Video:

Hello everyone, this is the new course called Drug Delivery Principles in Engineering. I
am Rachit Agarwal, I am an Assistant Professor at Indian Institute of Science in the
department of Biosystem Science and Engineering. And will be offering this course,
which will essentially go over some from the principles of drug delivery, why is the drug
delivery required? Why are we making this as a different format of a course and what are
the different engineering aspects we can add to it so as to get more efficient delivery?
Ultimately the major purpose is to improve the life of the patients. Let us say, if a patient
is coming with the disease, we want the patient to get cured as quickly as possible,
without having any major side effects. So, the current drug delivery is great. We have
helped lots of patient with the current drug delivery, but then what also happens is in a
lot of cases; you see lot of side effects being present; such as, in chemotherapy you see
patients are suffering, they are losing their hair, their immune system is weak, their
quality of life is going down.
So, what are the different things? Engineering aspects we can bring to it. So that, these
things the side effects are lower as well as the efficacy is higher.

(Refer Slide Time: 01:35)

So, some of the quick things about the course itself. So, the course eligibility this is open
to anyone in bachelors, who has completed his two years or higher or this is also open to
anybody, who is in pg or in some other form of postgraduation. There are really no
prerequisites to this; it will be; it will be good if you have some basic background of
biology.
So, any course in biochemistry, molecular biology, anatomy is recommended, but again
its not required. Well, as we go through the course, we will give most of the information
that is required for whatever we are teaching here. References again these are also not
required these slides well contained most of the material, that you will need to
understand this course, but and there are a couple of good references that you can refer to
if you want to gain some extra knowledge on this.
One is a book by Mark Saltzman this is Drug Delivery Engineering Principles for drug
therapy, its a very good book and then, another is the Drug Delivery Fundamentals and
Applications by Anya Hillery and Kinam Park. So, these are the two books that are
recommended, but again are not required for this course.

(Refer Slide Time: 02:45)

So, I will just go briefly over the course outline and how this course is going to go over
the next few weeks. So, during the start of this course, we will talk about
pharmacokinetics and that, typically involves the bioavailability of the drug, the
elimination of the drug and how therapeutic the drug is and will go over these terms in
due time in the course.
Then will talk about pro drugs and controlled release of these drug molecules some more
engineering aspects will start coming in at this point of time. We will talk about various
polymers and we can use, how they are synthesized? What are the properties of these
polymers? How do we characterize these polymers once you have synthesized them?
The crystallinity and amorphousness of these polymers will also be discussed. Then we’
ll go into biopolymers. T hese will be polymers, that we can use for bio applications,
these can be both natural or synthetic.
We will talk about their biocompatibility, when to use what? As well as, their bio
degradation and some of the very commonly used biopolymers in the field. As we move
forward we will talk about polymer drug conjugates, another engineering strategy to
enhance the drug efficacy; some of the major examples there include pegylation. And
then, we will talk about diffusion control systems. This will include some basic
knowledge of Fick’s law; reservoir type systems, non erodible type systems; again these

are some of the engineering systems that we will use to enhance our drug delivery and
we will describe them as we go along.
(Refer Slide Time: 04:18)

And in the second half of the course, we will talk about hydrogels, again another format
of delivery. So, hydrogels can be both physical or chemical getting in situ cross linking,
so, the delivery in hospitals may be improved. We will talk about nano and micro
particles some of the big hot words these days; some of the major ones including
dendrimers, liposomes, micelles along with the polymeric particles. Will also talk about
metal in polymeric particles, what is the effect of shape of the particle? What is the effect
of charge of the particle and elasticity of the particle? When this particle is traversing
through the body? Will talk about, protein adsorption and tissue engineering. This is very
important, because all tissue engineering application is required some or other delivery to
improve the tissue properties.
So, this could include cells, this could include drugs, this can include some other
proteins. So, we will talk about that. Then we will talk about, implant associated
infections; if you put anything in the body, that is susceptible to getting infections. So,
how do we prevent that? How do we proactively ensure that these implants do not get
infected? Will talk about route specific delivery. So, these could be oral route
subcutaneous several of them.

