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Video:

Hello everyone. Welcome to another lecture for Drug Delivery Engineering and
Principles. Let us quickly recap of what we learned in the last class. So, at this point we
are talking about a module which is on what route to choose for various applications.
And we have discussed few routes already and we have continued that discussion today’s
class as well.
(Refer Slide Time: 00:49)

So, in the last class we basically focused on the intramuscular administration where what
essentially that means, is the drug is injected into the muscles. This could be large
muscles such as thighs, biceps, hips. So, this is some of the common routes you might
have seen even for children this is a very widely used route.
And some of the advantages of this route are of course, patients can self-administer with
little bit of training. It is whatever you inject 100 percent of it goes their absorption is
fairly fast. However, there are some limitations that first of all there is needle involved,
so this irritation and patient compliant is low. So, we discussed all those factors and then
we discuss how we can use another route which is transdermal administration and that is

nothing, but injecting under the skin or through the skin in this case. So, this is through
the skin.
And this is in terms of the delivery it is similar to what you had learned for subcutaneous
the SC injections, but in SC injections you were then we need under the skin. So, this is
under the skin which means that the needle was penetrating right through the skin
whereas, in cases of transdermal delivery, you are still penetrating the skin, but not
throughout. So, you are injecting somewhere in your thickness of the skin. So, that is one
of the routes that we were discussing last time.
We discussed the one of the major barriers for anything to diffuse through the skin is the
stratum corneum. So, ideally what we would like is if you apply let us say a cream or
some liquid on your skin containing the drug that should be able to go through the skin
and go to the systemic delivery or to the site of location you want, but it is not really very
feasible just because the skin is a very good organ in keeping things out it. The main
purpose of the skin is to protect us from the external environment and so this act as a
very tight interface where it does not let anything pass through it very easily.
And the major reason for that is this layer called stratum corneum which is nothing, but a
layer comprised of lots of dead keratinocytes arranged in a very zig zag and lock fashion
which does not let large molecules, charged molecules to pass through its very heavy in
lipids as well. So, for any molecule to pass through those molecules have to be slightly
amphiphilic for that. So, that they can pass through the lipid layer as well as, then they
can go through the cytoplasm as well.

(Refer Slide Time: 03:31)

So, let us talk about more. So, this was so far what we talked about is something that has
traditionally been used, so applying creams and all or maybe even needles. In this part of
this topic will discuss what are some of the research base advancement that has been
made that can go to the clinic and also actually give us a lot more control over this
delivery as well as efficiency.
So, what we talk about is permeation enhancement and the word is self explanatory
where permeation is nothing, but permeation through the skin. So, how can we enhance
that? So, along with the drug what we can do is, we can give some chemical enhancers.
So, maybe your drug D gets added to some enhancer E and that causes a much higher
permeation of this drug D through the skin. So, that will allow you to monitor your dose
as well as increase your dose.
And in terms of chemical enhance a wide range of compounds are used that can increase
transcellular permeability, the whole concept here is used some chemicals that will
destabilize this lipid mortar layer present in the stratum corneum. And once this lipid
layer gets destabilized or gets removed the permeability of the drug will increase in a
dramatic fashion because as we mentioned before a stratum corneum is the layer that is
responsible for quite a bit of protection from the drug to permeate through the skin.
So, that is essentially the whole concept of most chemical enhancers that are used in the
field. And there are quite a bit of them, one is simple hydration. So, if you instead of

keeping the skin dry if you hydrated, it helps in an aspect not by a whole lot, but some.
DMSO an excellent enhancer where DMSO is a quite polar solvent and its able to
interact with the lipid mortar layer and able to somehow destabilize this layer packing
which then, so if you give a drug with a DMSO, it will result in quite a lot more
enhancement through your skin.
Then there are some polymers that are used. You have polypropylene glycols you have
oleic acids, azones and surfactants. Surfactants are again will be very good because as
we said surfactants can interact with both hydrophilic and hydrophobic components and
that can result in quite a bit of enhancement. Then ethanol itself is a very good permeable
molecule through the skin as well as it can also enhance the delivery so in fact, if you the
one form of ethanol penetration is through the skin.
So, if you are dealing if you are working in a job in which you have to touch ethanol
quite a lot you can actually get that ethanol levels so high in your blood that you might
even get intoxicated. So, all of these molecules are used for enhancement of permeation
of the drug that you are looking.
The one thing that you need to be careful about is the safety of these molecules. Again,
by definition, since these molecules are taken and are able to destabilize a lipid layer,
most of our live cells are also made up of lipid layers. So, they can be fairly toxic, like
something like DMSO, if you end up consuming it or if its buildups too much
concentration in your body, that is never good. Same thing with other kinds of
surfactants and ethanol as well. So, just need to be careful with that the safety.
And then not only that even if let us say it is not building up too much level even if let us
say you are putting it on a small patch of your skin the problem there is you have to
make sure that that area is then sterile and is maintained sterile for few hours, because
what you have now done is you have destabilized this lipid mortar layer which was
obviously, essential in protecting you from foreign pathogens let us say there are viruses
bacteria, fungus in the air.
At this point since my skin is well intact, they cannot really go through, but once I have
used these enhancers, they have now caused my skin to be not very intact and so not only
for the drug my skin is now susceptible to higher permeation for all these pathogens as
well. So, got to be very careful it should be pharmacologically inert obviously, should be

