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Module 1: Release Systems and Hydrogels

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Videos:

Hello everyone, welcome to another lecture for Drug Delivery Engineering and
Principles., just a quick recap of what we have done in the last class. So, in the last class
we continued our discussion with non erodible matrix system these are matrix systems
that can be used to essentially release out any kind of drug that you want to deliver to the
system, via mainly basis of diffusion or through some sort of solvent base extraction of
these molecules.
(Refer Slide Time: 00:56)

And so in this we discussed there are four cases and then in this last class we discussed
the last two cases. So, essentially in a non erodible systems, you can have systems where
the drug is either dissolved or dispersed and then the other scenario is, the drug just
diffuse out throughout the matrix or it diffuses through the channels.
So, we discussed the first two first which was the drug is either dispersed or is dissolved,
but it is coming out through the entire system and then in that last class we talked about
in the case where the drug is coming out through the channels. As its really nothing
much different here, but the porosity and the tortuosity of these channels gets accounted

for. Then we talked about the bio erodible matrix systems these are very similar to non
erodible matrix system these are systems which have encapsulated the drug into their
volume, but in this case they are now bio erodible; that means, that the when they are put
in media which is biologically relevant they can erode.
So, they can either degrade by surface or bulk some things that we again discuss in the
past. Then towards the end we talked about microchip based delivery, so this in this case
we discussed two cases, one was anode based in which you have a reservoir that is
capped with some thin metal anode films and then once the current is applied these
things degrade and whatever is in the reservoir gets dispensed into the system.
And then the other thing we discussed about was instead of having in this anode based
we can have it as a resorbable polymer and then this case became predefined as to this
will degrade let us say in either 1 day, 7 days or 30 days and then depending on if this is
1 day, this is 7 days, this is 30 days, then you will get that release which will look
something like.
So, at first it will be 0, at day 1 it will suddenly burst release out once this membrane
degrades, then again it will be 0 then it will release out again and then same thing again
depending on how much you have and what time points you are looking at.
(Refer Slide Time: 03:23)

So, today we are going to talk about another very important class of drug delivery
vehicles and these are called hydrogels. So, hydrogels are very widely used in the
literature there a big in fashion at this point of time currently for the last 5 years and they
have lots and lots of attractive properties which makes them very usable currently I am
going to talk about some of these.
So, if I strictly define hydrogels these are essentially nothing, but the three dimensional
structures, anything that has some sort of a length, breadth and height can be considered
as three dimensional and so like all the other bio erodible matrixes that we also talked
about, are all three dimensional and they are made up from a very hydrophilic polymer
networks.
So, these hydrophilic polymers can be a variety of kinds, can be a variety of groups
involved in there, but the essential thing is they are very hydrophilic and so because they
are so hydrophilic they tend to absorb water and because of that if you make a matrix out
of these hydrophilic polymers, it will absorb water and starts to swell.
So, here is an example here, where you can see that it is a jelly that some of you may
have eaten during your course of life and this is essentially nothing, but if you have ever
touched jelly it is a very squishy, very soft material, but again can have lots and lots of
water compared to the actual polymeric content that might be present in a system like
that.
So, as I said, they can swell, it depends on what polymers and what sort of cross linking
is being done to maintain this polymer in a structure, but then they can expand to even
thousand times there dry weight in fluid. So, you can have a dry hydrogel, but when it
comes in contact with the aqueous fluid, it can absorb lots and lots of water and starts to
swell and that swelling can be even up to thousand times.
They are of course, insoluble any kind of gel or any kind of device that we are talking
about these are all insoluble because they are physically or chemically cross linked and
that is how they provide the network structure. So, if it is soluble; that means, that
individual components will continue to break apart and then start to just kind of roam
around as soon as the solvent is put but if they are insoluble of course, that means, that
they will remain as intact as they were initially.

Of course, like all the matrix systems we talked about earlier this is also one sort of a
matrix system these could be bio erodible or non erodible; that means, that over a period
of time it is bio erodible and then essentially; that means, that the hydrogel will degrade
over time.
And then if it is non erodible; that means, that we will maintain structure it would not
really have any loss of the polymer itself the drug may or may not come out that depends
on the system what you are designing, but the biological fluid will not cause any kind of
erosion to happen. And there are several and several applications to this, they have been
used in contact lenses.
So, the contact lenses you will see people wear on their eyes in the front not only they
have power, but they can also protect the eyes and again hydrogels are the one that I used
very often to make that, they have used very widely in tissue engineering matrices and
we are going to talk about that as we go along in the course, they have been using
biosensors, they have been used in drug delivery. And I think one of the thing that really
makes them so attractive is the fact that, if you look at our own body and whatever we
have is, we basically have cells and proteins and different kinds of other bio molecules in
our body, but then the cells typically we will find are embedded in some sort of a 3D
structure.
So, if you look at cells, they just do not sit ideal in the layer, but there is some sort of a
3D matrix like, that it could be some kind of a ECM component like fibronectin or
collagen or laminin and there are few others, but then what you will find is the cells are
always sort of sticking to some sort of a structure if they are stagnant or unless they are
flowing in the blood then it is a different case, but most cells you will find in the body
are stabilized in some sort of a structure like that.
So, because of that the hydrogels can act as a mimic to this ECM structure that I have
drawn here and that can support both the cell adhesion, the cell migration as well as
releasing different molecules. So, that is why they are very widely used for tissue
engineering and again as I said as we go along we are going to give some examples and
talk more about this.

