposed to be a solid matrix then I would have required 1 to 5
microns from the actual diameter. But what you can do is, you can actually make a
bigger particle, instead of a solid matrix. Well instead of a solid matrix you have a very
porous matrix. So, very loosely bond and that then is starting to play around with the
density of this particular particle. And because of that you can then increase the size
range to let us say 8 to 10 micron and still have the same effect.
So, that is what we discussed; then we talked about Buccal administration and then this
one we were saying that; this is very similar to the oral route where you still have to
ingest the drug. But when you take it through the oral route, you do not have to actually
let it go all the way down to the stomach; you can just put it under the tongue and keep it

there. So, what is going to happen is whatever the mucosa is present under the tongue
and in mouth will causes the absorption of this route.
(Refer Slide Time: 05:49)

And what we also did is from the buccal cavity, so all this stomach and the intestine
whatever is absorbed goes into the liver and then it goes to the systemic circulation. So,
this is systemic circulation; however, from the buccal cavity it does not actually go to the
liver, it directly goes into the systemic circulation through another vein.
So, that prevents this metabolism by the liver and that way you can have much higher
drug in the systemic circulation compared to what you would have got if you, if you
would have taken it down to the stomach. However, there are again challenges associated
with this.
First of all, how do you get the drug to stay in that side for long because it is very
uncomfortable for the patient to keep big tablet in their mouth. Then we also talked about
rectum administration, so just like the buccal cavity, even in this case it also bypasses the
liver and directly goes to the systemic circulation through another vein and this is
another advantage; it is fairly rapid.
But then again there were some challenges treated with the biggest of them is again
patient compliance; it is not very useful if the patients are not going to agree to this. So,
that is a problem; however, with children and babies this could still be used because

parents can easily administer this without worrying about damaging the tissue, without
worrying about finding a way in which even for a trained personal can be very difficult.
So, that is some of the advantages why this is still around, compared to some other
routes.
(Refer Slide Time: 07:47)

So, let us talk further about different routes; today we are going to talk about another
mechanism which is intra articular administration and as the name suggests this is
injection into the articulate joints.
So, knee joint is one of the articular joints which is one of the major applications for this
administration. So, you can take the injection and directly inject to the joints. So, it goes
back again to what we had discussed, that it depends on the application. So, let us say if
you are trying to treat osteoarthritis of a knee; then it does not make sense to inject
everything into the whole system. Because what you will find is, if you inject 100
milligrams into the whole system; less than a microgram will actually go to the cartilage
just because cartilage is not very well vascularized.
So, you would may want to directly inject into the joint; obviously, this is a very difficult
injection; cannot be done by anybody, there is a big risk of these needle you can actually
damage your cartilage. So, it should only be done by trained personnel then you would
need an intervention by going to some hospital or something. But even then, it is much
better because most of the drug will then localize into the joint and you can have much

higher joint retention of the drug compared to if you injected in IV or intra muscular,
subcutaneous or some other side.
So, an example of this is Zilretta especially the bioengineering example. So, again you
can inject quite a lot of things in the joint, but joint also suffers with a similar challenge
that it has a good lymphatic system. So, if I actually expand on the joint capsule; let me
just actually draw a joint.
So, let us say this is femur which is nothing but a bone and this is tibia which is this bone
here. And then you have cartilage which is lining these two bones and then this is
actually being encased by something we call synovial membrane and this whole system
is called the joint capsule.
Now, that you have this joint capsule surrounded by the synovial membrane, this
synovial membrane is actually very well vascularized. So, lots and lots of blood vessels
are present and it is also having a good lymphatic system. So, now if you inject anything
in this joint space, that drug is going to get absorbed into the lymphatics into these blood
vessels and get cleared out from the joint. So, what do you find is even though you get
high local delivery and still quite a high concentration for a little bit of time; most drugs
typically within few hours 3 to 4 hours they start to decrease their concentrations
significantly in the joint space and at that point you do not really have much controlled
release.
So, whatever you are injecting is going to get released out fairly quick and the joint space
will be empty of the drug within a day or so. If the drug is fairly small which most drugs
are in this particular example, so going back to our concepts that we have learned in this
course; we can engineer biomaterial to have a longer residence time.
What is typically seen that, if you increase the particle size, or the drug site, that will
have a much longer residence time. Because now that the drug size is so big; it cannot
really go into the blood vessels it cannot really go into the lymphatics very easily. So,
that is what is being used here.