non toxic it should not really cause the allergic reactions,7 if the immune system gets
irritated that will be another problem which then patients will not likely to use any such
enhancers. So, those are some of the things that need to be taken care about.
Then we can go back to prodrugs. So, this was just simply mixing that to enhancer in the
drug. You can actually link the enhancer with your drug with some sort of a labile bond
and then this can be used to deliver. So, because now you are making the drug more
lipophilic in this particular case, this lipophilicity will cause the drug to move much
faster across the skin and in a much more efficient manner, but then eventually you do
not really want this enhancer to be present right till the end and in this case this enhancer
could be just moiety that makes it more lipophilic. So, you add this very similar to a
prodrug concept that we have talked about.
So, maybe you add a bond which is an enzyme sensitive bond, up regulated in a disease
or maybe this is just something that constantly present in our body. So, you put that in
here once the drug reaches the site of its action or at least crosses the skin barrier, this
bond get degraded and then the drug is free to move around and act on whatever target it
was supposed to act.
And then finally, you can use some physical method. So, in this case its written as
bombardment. And what you can do is you can come up with high pressure particles that
shoot into the epidermis. These are again we are talking about micro, nano sized
particles. So, they are not, they are not actually causing a pain to your skin or to yourself,
but what they are essentially doing is poking little very minute holes.
There might be some pain associated with it if they touch the pain receptors and the
nerve cells, but in that way what you can do is now you have created these holes which
are going to be transient obviously, the skin will heal itself very quickly. So, you want to
ensure that in that right before you apply your drug you shoot them with all these
bombardments and then you can come in and put your drug in there which is going to
enhance the permeability because now the stratum corneum is not even present there is a
hole in there. So, that can increase the efficiency by quite a bit.
Again, this is a very dangerous method. Several reasons, because first of all now you
have exposed the skin to external micro environment, where all these bacteria, fungi will
be able to also access your is your skin and be able to penetrate further inside. And then

secondly, it can cause pain. So, maybe it might not be patient compliant. And then there
are other systems like gene gun very similar concept - powderject system that you
essentially just bombard with some mechanical forces, you are causing the disruption on
the skin to happen.
(Refer Slide Time: 11:19)

So, let us talk a little bit more. You have another method which is called iontophoresis.
And this is a more recent method that has come up. And in this what you are doing is
you applying a small electrical current for long duration and because this small electrical
current is applied, the layer gets destabilized due to the movement of ions and all these
lipids also get charged they move around, so there are interlocking pattern that was
preventing the drug from going through is disrupted and now the drug can essentially go
through these channels that are formed due to the application of electric current for long
duration. And these electric currents are fairly low in terms of the voltages. So, it is not
like it is going to cause shock to your body. So, it is well tolerated by the patient.
Then there is electroporation, in this case you are applying a high voltage to cause
electrical disruption but for a very short duration. So, this is going to cause a little bit of
pain to the patient, but it is for such a small duration that the patient does not really feel
much of it. And again the concept is the same, because of this electric current either long
duration for short electrical voltage or short duration for high electrical voltage, you are

going to cause the destabilization of the mortar layer in the stratum corneum and that is
going to increase the permeability by quite an amount.
Then there are more financial systems you have ultrasound. So, this is sound based.
Essentially you send these acoustic signals onto your skin and these sound waves then
cause mechanical disruption to happen and causing cavitation in that area, which then
can essentially increase the permeability of whatever drug you are looking at. So,
essentially all these methods that we are discussing so far for the permeation enhancer
rely on the fact that somehow, we need to disrupt the stratum corneum layer, and
immediately before it heals itself, which again the skin has a very good healing capacity.
You have probably already seen that, if you get a cut the blood actually stops within few
seconds and then within few hours you have actually completely sealed of skin there.
So, it is a very good capacity. So, what you are essentially doing you are using this
property of the skin by disrupting the skins because you know that it is going to heal
itself very quickly, and then applying the drug for that little bit of duration let the drug go
through and because the skin will heal very quickly you do not have to worry much
about how different pathogens may go in if you keep the area and sterile environment.
And then another way very similar is the laser-based method. So, you can use these
photons generated by the laser to cause disruption again this was on the basis of sound,
this is on the basis of light, these two are on the basis of electricity. But, the common
theme here, is all of them are disrupting the stratum corneum and causing the drug to
enhance its permeation.