(Refer Slide Time: 08:13)

So, in terms of the drug delivery itself how does this work? So, you have a drug that is
dissolved into the polymer. So, in this case the drug could be lying, again like the
erodible and non erodible systems, the drug is trapped among these polymer chains that
may be present in this hydrogel and the drug itself is fairly big that it cannot come out of
these pores in these networks or even if it does it might be very slow, but once you put
this in a solvent as we said that the hydrogels are capable of swelling, its going to start
absorbing more and more water into the system and as it does that it will swell. So,
maybe the initial shape was like this.
But now what has happened it has swelled in all directions and so because of this
swelling, what will happen, these gaps would be in the polymer chains is going to
increase. So, let us say if this was the gap here, as its absorbing more water these chains
are getting stretched and stretched and what will happen is eventually it is going to turn
into a structure like this where now, as you can see this gap is much larger than the gap
here.
So that is how basically the drug will come out because now it can easily diffuse out, so
let us say the drug was just big enough to entrap here, in this case the drug is small
enough now or and the pores are big enough now that this drug can come out through
these pores.

So, advantages are, it has low burst effects and the reason for that is drug is basically
entrap it is not moving around. So, remember why was the burst effect present? It was
present because drug would typically come out and sit right on the edges. So, if there is
no movement of the drug because it is very entrapped in there it would not really come
out and you would not get a burst effect. We can derive the equations as to how much its
going to get enlarged, how much these pore sizes are going to become larger as it
absorbs more and more water.
So, you can have some known and predictable swelling rates. So, that way then you can
use mathematical equations to determine what sort of kinetics we are going to get for the
release of the drug. And again the vehicle is fairly well controlled in terms of what is the
pore size for different types of polymers and different types of concentration.
So, even if you change the drug from one to the other, its not like you have to now
reformulate everything and basically right start from the stretch, what you can do is you
can just replace the drug from whatever drug you were earlier using and if you know the
size of the drug you can very well know the sort of a release rate and what sort of
polymers to use to make this hydrogel.
What are some of the disadvantages? Generally, it is a very short release period we are
talking about because once this is swelled and the drug can very rapidly come out on the
basis of diffusion and that kinds of limits as to how long you can release drugs from
them, but again there are few strategies to counter that and we are going to talk about
that.
And again it is not really suitable for all delivery routes or targets now you have to worry
about your actual implant changing in size. I mean let us say I have a 1 millimeter
implant and I want to implant it let us say in my eye, but if I know that 1 millimeter is
going to become 10 millimeter I do not want that implant to start pressing on different
tissues of my eyes and causing damage, same with the blood vessels right.

(Refer Slide Time: 12:12)

I mean we know our blood vessels the minimum of them the smaller capillaries at about
5 to 10 microns, the blood capillaries and so let us say if I have hydrogel particle which
is let us say 3 micron. So, it is fine to inject that because its lesser than that, but if I know
that this 3 micron is going to then increase and become let us say 6 micron, then I cannot
inject into the blood right because you have inject it into the blood what will happen
these 5 microns, 6 microns capillaries will get clogged. And not only that, but their
downstream tissues where these capillaries were supplying, those cells will now would
not get oxygen, would not get nutrients and they may start to die, this may cause heart
attack or this may cause strokes, if it if those capillaries are involved in brain, so and this
is a big issue there.
So, again as I said its not really suitable for all delivery routes and targets, but then again
the good thing is we know what final product we will get, so we can choose where to
inject it. So, let us say if I want to put it in under the skin and I am if the skin bulges a
little bit and then I can use this.

