Hello everyone. Welcome to another lecture for Drug Delivery Engineering and
Principles. We have been talking about various kinds of strategies to improve drug
delivery. For the past few classes, we went into tissue engineering module where we are
talking about scaffolds which will stay in the body for quite a bit of time. While we were
doing that there were some issues and challenges that had come up, which is one of the
major challenges was the implant associated infections.
So, for the last two classes, we discussed how these implantation infections can be
(Refer Side Time: 00:56)
So, we talked about some of the major problems. That the tissue would not integrate, so
no integration. Once they are infected, we also talked about that they will even cause
damage to the surrounding. And then we talked about that there is really not much you
can do because those implants are sort of resistant to the immune system as well as
antibiotics and really the only option that comes after that is to remove the device. So,
whatever you have put in you have to remove it; make sure that the area is no longer
containing any bacteria and then you put another device or you take cognizance of what
needs to be done in the patient.
So, some of these strategies we also discussed to prevent this from happening. Of course,
this is a road we do not really want to go down to. So, if we can do it in such a way that
it does not happen that will be great. So, in that we discussed some of the alternatives
that we have; so, let us say for a particular application we have multiple alternatives in
terms of polymers, in the type of material we are using.
So, we can then go ahead and maybe use the ones that have been shown to be less prone
to infection than the ones that have been shown to be more prone to infection. Of course,
you have to make sure that the device itself is actually useful, if you want to grow a liver,
you do not want to put a stainless steel implant there just because it may be less infective
than let us say a polymeric implant, just because the stainless steel is not going to do
anything in terms of repairing the tissue. So, some of these things again you have to take
And some other strategy you discuss is to make surfaces hydrophilic. So, you can treat
surface with plasma or some other options you can explore to essentially make them
hydrophilic and what we typically find is bacteria adherence on the hydrophilic surface is
And another strategy we discussed was to release some antibacterial from the surface.
So, this could be antibiotics or some other small molecules. And if your implant is
already releasing these antibiotics out in the surrounding media then these bacteria are
not able to come and attach to the surface because this will kill the bacteria or the
bacteria will just go away. So, these are some of the things we discussed in the last class.
We are going to now move on to a different module in this course and that is essentially
what route you want to take for different applications.
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So, we are talking about route specific delivery. And again, the key point here, like in all
sort of modules we have discussed so far, is that the route you choose depends on the
application you are looking at. So, what is appropriate route and what is the delivery
system that you are using is majorly driven by what is the application you are using it
for. And we will go in quite a lot of detail about this in next few classes.
So, some of the most common routes that are used for administration are intravenous
route. So, that is a sending nothing but directly injecting into the blood system. Injection
in either veins or arteries and I am sure you all are very familiar with this particular
system, most of the time when we are growing up we need to get vaccines, some of these
vaccines are also given in all through these routes especially intravenous route. And the
next is the i.p. - injection intraperitoneal. Again, very widely used in literature, and what
it is, its essentially injecting it below your stomach cavity. So, it is between different
tissue space where you just inject whatever you want to give.
Then if intramuscular, which as the name suggests is directly giving it in the muscles.
So, typically you can use hip muscles, you can use biceps or you can use any kind of
other large muscles, thighs, to inject this just because that ensures that most of it goes in
the muscle than anywhere else.
Subcutaneous is nothing but just under the skin it is also abbreviated as s. c. And that
essentially just means that you maybe lift up your skin and you just inject it below that,
and that gets absorbed through that. And then you have intradermal which is nothing, but
is in the skin. So, instead of penetrating all the way through the skin you just penetrate
somewhere in the skin, so that when you inject whatever is given is gets entrapped in that
small skin layer through that which it can diffuse out of.