(Refer Slide Time: 14:45)

So, let us take a look at some examples here. So, this is an example from industry. 3M is
a one of the major companies in quite a bit of products including transdermal products.
And what they have done is : this is a different kind of system now. So, what they have
done is they have designed the system which we call MTS which is microstructure
transdermal system. And what it is? It is a series of micro needles. So, if you can see this
picture which is focused on this region, but there are several needles that you see here.
So, these are nothing, but these are micro needles which are arrayed on let us say a
silicon wafer or any small plastic tube, and this is how and in this case what you are
seeing is now here is the plastic mold on which these micro needles are all set up right.
Obviously, I am showing this area, but it is going to be in all two dimensions in this
dimension as well as in the in the dimension going back and forth. So, essentially this
dimension and. What is the concept here? The concept here is: patients do not like
needles because needles cause pain, it is not very patient compliant. So, why do not we
remove that pain? And so, what they observed and they are not the first one, a lot of
people observe this they are the one who marketed this.
What they observed is that, in the skin the actual pain network the nervous system the
neurons and all the nerves lie much below the skin, so that, if I say that this is the skin
this is the starting of the skin here is your stratum corneum, and then as you go further
down you have these nerves running through your skin, nerves and blood vessels. So,

you have nerves and blood vessels always go hand in hand. So, what is being utilized is
this gap that is present from the top of your skin to the nerves in the blood vessel layer.
So, let us say this is it. So, unless my needle actually touches the nerve, I will not feel the
pain because nerves are the one who tell our brain that there is something touching that is
what the gives the sensation of pain. So, there will be no pain unless the nerves get
activated.
And so, if I design a needle which actually only just comes up to these regions and not
really go beyond this, so what I am essentially doing is I have traversed this mortar layer.
So, the mortar layer is this. So, I have traversed this mortar layer which is the major
blockage for delivering things and so here is all your mortar layer and I have now
traversed this.
So, the permeation that was getting blocked majorly through this layer is no longer
applicable and once the drug is getting released at these heads the drug can very easily
permeate and diffuse into a system. So, that is the whole concept with this. And so, that
is what they are showing here. So, this is that initial system and this is they are showing
that a section of a micro needle in to a guinea pig skin.
So, as you can see these needles have sort of embedded themselves into the skin and if
something gets released now, the initial layer which was fairly impermeable is not going
to be able to have any effect on that diffusion. So, this resulted in quite a bit of
enhancement of your delivery.

(Refer Slide Time: 19:13)

So, here is some more images here. So, this time we are looking at a SEM micrograph of
these micro needles. So, again here is a side view and you can see several of these micro
needles, and if you look at the scale bar, we are talking about the length of these micro
needles from anywhere between 50 to 100 microns.
So that means, that up to 50 100 microns, which is the major thickness of your stratum
corneum you can diffuse that through and here on the part b, what you are seeing is these
micro needles being inserted into the epidermis and then you are looking from the other
side. So, what you can see is these needles is just poking out from the skin. So, again
clearly showing that this lipid mortar layer is being able to easily penetrate through and
you have much better delivery of your molecule.

(Refer Slide Time: 20:19)

And here is some of the data for that. This is the skin permeability value. And so, what
do you; what do you see here is basically, you have different molecules like Calcein,
insulin, BSA, just some of the model molecules even some small nanoparticles? And
what you are trying to see is whether you are skin permeability is increasing or not. So,
you have these empty squares which are nothing, but when you have inserted the array
and you see that the skin permeability is fairly and almost an order of magnitude low, but
once you have used these micro needles, your skin permeability has increased for all of
these molecules, by quite a bit amount. So, that way you can and this is for various radii
as I was saying.
And so, you can increase the skin permeability by quite a bit amount using this method
compared to the enhancer’s method talking about, they would usually only give marginal
increase by let us say two fold, three fold here you are talking about an order of
magnitude that has a increased.