So, we will talk about, when to use which route? Which will be needed for different
applications? And then, towards the end of the course, we will talk about vaccine
delivery again one of the major success of the current drug delivery; cancer vaccines, cell
and gene delivery. So, if you are only looking to deliver cells or certainly not. So, genes,
how do you deliver them? What are the challenges associated with that? We will talk
about smart responsive delivery? How do we make them smart?
So, maybe you want it to only come out at a certain time or maybe you want it to only
come out when we give them certain triggers. So, we can kind of engineer those drug
delivery systems as well. And towards the end of the course, we will talk a little bit
about, nano toxicology and how you can lead to market translation of whatever these
research products that you are developing through this course..
(Refer Slide Time: 06:24)

So, let us start into the course. So, what is drug delivery? As you can see from this
picture is essentially nothing, but administration of the drug; of course, in this particular
picture it is been shown that, this is being administered through an oral route; however,
the route can be chosen depending on the application. And nearly, I mean, almost all
diseases need some kind of drugs to be delivered; these could be painkillers, these could
be chemotherapeutics, these could be some other form of the drug, but nearly all
applications of drug delivery is directly ready to treatment of a disease.

The field is extremely interdisciplinary this involves several different kinds of subjects,
that may include biology, physiology of the body, the materials, that will talk about
extensively through this course and then of course, engineering them, so that, they can be
more efficiently delivered in the body. And then it is also recently evolved to take into
consideration several factors, which is drug physico chemical properties.
So, how is the drug going to interact with the body? What are the chemical properties?
The body effects and interactions. So, how does the body respond to a certain drug? How
can we improve these drug effects? And then ultimately the major goal the milestone, we
are looking for is to ensure patient comfort and well being and making sure that, patients
are not suffering from side effects and getting cured as quickly as possible.
(Refer Slide Time: 08:00)

So, the magnitude of drug response again depends on, how much you can achieve
concentration at the side of action? So, let us say, this is a wound which is on a skin,
maybe we got into an accident and we have a small cut on the skin, at that point there is
really no need to deliver the drug throughout the body; all you want to do is just local
application. So, it is very important to achieve high concentration of the drug in the site
of action, that may be required to treat that particular illness or particular disease and
then, not give it everywhere, where made it may cause some harmful effects some side
effects.

So, again all of this will depend on dosage; as I just mention how much you can deliver
and how much is required? What is the extent of absorption? So, how much the drug can
get absorbed in that site? So, unless the drug is absorbed and becomes bio available;
essentially meaning that, it is in the system for it to act, the drug will not be useful. How
it distributes to the site?
Again related to absorption, once it gets absorbed; let us say, if it is in the whole lever
then, the drug has to diffuse and distribute throughout the whole lever and then
ultimately, you do not want the drug to be there all the time; once you are cured, you
want the drug to also get eliminated. So, what is the rate and extent of this elimination of
the drug?
(Refer Slide Time: 09:21)

So essentially, there are two major components of any drug delivery. These are
pharmacokinetics and pharmacodynamics. So, as the name suggests, pharmacokinetics is
essentially the design of the dosage regimen. So, where do you want to give it? How
much do you want to give it? How often do you want to give it? And how long do you
want to give it? It may include several other things, but these are the major criteria that,
before you even go into the body you want to ensure that you know the answers of these
things for a certain application.
So that, you can decide what are the different characteristics of a drug that you are
looking for? All of this is going to lead to a certain plasma concentration; if it is needs to

distribute throughout or even if it is given locally, these drugs will diffuse into the
plasma. And once it goes into the plasma or the site of action, then the
pharmacodynamics comes in, where the next questions we are asking is what are the
effects of these drug once it reaches the plasma? So, how it interacts with a certain
receptor that the drug may be binding to? How the body is interacting with these
molecules? How it is being degraded? So, all of these are essentially pharmacodynamics.
So, for the purpose of this course will essentially focus on pharmacokinetics and then try
to improve the pharmacokinetics of the drug; the pharmacodynamics is a separate field
that, we are not going to talk about in this course, but you will see me talk about a little
bit throughout the course, but the major focus will be on the pharmacokinetics.
(Refer Slide Time: 11:00)

