96 - Controlled Release & Targeted Delivery (S7E6)

Welcome back everyone to the Deep Dive. Today
we are gonna try and wrap our heads around controlled
release and targeted drug delivery systems. Yeah,
these are pretty fascinating. Like imagine if
we could make medicines work better, you know?
Right. More effective and for longer periods
and cut down on those pesky side effects. Yeah,
no more taking a pill every few hours and then
having it wear off before you know it. And definitely
no more of those unwanted side effects that make
you feel worse. than the actual condition you
were trying to treat. Definitely. It is all about
optimizing the benefits and minimizing the downsides.
And honestly, it's not just about creating brand
new drugs. It's about using existing ones more
effectively. Yeah. And to do that, we will be
exploring a couple of key approaches. Right.
Polymer based systems that kind of act like tiny
time release capsules for drugs. Yeah. And then
there are these mechanism driven designs. Yes.
These are super cool. They actually use specific
triggers in the body to release the drug exactly
where it is needed. So we are going to pull some
real -world examples from research papers, especially
those OPR and D publications we keep coming back
to. Absolutely. The goal here is to understand
the fundamental principles behind these technologies.
Right. And also why they hold so much promise
for the future of medicine. Yeah, this is going
to be a really interesting deep dive. OK, so
before we get too far into the specifics, let's
take a step back. Sure. What is the main issue
with traditional drug delivery methods that makes
controlled release and targeted delivery so necessary
in the first place. Well, the core problem is
this. With the traditional way we take drugs,
you often end up with this fluctuation in the
drugs concentration in your bloodstream. Okay,
I have follow you. Like when you swallow a pill,
it gets absorbed pretty quickly, leading to a
sudden spike in the drugs level in your blood.
And sometimes this peak can be so high that it
actually causes those nasty side effects. Yeah,
nobody wants that. Then as your body starts breaking
down the drug and getting rid of it, those levels
start to drop. Yeah. And often they drop. below
the level where the drug is actually effective.
Oh, I see. This is called the therapeutic threshold.
So it is like a roller coaster ride for your
body. Exactly. Up and down, up and down. And
that is exactly what controlled release systems
are designed to fix. OK, so they are like the
steady hand that keeps the drug levels right
where they need to be. Precisely. No more dramatic
peaks and valleys. Exactly. So how do they achieve
that steady state? So controlled release systems
basically release the drug gradually over a much
longer time. Okay. instead of that initial burst
you get from a regular pill. Right. It's like
a slow and steady stream. Interesting. And this
means the drug concentration in your body stays
within that therapeutic window for a longer time.
So it is more like a constant drip instead of
a sudden flood. Exactly. And this not only improves
how well the drug works, but it also. Yeah, it
also dramatically lowers the chance of those
side effects that you get from those initial
high peaks. This makes so much sense. It's all
about consistency. OK, now let's talk about targeted.
Yeah. This seems even more sophisticated. It
really is. How does it take things to the next
level? Targeted delivery is all about precision.
Okay. It's about directing the drug to a very
specific location in your body. Like a guided
missile. Exactly. Instead of it just floating
around everywhere. It could be a tumor. Yeah.
An inflamed joint. or even certain types of cells.
Wow. By getting the drug exactly where it is
needed. Right. We can use a much lower dose overall.
Makes sense. But still achieve a higher concentration
right at the problem area. So maximizing the
impact on the disease. Exactly. But what about
the rest of the body? And that's the best part.
Yeah. Because we are targeting so precisely.
Right. It means we are drastically reducing the
drug's exposure to healthy tissues. Which in
turn significantly minimizes those systemic side
effects that can be really troublesome with some
medications. It is like a surgical strike. Instead
of carpet bombing your whole system. Exactly.
Okay, I am really starting to see the potential
here. It's a really exciting field. Now you mentioned
polymer -based systems. Yes. As a key approach
in controlled release. Yeah. Can you break that
down for us a bit? So polymers are these big
molecules. Okay. Think of them like long chains
made up of repeating units. I see. And they are
incredibly versatile. In what way? We can engineer
them to have very specific chemical and physical
properties. Oh, wow. So in controlled release,
we can actually use them to encapsulate the drug.
So the drug is trapped inside this polymer structure.