(Refer Slide Time: 21:35)

And so how would the actual delivery happen through these micro needles? So, you can
make these micro needles hollow and you can fill up your drug in this compartment, all
of this compartment can actually have your drug. And this is basically showing one of
the type where we had titanium and nickel were being used, but you can make it from
other materials as well. And because of these holes you can even cap these holes with
some let us say water soluble polymer. So, once it comes in contact with the body this is
going to get dissolved away and then the drug can diffuse out from these holes. So, that
is the major concept here.
So, in this case you are basically seeing micro needles with the taper of three hundred
microns to a tip diameter of about 75. So, basically what they are saying is this is 300
microns, this is 75 microns, and so, you have quite a bit of space to which to fill and this
is of course, 500 microns. So, you have quite a bit of space to fill this in and not be able
to worry about the amount of drug and not only that you have this is just one pillar, but
you are several of them. So, you can actually load quite a bit of drug and permeate it
through the skin.

(Refer Slide Time: 23:03)

So, how will you quantify release from this? What kind of a system would this be? So,
again if you look at this, what kind of system do you think it is? I will give you a
moment to think about this. So, remember we have done several types of system right,
we have done, we have done matrix based, in matrix base we have erodible, non-erodible
or any of these that? You know it is not just because we know that in matrix system that
drug is actually entrapped between the polymer chains this is not the case here. So, it
cannot be this and what about a reservoir system?
So, in reservoir system we basically have some volume in which the drug is there and
then there is some pore through which it can come out or some membrane, some osmotic
driven pressure or osmotic pumps like things it can come out. So, this is actually what it
is these are mini reservoirs, and so if you then can consider it with a very similar
equation as we had initially talked about the reservoir system, in early earlier part of the
course and since it is in the skin the diffusion into the system circulation may become
also an important criteria. But essentially, at least for the drug to come out from these
micro needles you can consider the same kinetics and equations as you did for these
osmotic pumps base reservoir systems.

(Refer Slide Time: 21:51)

So, here is a more example here they are delivering insulin across the skin through some
hollow micro needles. And so, what you see here is you have either, so in one case they
have used these insulins or these insulin through the micro needles or in this open square
they have only put the insulin on to the skin. And so what they are looking at is the level
of the blood glucose in some animal and what they find is if you put it on the skin and
this is a duration for which the treatment was given, you do not really see any change
from the levels here to the levels here not any significant changes and then obviously,
based on level changes is the mouse, so the animal itself is causing. But if you use the
micro needles you see a stark drop in the level of the glucose.
So, not only, so this basically is showing is not only is the insulin permeating at a higher
rate, it is also functional. So, we are not really causing any functional damage to the
insulin because it is able to do its job in the body because we are measuring the blood
glucose, so blood goes will only go down if insulin is functional and is able to act on its
receptors.

(Refer Slide Time: 26:11)

So, again because these sharps are also problem and you do not really want to use quite a
lot of these titanium and metal-based things. So, you can also make biodegradable micro
needles. And what it is? It is you have a master structure this could be of some metal or
some other some other element. You pour PDMS which is one of the polymers that
cures, because it is going to cure, it is going to cure and take the shape. So, you will
essentially when you take this polymer off you get a mold like this and then you can
come in with whatever polymer you want to make it out of, and just pour it over it give it
some center position. So, that these cavities get filled.
So, you will get a system like this. You can pour another layer if you want to make
multiple layers in that in that regards, and once you have done this you can cause the
polymerization to happen either by heating or by some other trigger. And then you can
again peel this off and what you have is micro needles of various kinds of polymer
whether biodegradable, non-degradable, various properties in them and there are small
structures.
So, even though you may you may think that these are polymer and they may not be
structurally strong, but because they are such a small structure and they have a strong
base for applications of micro needles they are actually fairly strong for them to
penetrate the skin as well as not be able to kind of just break off or something like that
for happening.

And then these could be water soluble or these could be water degradable, and what will
what we mean is once you put it on your skin and it comes in contact with the water the
skin is actually going to just cause in the degradation, and the drug to release and now
this is going to become a matrix like system. And now you do not even have to worry
about waste, right? I mean this is no longer sharps anymore because everything is going
to degrade once you peel it off all you have is just a layer, a flat layer of polymer which
is again degradable. So, you can you can just put it in water or you can discard it in a
much safer manner then you will be the such a high number of needles that is currently
being done.
So, needle ways discard is another big problem that is there in the field. So, this
eliminates that. Especially in rural areas where there is not enough incineration of these
tips or these needles happening it is a big problem. In fact, you may actually see quite a
big piles of waste, and those wastes are actually very dangerous for people who work
there because when they walk through them they can actually get these needles poked
into their body and you never know what the needle was used for maybe it contains some
pathogen and all. So, it is a bigger issue, ok. So, we will stop here, and we will continue
rest in the next class.
Thank you.