So, this is again a complex graph, but essentially depicting what was depicted in the last
figure? So, you can treat the drug through several routes and again, these are not the only
routes that, we are limited to there are several others, but these are some of the major
ones. So, you can either take the drug orally; once you take it orally, it is going to go into
the gastrointestinal tract; basically, your stomach an intestine and from there it can either
get excreted or it can get absorbed and go into the circulatory system, which is basically
blood.
The other way is, you can either give an intravenous injection, which will directly lead
the drug into the blood and from there, it can again either get excreted or from the blood,

which goes everywhere in the body; it can go into the gastrointestinal tract as well as
other tissues in metabolic sites. The same type of pharmacokinetics is seen with
intramuscular injection you give it intramuscularly, typically at a certain region it may be
on your thighs, it may be on your biceps. So, the drug is going to go directly into those
tissues and from there the drug can then diffuse out into the circulatory system; can get
excreted; can be metabolized and then, get excreted and the same thing applies to the
subcutaneous system.
(Refer Slide Time: 12:18)

So, then what are the implications of this pharmacokinetics and pharmacodynamics in
drug delivery? So, first thing is the drug may be affected depending on what route it is
administered in? So, again if you give something; let us say, if you are trying to deliver
proteins; if you give it orally versus intramuscularly they may have different activity
once they reach the blood because these proteins are fragile molecules if you give them
orally and they have to go through the gastrointestinal tract your stomach, which is a
very low pH that, would lead to denaturation of these proteins and maybe the drug may
not be active versus if you give it directly intramuscularly for let us say some muscle
pain then, these protein may be much more active as well as much more available at the
site. So, these are some of the examples here. Another example is morphine the same
considerations here, where exactly you want to give it and then, essentially the PK PD of
a drug delineates the therapeutic window, that it is going to work in.

It is going to give you an idea of how much of the drug is going to absorb? So, let us say,
if I say that, if I give a drug x, 100 milligram of it, only 10 milligram of it gets absorbed,
then that helps me then, define as to how much drug should I give? Because if I want
finally, in my blood the concentration of total of 10 milligram then, 100 milligram is ok,
but if I give less than that, then I would not be able to get to that therapeutic levels it may
be required. And then of course, it also tells you at what rate its eliminated or
metabolized?
So, let us say, if a drug is getting metabolized very quickly then, you will have to take it
again and again in short periods of time. For example, in infections, tetracycline is given
every 6 to 8 hours whereas, another in another example a cardiac failure drug digoxin is
given daily. So, this is on the basis of how much of the concentrations you want in the
plasma and how fast it is getting cleared away from the plasma?
(Refer Slide Time: 14:22)

So, again there are several factors that, affect pharmacokinetics. I have only listed three
here, but there are several of them and we will discuss these major ones in a little more
detail in upcoming slides. So, these are partition coefficient, solubility, ionization and
again several others. So, let us talk about each of them one at a time.

(Refer Slide Time: 14:41)

So, starting with solubility; so, drugs must be in solution right; I mean if the drugs are
not in solution, they are in precipitated form, they cannot get solubilized in the bio fluids
and flow around, then they will not be able to interact with the receptors and targets. So,
the solubility of the drug is must; if it has to act and then, again drugs may have some
degree of solubility in both aqueous as well as organic solvents.
So, in this case lipid compartments and the ratio of this is called the PC, the partition
coefficient and we will talk about that, again in upcoming slides. So, solubility is a
function of lot of things; typically, the things that are charged have much higher
solubility in water; the molecular structure, how hydrophobic and hydrophilic it is? How
big is it? So, to lead to the molecular weight and of course, the electronic structure also
tells us, how soluble it could be in the water?