(Refer Slide Time: 12:23)

So, in this particular product which is zilretta; which is already again out in the clinics
the whole concept is to use about 35 to 55 microns PLGA particles. And because these
are so huge particles, that they cannot really escape out. Even the immune cells which
are of the order of 10 to 20 microns cannot really clear these PLGA particles away. So,
now, you have created deep on the system. So, this PLGA particle is going to sit in your
joint space of course, it needs to be compatible. So, it does not damage your cartilage
itself, but this is going to sit there and nothing can clear it out. And the only thing that is
going to happen, it is going to start degrading and releasing whatever it is encapsulating
over time.
So, in this case encapsulated molecule is this acetonide and it is a short acting
corticosteroid which is used to decrease the inflammation; as well as help with the pain.
So, it gives you a very long-lasting pain relief for more than 12 weeks. So, single
administration is enough for you to get relief for 3 months. So, it becomes very patient
complaint in that regards and then what this particular particle is engineered by?
It is engineered with 500 nanometer channels. So, here is a graphic of a particle that the
company is giving the zilretta that you have these depots inside these particles of the
drug. And then the drug then slowly comes out through these 500 nanometer big
channels that are present. So, as the particle degrades more and more channels open;

more and more depot of these drugs come out and that helps in the pain relief for this
particular joint okay!
(Refer Slide Time: 14:11)

Next thing we are going to talk about is intravenous delivery and this is again by far one
of the most used methods in the hospitals. There are several advantages to this the drug;
it is immediately 100 percent bioavailable. So, the moment you inject, it is in the
circulatory system, it is going to immediately distribute throughout the body. And it is
going to be immediately bio-available and remember when you say bio availability it is
basically when the drug is able to access wherever its target are.
So, once it is in the blood; it can go all over the place in the body and it will be bio
available. It is very rapid response; again, goes back to the same point that is
immediately available. So, it can act on its target much more quickly and very rapid
response is seen. So, if a patient is actually suffering from let us say a condition in which
if something is not done within few minutes; the patient may die, then IVs are out to go!
You cannot really wait to inject inter muscularly or subcutaneously and wait for 10-20
minutes for the drug to take effect. You want that drug to take effect immediately; maybe
it is something that is causing the heart to stop and you want to give some biomolecules
that may cause pumping of the heart to begin in normal scenario. So, in that ways the IV
is the best route to go.

You have a total control on the concentration and this is important because again, even
though you might be injecting somewhere intramuscularly or subcutaneously and you
think all of that is going to go to the blood. But then there is a whole kinetic set as the
things are building up in the blood; they are also getting excreted. So, you do not really
actually know how much is the peak concentration, you may get in the blood at a time
even though you might have done some experiments, but it will vary with the site to site
you inject.
So, all of that variability is still there, but in the IV injection you know that whatever you
injected is immediately in the blood; even before it gets start to gets eliminated. So, you
have a fairly well control of what your pharmacokinetics is going to look like.
Immediately you will have a certain blood concentration and only then it will start to
drop out.
You then also maximize the incorporation of degradable drugs. So, what that means, is
whatever drug you are injecting is, immediately getting incorporated into the blood
system. Whether they are degradable or not going back to the point that if you injected
intra muscularly or subcutaneously, they might start to degrade even at that site and
again you do not know how much of the constant in the blood you are going to get.
And since not everything is going to pass through the liver, you bypass the first pass
metabolism. And here are just some examples; so, what you are looking here is bolus
doses of injections are typically given; I am sure you all of you must have seen these IV
bags that are being infused to; infuse maybe some fluid into a patient or maybe some
drug into a patient.
So, these are very traditional forms of delivery that are extensively used in clinics. What
are some of the disadvantages of the IV injection? So, first is of course, is extremely
invasive we all have gone to injections; it is painful; we do not really want to get an IV
injection unless we have to; so that is a major challenge. The second is not everybody
can do this procedure; we cannot do it sitting at our home; we need some trained
personnel to be able to find the right location of the blood vessel in which to inject it.
You do not really want to inject it in a side which is not correct, you do not want to
damage a blood vessel either multiple times and trying to find a blood vessel. So, it has
to be trained personnel who can do this and then there is possible toxicity to doing

incorrect dosing. So, let us say if you do inject it trying to inject it in the blood, but
eventually having injected only some in the blood, some in the surrounding muscle you
are doing some incorrect dosing and it may cause toxicity.
And not to mention that you have to be extremely precise with the dose, because it is
going to build up the concentration in the in the blood immediately; so, if you do end up
going to the toxic level, it will cause toxicity. And of course, one of the major challenges
is the sterility which is also very important. So, if you are directly putting in the blood;
you are giving if your injection is not sterile and it contains let us say some pathogen or
some infectious agent; you then actually put it in the system of circulation which means
So, if let us say the pathogen only infects lung; it will be able to go to the lung as well
because all blood goes to pretty much every organ that we have and that is a big
problem. So, it is a very stringent procedure sterility and maintenance that should be
followed before doing the IV injection. That is why you see patients before they get
anything, they are swabbed by an ethanol wipe or something to sterilize the area as well.
So, even if your drug is completely pure, but maybe your skin has some pathogen even
that gets removed off. Okay!
(Refer Slide Time: 19:21)