Exactly, like a tiny time release capsule. Okay,
I'm with you. This encapsulation allows us to
control how quickly the drug is released. So
the polymer... Axe is a gatekeeper. Yeah, a gatekeeper
that regulates the flow of the drug. Okay, I
am getting the picture. Yeah. But how does the
drug actually get out of this polymer prison
to do its job? There are a few different mechanisms
that play here. Okay, fill me in. And the specific
mechanism depends on the type of polymer we use
and how we design the system. One common way
is through diffusion. Diffusion. The drug molecules
kind of dissolve within the polymer matrix and
then slowly move out, driven by the difference
in concentration between the inside and the outside
of the polymer. Interesting. Another way is through
polymer degradation. Degradation. Some polymers
are actually designed to break down over time.
This can happen through reactions with water.
Right. Or with enzymes in the body. And as the
polymer degrades. Well, the trapped drug is slowly
released. I see. And the cool thing is we can
actually control the rate of this breakdown by
choosing the right polymer and tweaking its structure.
So it is like a timer on the drug release. Precisely.
We can set it to release the drug at a specific
rate over a specific period. You got it. This
is really impressive stuff. It is pretty amazing
how much control we have. Now let's move on to
the mechanism -driven designs you mentioned.
Yeah, those are really cool. How do those work?
These designs are all about taking advantage
of specific conditions in the body. Okay. Things
that are unique to the area where we want to
deliver the drug. Give me an example. Well, for
instance. Yeah. Many tumors have a more acidic
pH than healthy tissues. Oh, that is interesting.
So we can design a delivery system that stays
stable at the normal pH of the blood. Right.
But then breaks apart and releases the drug when
it encounters that lower pH in the tumor. So
the change in pH is like a trigger. Exactly.
It tells the system, OK, this is the spot. Release
the drug. It's incredibly precise. This is fascinating.
And there are other examples too. Like what?
Well, we can also use special receptors that
are found on the surface of certain cells. OK.
Say cancer cells. Right. And we can attach molecules
to the drug delivery system. OK. Molecules that
bind specifically to those receptors. I am following.
It's kind of like a key fitting into a lock.
The drug is only delivered to cells that have
those specific receptors. Yeah, exactly. This
is amazing. It's all about exploiting the unique
features of the target site. It seems like science
fiction. But it is really happening. It is the
future of medicine. OK, let's bring some of these
concepts to life with some real world examples
from the research you've been looking at. Yes,
let's do that. One paper that caught my eye is
OPRND2020S .PDF. Yeah, I remember that one. It
talks about making the process of synthesizing
GW64 -1597X better. Right. Now, this paper is
not directly about drug delivery. No, it is not.
But what can we learn from it about how important
it is to manufacture these drugs efficiently?
That's a great point. Because even with the most
amazing delivery system, if you can't produce
the drug itself reliably and at scale, it's all
for nothing. Absolutely. This picture highlights
that. It shows how crucial process chemistry
is. Yeah, things like fine -tuning reaction conditions,
using the right solvents, getting rid of impurities
efficiently. It's all about making the whole
manufacturing process smoother, more cost -effective,
and less harmful to the environment. And ultimately
it's about ensuring a steady and dependable supply
of the drug. That is the foundation. Without
it, even the most brilliant delivery system is
just an idea on paper. Okay, now let's move on
to OPRND2021D .PDF. Ah, yes. This one delves
into the world of phase transformations and the
importance of understanding a drug's... physical
property. Yes, that's a really interesting one.
How does this tie into designing effective controlled
release systems? Well, this paper underscores
something crucial. What is that? We need to pay
close attention to the solid state properties
of the drug itself. OK, I'm listening. In many
controlled release formulations, the drug is
mixed with a polymer. Right, like we talked about
earlier. And how that drug exists within that
mix, like whether it is in a crystalline form
or as an amorphous solid. That can actually have
a huge impact on how stable it is over time.
I see. And more importantly, how it gets released
from the controlled release system. So it is
not just about what the drug is made of. It's
also about its physical form and how it interacts
with the other materials in the delivery system.
Got it. And these phase transformations where
the drug might change its form during storage,
those can really mess things up. In what way?
They can change how soluble the drug is, how
quickly it dissolves, which directly affects
its release and ultimately its bioavailability.
So controlling those material properties is super
important. Absolutely. It's all about ensuring
that the controlled release system works consistently
and predictably. Exactly. OK, another paper that
caught my attention is OPRND2022 .PDF. OK. This
one really emphasizes the importance of getting
a high yield impurity in the drug synthesis process.