(Refer Slide Time: 15:36)

So, here is an example, here are three drugs; you have indomethacin, tetracycline and
chlorpromazine and here is the aqueous solubility with respect to the pH. So, you can
clearly see that, the pH affects the solubility as well as even at a single pH. Let us say,
the pH of 6; you have drugs which have different solubility. So, again this helps you
then, these parameters are required for you to know, that how should you administer
each of these drugs. So, let us say, if I want to put something directly into the blood,
which has a pH of 7.2 to 7.4 I and I want a high concentration of this particular drug, I
cannot do that, just because this drug has very low solubility at a pH of 7 and if I inject it
in the blood it is going to precipitate out, which is not good because, that may cause
blockage in the arteries and veins leading to strokes and other problems.

(Refer Slide Time: 16:35)

Partition coefficient another major parameter, that is required for you to know before
you, even attempt to use the drug and this is really nothing, but its the ratio of the
concentrations of that particular drug in two immiscible liquids.
So, this essentially defines what is equilibrium of the drug between the interface of these
two liquids? So, if I express it mathematically; we are essentially saying that if I have
two immiscible liquids the drug may have a certain concentration in water and a certain
concentration in oil and this is essentially in equilibrium with each other.

So, PC is property of a drug; it is not going to change with the amount of the drug; it for
a molecule x the PC will remain constant regardless of what is the amount and things
like that.

(Refer Slide Time: 17:39)

So, essentially what we are saying is that the higher this lipid to water the ratio the
greater is the transfer across a membrane. So, membranes are lipids. So, if you want the
drug to diffuse in through the lipid membrane then they need to have higher lipid to
water ratio. So, essentially higher partition coefficient.
So, in this case, we are saying that, if the polarity of the drug goes up, which means that
it is increasing the ionization which will essentially mean what? That the solubility in the
water is also going up. So, if the solubility in the water is going up then, this partition
coefficient will go down and that essentially means that, is diffusion across a lipid
membrane will be lower although it will be highly soluble in water. Similarly, if the
polarity of a drug is going down, which means that, it has lower ionization, then it
solubility in the water will also decrease increasing the partition coefficient, which
essentially would mean that these drugs will be fairly well soluble in lipid components
and will be able to diffuse through the cell membrane.

(Refer Slide Time: 18:47)

So, this is represented here through picture. So, you have charged molecules and
typically, these lipid membranes are very good at repelling the charged molecules. If you
have an ionized drug coming in; those drugs will not be able to go into the cell
membrane. However, if you have non ionized drug and it is fairly hydrophobic with the
high partition coefficient, then it will be able to diffuse through the cell membranes.
(Refer Slide Time: 19:11)

Of course, one thing that, I should mention is cells have their own mechanisms for taking
up ionic molecules. So, they have channels and special proteins that carry the ions