So, and then there other routes as well there are transdermal. So, and it is just something
that you can just deliver through the skin and, so any kind of injection is essentially
transdermal, but in this case, we are talking about just right under the skin very similar to
subcutaneous route. And then you have any mucosal route, which means that that route
has some kind of mucous that is experienced when you are injecting it. So, this could be
oral. So, our oral cavity, our oral route is completely filled with mucous everywhere. So,
there is mucus in our mouth, there mucus in our stomach and intestine. Could be
intranasal. So, you can deliver things, especially, if you are looking to deliver things to
brain intranasal is use quite a lot. You have pulmonary, again our lung is full of mucus
and this is nothing, but delivery to the lung. So, this could be either through inhalation or
nebulisation. Could be intravaginal, could be rectal. So, all of these routes have some
sort of mucous layer that is experienced while injection or while administration. And so,
again, we will discuss most of these routes in quite a lot of detail as we go along in this
class and the next.
So, these are essentially giving you a laundry list of different administration options and
there could be others as well. You have taken eye drops and that is nothing, but
essentially you are giving intra optically. So, there could be other routes as well, but
these are some of the major routes that are being used.
(Refer Side Time: 08:03)
So, what are the factors that influence the selection of the delivery route? So, we have
already talked about application is the major criteria. So, if it is, let us say, if it is a
disease that is only on skin. There is really no point in giving an IV, if you can give it
just topically onto your skin. Similarly, if the disease only localized to lung maybe
giving it through a pulmonary route might be better than again giving it throughout the
Then it depends on what is the drug you are using. So, whether that drug is going work
in that route or not. So, let us say again, taking example of the skin. Let us say if a drug
is not able to diffuse through the skin, then there is really no point in giving it on the
skin. If you want that drug to go all over the body, there is really no point in giving to the
skin if the drug cannot go through the skin. And then similarly, so the drug physic-
chemical properties become important if the drug is let us say insoluble in pH of 2-5
where which is what is going to experience when you take it orally, again there is really
no point in taking that drug orally, because most of its going to precipitate out.
And this again involves a lot of things. So, what is the drug molecular size? So, how big
the drug is essentially? What is the half-life in whatever route you are giving it, so maybe
it gets cleared very quickly. How much stable it is? Again, if it is not stable at a low pH
or if it is not able to penetrate the skin maybe gets degraded by the enzymes present in
the skin, you need to consider all those factors. And whether whatever aqueous solution
it experiences this goes back to the pH, whether it causes denaturation or degradation of
the proteins that you are administering.
(Refer Side Time: 09:52)
And then of course, it also depends on what is the desired pharmacological effect. So, as
I said if it is something that is localized to lung and you do not really want to give it
systemically. Similarly, if it is something that requires quite a heavy dose of the drug, let
us say, if I need to have let us say grams of the drug, it is not going to go through the
skin very well.
Then again, if the desired pharmacological effect is local so, like topical, vaginal these
are some of the routes that can come in. If you want it to be everywhere, so let us say if
its paining throughout the body or if its fever throughout the body, you may want it to be
systemic and in that case any of these routes can be chosen. And if you want immediate
response so, again if you apply something on the skin, it may take some time to diffuse
in and actually reach the site where it is going to act and so that may take some time. But
if you want some immediate response to happen the best route is the IV because that will
essentially mean it distributes everywhere in the body within few seconds, and then other
routes can again also be used if you want immediate response.
And again, we talked about this. So, what is the dose size? So, if you want quite a bit of
dose to be delivered, maybe you cannot inhale that much amount of dose, maybe it is
hard for you to inject that much dose in the muscle then you may be looking at
intraperitoneal route or maybe oral route. So, all of these play a role and then of course,
the size which is going to define a lot of physio-chemical properties, so if the size is let
us say too big it cannot penetrate through your skin layer and so that all affects
ultimately what is the delivery route that you should choose.