So, this was a basically many on the traditional form of delivery using IV injections;
what about more on the bioengineering aspect of it? So, here is a diagram showing how

various aspects of the blood that needs to be considered when we are looking for the
delivery through the blood.
You have seen this before; so, what it is? Let us say you are injecting some dose into the
blood; you have a circulatory system. The first thing was going to happen is heart since
its pumping continuously it is going to start pumping whatever you have injected in the
blood to all parts of the body. And so, I have only shown few organs here, but it will
pump it to every part of the body.
The smallest capillaries that we have are about 5 microns. So, which means that if you
inject anything which is bigger than 5 microns; what is going to happen? Let us say if I
inject this particle which is about 10 micron; it can flow through this big muscle no
problem, it can then start to diffuse in and is pumped into the small vessels still it is ok,
but as it goes down to a smaller and smaller vessels; it may just get lost there.
Because it is physically too big it; it has really no way to go because it cannot move
forward unless it ruptures the blood vessel; it cannot go back because the flow is pushing
it forward. So, it may clog this vessel, now if this vessel is going to your brain then
basically, we talking about stroke. Because suddenly a part of the brain is not devoid of
oxygen, the cells will start to die and as the cells die your brain will stop functioning a
part of the brain will stop functioning and that will lead to stroke.
The same thing can happen in the heart also; similarly, if one of these vessels is feeding
the heart cells; then and that suddenly stops then you are talking about a heart attack. So,
it is a very serious problems; if you inject something which are bigger than 5 microns.
So, definitely we will not be able to inject things which are bigger than 5 microns.
Then the other organ you already talked about quite extensively is liver; now liver as I
had already mentioned is a metabolizing organ for most things and lot of the blood does
pass through the liver it is a fairly large organ. And so, it will metabolize quite a bit of
your drug when you inject it into the circulation. And not only that the liver cells are
actually very good in sampling anything for it. So, the blood vessels in liver are actually
lined with this Kupffer cells which are the resident macrophages in liver tissue.
So, these resident macrophages keep on sampling whatever is flowing. So, if there is just
a blood cells or our bodies own cell these do not really do anything, but when they find

any foreign particle or pathogen that is flowing through this; they will engulf it and try to
kill it. So, that is one place where you lose quite a lot of your particles and again since I
said its macrophages and we discussed in the inhalation part of the things that
macrophages do have fairly high up take between 1 to 5 microns.
And in fact, even we can say that from 500 nanometer; they will start to clear things. So,
now we said, we cannot have bigger than 5 microns; the other thing we are saying is
even at 500 nanometers; we will get some clearance. So, ideally, we want long
circulation, we would want to go below this size; now let us talk about another organ.
So, here is kidney and this is in the very early part of this course; we discussed that
kidney can clear anything below 6 to 10 nanometers. So; that means, if size is less than 6
nanometer or 10 nanometers; it will have a very fast clearance from the body because
this kidney will continue to filter it out.
So, that is again something that we do not want because if you want the long circulation;
we want to make sure that not everything that you have put in, goes out through the
kidney. So, you want to make sure your particles are greater than 10 microns. So, now
we have already said here we are saying less than 5 microns; here we are saying greater
than 10 nanometers; so that is one limit.
Now we are saying that the liver will also take out 500 to 5 microns; even though with
not very good efficiency, but it will still take them out. So, ideally, we really want long
circulation we are talking about 10 nanometers to 500 nanometers. And now another
major organ the spleen and so what does spleen do? so this is a bit of a repetition, but the
blood that comes into this plane actually gets filters out in this spleen.
So, most of the blood empties itself in the spleen and then goes back into your blood
vessels. Now these blood vessels are comprising of all these endothelial cells and all
kinds of smooth muscle cells. So, they create a pore size here which is about 200
nanometer in a healthy; in the healthier person; so, if now you have anything which is
greater than 200 nanometer it will be very difficult for it to go through this. So, what will
happen is that will start accumulating in the spleen and in the spleen is rich in lots and
lots of immune cells and they will come and start gobbling these cells these particle cell.