throughout the membrane. So, again this is a pictorial representation of what happens,
when you take a drug orally. So, eternal absorption essentially, mean absorption through
the GI tract (gastrointestinal tract). So, there are several forms of absorption that can
happen here. When you take a drug orally, first it goes to the buccal cavity, which is
essentially nothing but, your mucosal surface in the mouth from there also the drugs can
get absorbed. This is also called sublingual administration, but since the surface area here
is low and most of the drug is immediately swallowed by us; most of the drug is passed
into the stomach, the stomach again has a very low pH and lot of bile to digest the drugs.
From the stomach, the drug goes into the intestine, which is a very very large surface
area and lot of absorption, that happens after you eat a food is through this intestinal
absorption. From here, nearly all of the drug goes into the portal vein, which goes to the
liver, which is again a detoxifying organ in our body, which can then clear any kind of
harmful metabolites or metabolize whatever is foreign agent as well as any food particles
and then, that goes back into the blood.
And finally, whatever is not absorbed in the intestine goes to the rectum. At rectum, it
can either go out from the anus or the urine. There is also a big vein that goes through the
rectum which can absorb a lot of fluid as well as a lot of molecules. So, a separate field
has evolved for the rectal administration targeting this route so, absorption can happen in
all of these places. So, again just to point out some things sublingual has low barriers;
from here the drug directly goes into the buccal cavity; however, it is not very
convenient for patient to keep the drug in the mouth for long durations. And so, the
absorption is low as well because, first of all the residence time in that area is low and as
well as the patients do not keep it there plus the whole surface area is not enough for the
drug to go through.
And then we will talk about the first pass metabolism, but essentially, all the drug that
goes to the liver, because liver is a detoxifying agent it gets metabolized quite a lot, but if
you give it either by rectal or by sublingual, you avoid the passage of the drug through
the liver, which is always good; if you do not want the drugs to get degraded. So, we will
talk about this first pass metabolism in upcoming slides.

(Refer Slide Time: 22:09)

So, what is first pass effect? So, typically as I just said if you take anything orally, all of
it that is absorbed through the intestine which is the majority of the drug will go to the
hepatic metabolism essentially metabolism in the liver. Once these are absorbed through
the gut and delivered to the liver through the portal circulation, the liver will degrade it
and this is called the first pass effect. So that means, that even before the drug has
reached your blood, there is a lot of drug it is degraded in the first pass itself through the
liver.
And so, less of your agent is going to reach the systemic circulation and that will
decrease that therapeutic efficacy, but this is only applicable, if you are administering
something orally. If you give it via some other route, you may prevent the first pass
effect.

(Refer Slide Time: 22:59)

So, let us see how we are doing here? So, if I say the first pass effect refers to; is it the
absorption of drug from the side of administration? Well not really, I mean if I give an
IV injection or if I give some other route the first pass effect is not even involved. So,
this cannot be correct. This is how the drug reaches its first site of action, again this is
incorrect, if I give an intramuscular injection this thing is reaching immediately to the
muscles, but there is no first pass effect involved here; is it how the drug is metabolized
after it reaches the systemic circulation; again no this is before it reaches the systemic
circulation.
So, it goes to the liver where it gets in metabolized. So, the answer is c, which is the how
the amount of the drug can be reduced by metabolism, before it reaches the systemic
circulation by the liver? So, the answer here is c.

(Refer Slide Time: 23:52)

So, we will talk about bioavailability; again whatever you administer it needs to be bio
available and what that means is, it is present in the body for the body to be able to feel
the effects of the drug or for the drug to be able to go and do whatever it needs to do;
bind to a receptor, change the pH or whatever it might be needed to do in the body.
So, different routes can lead to different bioavailability and it just said you can take
things orally, but lot of it will first get degraded into the GI tract and then, also get
metabolized during the first pass effect. So, not all of it is going to be available.
However, if you do administered something through IV route and if it is completely
soluble; then all the 100 percent of the drug that, you have administered is available.
So, again depending on the route you are using the bioavailability will change. The other
routes may have different efficiencies of drug that are bioavailable, when administered
the same dose. So, this explains why sometimes a drug may be toxic through a certain
route, but may not be toxic through some other route. It is because the concentrations
may change depending on what route you are using to take the drug.

(Refer Slide Time: 25:03)

So, here is just a quick recap of oral delivery by availability. So, let us say you take a
certain dose of drug most of it get destroyed in the gut itself; then, lot of it does not get
absorbed and gets excreted out; whatever does get absorbed might not be able to pass
through the gut membrane itself. So, lot of it gets stopped there and then whatever does
reach through the hepatic portal vein its gets metabolized in the liver and only a small
fraction of this.
So, you started with lot of drug here and only a small fraction of this is going to the
systemic circulation. So, whatever now goes into the systemic circulation is essentially
bio available.