(Refer Side Time: 11:43)
So, just an example of how different administration route can be. We talked about a
similar case at the very start of the course. But let us say you have 500 milligram dose of
a drug that is either given orally or is given intramuscularly to the same subject on
separate occasions and this is an actual clinical data. And so what you typically see is
that the plasma concentration of the drug is being reported here with time and what you
are seeing here is when you are giving intramuscularly, you get a very high plasma
concentration and the peak is also a little earlier than when you are giving it orally. So,
this is the peak for oral, this is the peak for intramuscular.
So, first of all you see that there is a big difference in the peak value that you can get and
then secondly, you can see that there is a time difference also. So, intramuscularly is able
to have a lot more concentration of the drug at earlier time point then let us say oral. So,
even though the same order drug is given in you see differences. So, that is why it
becomes very important to choose a good route before you start your procedure.
And again, these biological barriers will affect your drug absorption. I mean obviously,
we have discussed this previously, that the oral route is has lots of challenges the drug
get destroyed in the gut there is absorption, then there is the first pass metabolism all of
these things will lead to lower amount of drug being present when you give the same
drug orally compared to intramuscularly.
(Refer Side Time: 13:26)
And then methods of delivery are important. So, whether it is going to be implanted or
its going to be some other route. So, if it is implanted you are looking at a big implant,
by big I mean something that can be used for a surgery or something like that. So, you
are looking at some macro device or this could be injections. So, you know you required
you do not really require surgery, but you would still require some sort of procedure to
be done. This could be small particles.
So, again micro and nano, it could be free drug actually which is what is currently done
very widely in the literature or this could be in-situ gelling polymers. Let us say in-situ
gelling hydrogels which once they go in, they will form a depot at that side. So, or this
could be again implantation which will essentially involve surgery. So, all of these
factors need to be taken into account when in trying to develop or trying to administer a
particular cure to a patient.
(Refer Side Time: 14:40)
So, let us talk about oral administration one of the most widely used method. So, what
are some of the advantages? One of the advantages is its very patient compliant. So,
again we have all taken drugs orally, so all you have to do is just take a tablet, drink
some water, and you have done for that particular time. So, it is a very high patient
compliant very non-invasive method.
The manufacturing facilities are well established. I mean this has been done for now
several decades and there is a quite a lot of literature and quite a lot of industry-based
setups that can help you produce these tablet us in very mass number. So, that is always
good because then you can take your cure to a lot more population.
What are some of the disadvantages? First of all, unconscious patients cannot take it. So,
the patient is not awake it would not be able to swallow or eat it. It has fairly low
solubility it has to go through very different ranges of pH and all. Low permeability, so
even if you are able to get to your gut not everything is going to get adsorbed some of its
just going to get excreted out.
A fairly harsh environment, so there are lots and lots of enzymes that are present that is
going to cause it to degrade, there is low pH as well. So, all of these are an issue. Then
you are talking about first pass metabolism, which is basically liver. Even before it is
gets circulated into the blood system most of your drug may get metabolized by the liver
during the first pass metabolism through the hepatic portal vein.
Then you do not know how it interacts with the food. So, maybe if you have just eaten
the food the pH is different, the environment is different, there are less enzymes whereas,
if you have not eaten the food for past two three hours then you really have no food in
your stomach and your intestine, at that point the interactions on the food will be fairly
variable. And that is the problem because then you do not know how much of the dose
you have given. Whether the dose you have given is lower, then what should be whether
it is exactly what it should be or whether it is much higher and you might reach toxic
levels and with that particular dose. And then of course, there is a regular absorption, so
it is fairly variable, that is a major problem here.
(Refer Side Time: 17:01)
So, again here are some of the traditional oral delivery systems. So, I am sure you have
seen all of these. So, you have tablets, one of the most widely used, you have capsules,
you have gelatin capsules as well which are slightly different in characteristics, and then
you have suspensions like cough syrup and things like that that you directly ingest.
(Refer Side Time: 17:27)
And so typically to form a tablet some of the traditional formulations is extremely cheap
and rapid to manufacture and package this. It is it is in dry formulations its typically very
stable. So, that is one of the advantage of a tablet that you do not worry about it just all
dry. Typically, you will find that the biomolecules when they are in water they are more
prone to degradation and losing their activity then when they are in a dry format.