(Refer Slide Time: 13:27)

So, some of the polymers that are used in hydrogel formulations, so again as we
discussed this can be natural polymers or this can be synthetic polymers. And of course,
when I say polymers, we also talk about cross linkers these are small molecules or big
molecules that are involved in cross linking these polymers to form a mesh like network
and but right now we are mainly talk about the polymers themselves.
So, they could be anionic polymers for natural, so HA very commonly found in our
joints, alginic acid, pectin, chondroitin sulfate again something found in the joints the
sugar moieties like dextran sulfate. You can have cationic polymers such as chitosan and
poly lysine. So, these are again very well characterized and found throughout the body.
Then you can have an amphipathic polymers like collagen, so these are not really
charged, they have both charges and essentially the charges are balancing themselves out
you can have fibrin, you can have CMC or it can be natural polymers these could be
dextran, neutral polymers, these could be dextrans, these could be agarose and other
molecules. Again remember all of these molecules need to be hydrophilic right as I said
the hydrogel will only form with the hydrophilic polymers.
So, again all of these can also form various other kinds of things along with some other
polymers too, but if it has to be hydrogel it has to be hydrophilic. And then let us talk
about some synthetic polymers, so polyesters again PEG is a very hydrophilic polymer
and again very widely used for making hydrogels. So, in this case it even list as

combined with the PLA which is not as hydrophilic, but then the whole combination of
this product is fairly hydrophilic.
So, you can combine PEG with different kinds of polymers, you can have some other
polymers such as polyacrylic acid and Poly NIPAAm, PVC, so all of these are again
used quite often. And then you do not really have to have categorically different that it
has to be either natural or synthetic you can have something you can combine the two.
So, you can combine PEG with other peptides to form a polymer, you can combine
alginate with other PPO type polymers to make them, you can have collagen and
combine it with some sort of an acrylic polymer. So, all of this is again widely used in
the literature.
(Refer Slide Time: 16:09)

So, how do we classify hydrogels? So, there are various ways you can classify hydrogel
one is on the basis of first of all how they are forming their structure. So, this could be
either a physical hydrogel or and this could be a chemical hydrogel. So, let us talk about
physical hydrogel first. So, these again are polymer networks that are held together by
neutral or ionic bonds. So, when I say neutral bonds I am talking about Van der Waal
forces right.
So, this could be Van der Waal forces and ionic would be either H bonding or it just
could be interaction of cation and anion. So, these are essentially nothing, but these are

molecular entanglements. So, you can consider it as if you have very long chains of these
polymers and they just cross each of the several times. So, I am sure if you guys have
using earphones, you have seen sometimes it gets entangled and form this knot like
structure.
So, if you have enough of your headphone leads which are very long and you will
essentially end up with some sort of a giant mesh of a network that will be molecularly
entangled with each other to form sort of a 3D structure. So, that 3D structure is now
made about hydrophilic polymers and happens at a much smaller scale then we are
talking about a hydrogel.
So, as I just said there are some ionic hydrogen bonding in hydrophobic forces involved
essentially Van der Waal forces, they are typically non homogeneous as I said they are
this random entanglement of chains. So, it is not like they are very well ordered or
structured, so at some parts of a hydrogel, so, let us say if this is my hydrogel at some
part of the hydrogel what you can have, you can have quite a bit of chain coiled around
to form a gel and in the other parts you can have very sparse chain forming around.
So, they can be micro clusters like this, where it could be high molecular entanglement
versus low molecular entanglement. So, in this case low and high and so if you start
comparing between the two, you can find that the drug release from this area will be
much slower just because the cross links are quite a bit and the drug cannot diffuse out
very easily, while the drug from this is fast compared to the overall structure. So, they
tend to be non homogeneous.

(Refer Slide Time: 18:50)

So, let me just delete this. As I said there are physical cross link these are formed by
hydrophobic association, Van der Waal bonding, ionic bonding, hydrogen bonding
between two monomers in water they have significantly lower strengths. So, covalent
bonds are typically much higher strength than these physical interactions. The strength
for these physical interactions lie in the numbers. So, you have a one covalent bond
whereas, for each one covalent bond for these physical interactions they might be almost
hundreds and thousands of a small interactions happening here. So, just to keep in mind
that, there individual bond strengths are fairly low whereas, in covalent bonds it is fairly
high.
So, thus formulation of even transiently stable hydrogels require block copolymer
structures where cooperative binding can occur. So, what essentially this means is let us
say if I have a block copolymer with let us say monomer A here and B here.
So, if I have these and then there could be multiple chains of these right its easier for
them to then come together and because there are let us say A can roll around and
interact with the B here there lots of interactions here, they typically tend to form a better
physical hydrogels than the individual units and that is how these ones will be much
stable.