And we discussed previously that if you can play around with elasticity; so that it can
actually become soft enough, so it can squeeze through. But in generally speaking, these
500 nanometers are now becoming 200 nanometers. Because again if you have particles
between 200 to 500 nanometer range; they will tend to be cleared out by the spleen.
So, these are some of the major limitations that have been put by our bodies internal
healthy organs that we need to take care of when we are looking into IV delivery; using
some bio material based particles. Of course, you cannot put any macro device; so that is
completely off the question; since that has to be less than 5 microns. And then further if
you want long circulation; it has to be within this range of 10 nanometer to 200
nanometers.
And then finally, we have in this particular example I have also given tumor here and it
is been described here and we will go into a lot more detail of this in this next slide.
(Refer Slide Time: 26:13)

So, let us look at more on the tumor environment and we have also discussed a bit of
this, but what tumor is? It is an organ/tissue which was never supposed to grow there. So,
this is extra mass of cells that have come in which body had never programmed.
So, if you look at healthy cells or healthy tissues; let us say if this is a healthy tissue then
pretty much every part of this tissue is being fed by a constant supply of very regularly
arranged blood vessels. So, these blood vessels have been growing as we were growing

and the tissues were growing and they ensured that pretty much every part of this tissue
is well vascularized.
So, even the widest differences between the two blood vessels is never more than few
hundreds of microns; so maximum 100 microns maybe. Now this is for the healthy
tissue; however, when you compare this to a tumor tissue, the tumor was something that
body had never programmed for it. So, the blood vessels had never really tried to grow in
into the tumor tissue, but what is happening the tumor tissue is inducing blood vessel
growth.
So, it can get nutrients while it is growing. So, when you look at let us say if I make a
diagram of a tumor tissue; you may have certain regions which have high density of
blood vessels and then you may have regions which have really no blood vessels. So, I
mean all of that area is now relying on these blood vessels to feed them.
Now, this is a big area for things to diffuse into. So, what does tumor do? It causes the
blood vessel to dilate and these blood vessels have formed also very rapidly; so, they are
fairly immature. And so, what I am basically getting at is this diagram, where if you see
blood vessels in healthy tissue; you see the lined very well and fairly mature with some
very basic amount of gap between these cells.
However, when you look at the tumor blood vessels, these are fairly immature and the
fairly leaky. So, you can find that there are actually gaps here which are 100 to 200
nanometers big; maybe these gaps are about only 5 to 10 nanometers. But these gaps are
huge and because of that; if you now design a particle which is let us say 50 nanometers
in size.
So, while that particle is flowing here; it is just physically too big to be able to go into
your healthy tissue. Whereas, in the tumor tissue these particles can very easily diffuse
out and go into the tumor; go into within the tumor cells. So, because of that we say that
these tumor vessels have enhanced permeation.
So, this is called enhanced permeation and then the other thing which is shown here is
lymphatic vessels. So, similar to that the lymphatic vessels are not very formed. So, the
major job of the lymphatic vessels is to take extra fluid out from the system. So, since the

lymphatic vessels are not very good, you are getting fluid accumulated in the tumor
region as well.
So; obviously these blood vessels are putting pressure on the tissue; on this direction, the
lymphatic since it is not there. So, there is a lot of water which is putting the pressure on
the tissue in this direction. So, because of that whatever particles that come in are not
able to then diffuse out from this tumor. So, this pressure on this direction the pressure
on from this direction. So, these particles are nowhere to live, but to get retained in the
tumor this is called enhanced permission and retention.
And this is not only for tumor if there is a inflammation in certain place then that causes
a lot of immune cells to go and very similar to the tumor there are lots of cells in the
surrounding. So, they also have their vessels dilated and they also are slightly leaky. So,
this works with both the enhancement permeation and retention which will be seen in
tumor and inflamed tissues.
So, to be ideally speaking; anything below 100 nanometers will be able to utilize this
effect and to a very nice effect; to a very nice extent. Whereas, anything above 100
nanometers may be difficult it may diffuse into certain areas, but not through all areas of
the tumor vessels. So, ideally you want to have your particles anywhere between 10
nanometers to 50 nanometers, if you are trying to target these tumors and inflamed
issues.
Even 200 nanometer is, but beyond that it is; it is not going to work very well at least
with this concept. So, that is what people then do when they make these particles for
tumor replication. And you will find them quite a bit in the literature and we will go over
some of the examples; they will use anywhere between 10 to 100 nanometers. So, we
will stop here and we will continue further in the next class.
Thank you.