(Refer Slide Time: 25:50)

So, there is a parameter to define it, as I said if you inject something through IV route
100 percent of it is bio available. However, you can define a bioavailability of a route
depending on what is the AUC, which is essentially area under the curve for a particular
route. So, what do you mean by area under the curve?
So, let us say, this is the plasma concentration plotted against time and you have two
different curves for different routes administration. So, let us say, if I give something
orally at time 0, immediately is going to shoot up to a certain plasma concentration
depending on how much of it we had given. And then, eventually it is going to start
getting excreted or metabolized from the body; whereas, if I give the same amount of
drug through some other route; in this case, let us say oral route; then, only a fraction of
it is going to reach and then, it is going to get excreted out as well.
So, this area under the curve with the IV route versus the area under the curve with the
oral route, will give you the bioavailability of the oral route. So, as I said bioavailability
for the IV route is always going to be 1 or 100 percent in this case.

(Refer Slide Time: 27:00)

And this is again just a pictorial representation of what happens to different
compartments of the drug? So, you give a drug at a certain site; let us say I do a
subcutaneous injection.
So, at the site at that, point of time this 100 percent of the drug this could be
subcutaneous this could be intramuscular or this could be even IV route. So, I injected
into a vein at time t equal to 0; there is a lot of drug at the particular vein that, I injected
it in; over time what will happen? Is the drug will start to diffuse and absorbed through
the system? So, this drug concentration the absorb site will decrease and of course, these
are arbitrary units. So, this could be seconds milliseconds hours just depends on what
route you are choosing and it will eventually get excreted out. Whereas, as this is going
down the drug in the body is increasing because, from the site it is getting diffused into
the body. So, the drug in the body increases for a certain time and then the body starts to
metabolize, starts to excrete it. So, then it eventually starts to go down.
The metabolites of the drug; we will start to increase as the concentration in the body is
increasing and then, will continue to increase as more and more drug from the body gets
metabolized and at a certain point reach a steady state and eventually, will start to fall
out, when these metabolites get excreted and then, some of the part of the drug will also
get excreted out, again also depending on the concentration of the drug present in the
body at the time.

(Refer Slide Time: 28:26)

So, how do we study this drug distribution? How do we know that how much of the drug
is in the plasma available throughout the body versus how much of the drug is present in
the whole body? So, may have diffuse out from the plasma of different tissues. To do
that, we have a term which we define as Vd.

So, this is called the apparent volume of distribution. This is just an arbitrary value this
has no physical meaning, but it is a value that, helps doctors and engineers to kind of
understand how the drug get distributed in the body and where it is compartmentalized.
So, let us do a quick exercise. So, let us say for a 100 kg human; we know that the
volume in the body for the water is about 50 to 60 liters and then, the total blood is about
8 liters. So, if we assume that, lets do a quick example.

(Refer Slide Time: 29:29)

So, I have these three drugs, these are actual values. So, this warfarin chloroquine and
ethanol and I have listed the uses here; one is anticoagulant, another is anti malarial drug,
another is disinfectant. So, let us talk about warfarin first. If I say, the Vd is 8 liter what
does that mean? So, does it mean that, the apparent volume distribution is 8 liter, which
means that, the concentration? So, what was Vd again? It was concentration of the drug
in the body divided by the concentration in the plasma. Actually, amount of drug in the
body divided by the concentration in the plasma.
So, if I say its 8 liter; that means that we are saying that all the warfarin, that we have
given is distributed within the 8 liter volume and this is very close to the volume, I said
the total volume of the blood in the humans so; that means that, we can predict of course,
these values may not be direct indication, but we can with fairly well confident say, that
most of the drug is distributed in the blood itself; it compartmentalizes itself in the blood
it is not able to diffuse out of the blood. Let us talk about chloroquine.
So, this we are saying is an anti malarial drug and has a Vd of 15000 liters. So, what
does that mean? That means that, it is distributed quite a lot.