(Refer Slide Time: 20:41)

And then formation of one physical bond is immediately followed by bonding of several
others. So, at the time you are basically talking about zipping up these contacts. So, you
can have; you can have one bond forming between these two, let us say this is A A A
from one chain and this is B B B from another chain and as soon as they come in contact
and start interacting, now these surrounding chain surrounding atoms are also in close
together. So, they will start two kind of zip this through. So, very soon you might have
something like this forming where now you have A,A,A from one chain interacting with
the B domain of the other copolymer.
So, that is how their structure goes and again you can assume that there are thousands
and millions of these scenes and they will cross each other as well and make this a very
stable structure.

(Refer Slide Time: 21:53)

So, something more on the physical hydrogels, sometimes physical gels can form by a
bio specific recognitions. So, it may not be a covalent bond and it would not be any of
these interactions, but then we know in biology there are lots and lots of specific
interactions. So, you have a concanavalin A, which is a lectin; lectin are essentially
proteins bind into the sugar. And so again this has a natural affinity to bind sugar. So, if
you mix this lectin with this polymeric sugar what will happen is let us say if this my
polymeric sugar which is large unless that this protein is fairly small. Once this protein
binds to this chain on one side it will tend to bind to another chain and then you can have
several of these proteins at several locations kind of acting as a cross linker and that
essentially causes the bond to form.
Another good example is avidin with the polymeric biotin, so avidin again has a very
high affinity for biotin one of the strongest affinity pairs out in the system in biology. So,
again the same thing goes here let us say you have a polymer chain that is conjugated to
avidin and now if you come and put biotin in this system. So, what will biotin do? The
biotin will bind this as well as take another avidin from another place and bind to another
chain. So, that is also kind of acts as a cross linker for avidin modified polymers. So,
both of these are fairly feasible and again there are several systems out there this is just
two examples I am giving you right now, but something like that can progress to
hydrogels.

And then these are again there were several interactions these can be disrupted by some
physical factors as well. So, let us say this interaction maybe is not stable at a low pH
maybe this evident gets denatured or the lectin gets denatured or maybe the temperature
is too high and the molecular movement masks the energy because again as I said these
are very small bond forces that we are talking about. So, these can be then disrupted.
So, so something like ionic strength is one if there is an essentially ion-ion interaction
happening between cation and anion if they increase and ionic strength what will
happen? The dielectric constant will increase and so the by the Coulomb’s law the
dielectric constant is at the denominator. So, what will happen is the attraction force will
decrease and that may be sufficient to kind of disrupt this physical hydrogel and so all of
these can be used as a trigger to actually release the cargo faster right.
So, let us say if I want a system that only releases things at a pH of let us say 5 and I
know that maybe the two polymers that I am using to form these hydrogels stop
interacting with each other at pH of 5. So, what will happen is at a pH of 7 they are
interacting well and it will remain as a structural particle or a structural gel, but once let
us the cell takes it up and brings the environment locally down to pH of 5, then they will
just break apart and release whatever was present in the system .
(Refer Slide Time: 25:16)

So, another class of a physical hydrogel is ionic hydrogels. So, these again like the
physical hydrogel we talked about these are polymer chains that contain cationic or
anionic groups. So, essentially this is just one special case for your ionic hydrogel.
So, these gels are typically an ionized because there are equal amount of cationic-anionic
chains have come together and of course, as I said, if you change the pH the molecules
that are making a cationic or anionic may change and that may itself cause either the gel
to just fall apart or may cause a differential in swelling which could be completely
reversible.
So, an example here let us say these chains were initially all bonded together and they
are very stable, but along with these cross linking places there is a functional group let us
say carboxyl, which or let us say amine let us say amine in this case.
So, at a pH of 7 we know that this amine is going to be typically; that means, will have a
pKa which is much higher than 7. So, they may be charged and then once the pH has
now dropped a little bit, if the charges may change and because of that since there are
lots of amines and they will start repelling each other if they are charged, they are
similarly charged and then these cross linked distance will increase. So, you can have a
system, so, let us say if you have a cationic gel, then that cationic gel will be uncharged
because all the positively charged will not be present on amines.
But then and let us say the cationic gel here let us say for an example is an amine and
then anionic gel for an example is a carboxyl. So, let us say at certain pH let us say 8,
these amines are positively charged below that pH and as the pH increases this amine
basically undergoes transformation to a neutral molecule.
So, because of that, now they do not tend to repel each other they may have a certain
amount of stretching present, but as you change the pH this stretching may further
increase because now not only there is absorption of water, but there is also an
electrostatic force that is repelling each of these chains.
So, you see that now this swelling has increased quite a bit, vice versa for anionic gels
and now you are essentially talking about changing the pore size, which will cause the
change in the release rate of whatever drug is encapsulated. So, we will stop here, we

will continue our discussion with anionic gels and further the physical and chemical
crosslinked hydrogels in the next class.
Thank you.