The patients recognize it accept it, so the patient compliance is fairly high and it is all in
and there is all kinds of processes that are present in there. And then there is a taste
masking process as well. So, if let us say your tablet is extremely sour or something that
is not a good tasting tablet then you can mix some good tasting molecules in there. So,
that your taste can be masked and actually patients are okay in taking that tablet through
oral route as well.
And, so it involves obviously, two major components one is the drug itself. So, whatever
drug you are giving and then the next is the excipients. So, these excipients could be of
several types this could be diluents to sort of make it bulk let us say if you only require a
microgram of drug, then they cannot make a tablet out of microgram of drug because a
microgram of drug will not be even visible if they make a tablet out of it.
So, what you do is you then make a tablet which contains this microgram of drug and
everything else is sort of a filler. So, it could be a dilutent and it could be a binder, it
could be a glidants anything in that sorter or maybe you want to give some more
functionality to it, so you are adding some antioxidants to it as well. So, the patients are
more likely to take them as well.
(Refer Side Time: 19:15)
So, here are some of the examples. So, you have diluent which is essentially is a bulking
agent for low doses as we just talked about it and here are some of the major compounds
that are being used as diluents. So, it could be salt, it could be sucrose, also improve the
taste lactose cellulose all of this is actually use the diluent quite often.
And then you have binders. And what do you mean by binder? So, essentially if you just
put salt the salt is not going to form a tablet. So, you have to put some things in there that
holds the whole tablet together. So, that improves the cohesiveness of this powder. And
again, there are several examples of this you have starch, PEG and several other
molecules it can be used for this. Then you have lubricants. So, lubricants are not really
required once the tablet is formed, but before the tablet has found you need these
lubricants and these glidants which will help in the flow of the powder, and this is
required because when the tablet is being formed the tablet is essentially first in powder
form and then this powder has flowed into a sort of a mould.
So, maybe if let us say this is my reservoir of the powder, it is then flown through some
nozzle into a mould which is going to take the form of a tablet. But for it to flow well,
because you do not want this powder to be very sticky. So, for it to flow well you need to
add these lubricants and glidants, so that it can be rapidly scaled up. Then you have
disintegrants. So, essentially once you have taken it up you want this tablet to break up
very quickly. So, you want something that once it goes into the stomach environment it
either dissolves away completely or breaks down completely, so you then add those
things as well.
And then of course, there are flavouring molecules that we briefly talked about, so
maybe you want to improve the taste, maybe you want to increase patient compliance,
especially in children you want to add coloring agent to help companies distinguish as to
which product is for what applications. So, all of this can be then adapted.
(Refer Side Time: 21:33)
So, here is briefly what I was basically talking about before. So, here is a typical tablet
machine and you are using some compression and filling to form these moulds and this
again this technology has been used for quite a bit of time and its very well established
up to the fact that you can make 1 lakh tablet us per minute. And so, in terms of scale up
this is not a problem at all.
(Refer Side Time: 22:01)
And then the similar thing for capsules the compositions again very similar to tablet, but
they are not compressed. So, if you have ever opened the capsule you realize there is
some free powder and so it is a free flowing powder within either a hard or elastic shell
obviously, the manufacturing cost goes up because now you are using quite a lot of
material and it is a little more cumbersome I will say a tablet which is just compressed.
But if your drug is not very stable in that compression in the high pressure in those cases
capsules become important.
And again, you can get them at various sizes each of these size has their own code. So,
you can see them triple zero, double zero, and all the way up to five. And again this just
defines as to what is the relative size and then there is also hard gelatin, soft gelatin that
you can use as elastic shell for these capsules which will then once it comes in contact
with water they will essentially degrade or dissolve away.
So, we will stop right here, and we will continue in the next class.
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