Right. How does this tie back to our discussion
on advanced drug delivery? Well, no matter how
fancy your delivery system is, the drug you are
delivering has to be top notch quality. It is
the foundation. Exactly. This paper stresses
that. Any impurities lurking in the drug can
cause problems. Like what kind of problems? They
could lead to unexpected side effects or mess
with how the drug is supposed to work. So even
with a targeted or controlled release system,
if the drug itself is not pure, you are not getting
the full benefits. Right. And you might even
be introducing new risks. A clean and efficient
synthesis process is non -negotiable. It's the
starting point for everything else. OK. And finally,
we have OPRND 2024 .PDF. OK. This one gets into
the nitty -gritty of experimental procedures
and analytical techniques like HPLC. Why are
these so important in the context of controlled
release and targeted delivery? They are essential
for really understanding and controlling how
these systems work. Tell me more. Techniques
like HPLC allow us to precisely measure how the
drug is released from the formulation over time.
Okay. And we can also see how much of the drug
actually reaches the target site versus how much
ends up elsewhere in the body. So it is about
having the tools to see if these systems are
doing what they are designed to do. We need the
data to prove that they're working as intended.
And that is the only way to optimize and refine
these complex systems. OK. Let's zoom out a bit.
Sure. And talk about how all this fits into the
broader world of drug development. OK. You mentioned
bioavailability a few times. Yeah. And we have
touched on this concept in some of our previous
deep dives, specifically in season two accounts
in drug discovery and season three ABM processes.
Those are great deep dives. Bioavailability basically
refers to how much of the drug gets into your
bloodstream. Yeah, and how quickly it gets there.
And how does that connect with controlled release
and targeted delivery strategies? So many promising
drugs fail because they have low bioavailability.
What causes that? It could be that they don't
dissolve well, or they get broken down by the
body too quickly, or maybe they are not absorbed
well from the gut. And these advanced delivery
methods can help with that. They can make a big
difference. How so? Controlled release can keep
the drug in your system for longer. Okay. Giving
it more time to be absorbed. Right. Targeted
delivery ensures that more of the drug reaches
the specific area where it's needed. So even
if the overall and the bloodstream is low. Yeah.
It's still concentrated where it matters most.
Interesting. And we actually see this play out
in the development of the drug saxagliptin. Saxagliptin.
Yeah. It is a DPP4 inhibitor. And its story is
discussed in season two accounts in drug discovery,
right? It is. They face some challenges optimizing
its pharmacokinetic properties. Including its
bioavailability. And controlled release could
have been a solution in that scenario. Definitely.
Now we have also talked about preclinical development.
Yes. In previous episodes. Like in season three
preclinical development and IND enabling transcripts.
Right. Those are really insightful. Preclinical
studies are all about testing drugs in the lab
and in animals before they are given to humans.
Yeah. How do the principles of controlled release
and targeted delivery apply to that stage of
drug development? Understanding a drug's pharmacokinetics
is absolutely crucial in preclinical development.
Pharmacokinetics. That's basically how the drug
moves through the body. Right. How it is absorbed,
distributed, metabolized, and eliminated. Yeah.
ADME. Exactly. And this is where those pre -clinical
studies come in. Yes. They help us determine
key parameters like the drug's elimination rate,
constant. Uh -huh. And it's half life. That's
how long it takes for half of the drug to be
eliminated from the body. And why is that important
for controlled release? Well, if you are designing
a sustained release formulation, the rate at
which the drug is released from that system needs
to be carefully matched to how quickly the body
gets rid of it. So you are aiming for a balance.
Yes. To keep the drug level steady within that
therapeutic window. Exactly. OK, and finally,
what about the regulatory aspects? Oh, yes. We
have explored this in season four clinical trials,
phase I and A, and season five clinical trials,
phase three, and regulatory approval. Yeah, those
deep dives were really helpful for understanding
the whole process. It is a long road from those
initial preclinical studies to eventually getting
a new drug approved. for use in patients. It's
a highly regulated process. Rightfully so. Absolutely.
So how does that apply to these more advanced
drug delivery systems? Well, the same rigorous
standards apply. Any new pharmaceutical product.
Whether it is a traditional drug. or one using
controlled release or targeted delivery? Yeah,
all of them. They have to go through extensive
testing before they can be used in humans. It's
all about ensuring safety and efficacy. And the
regulatory agencies are particularly interested
in data on the performance of the delivery system
itself, right? Absolutely. They want to know
how well it releases the drug, how accurate the
targeting is, how stable the whole system is,
and ultimately, how it affects the patients.
Both in terms of how well it works and its safety
profile. It is a comprehensive evaluation. It
has to be. Okay, as we wrap up this deep dive
into the world of controlled release and targeted
drug delivery, what are the main takeaways for
our listeners? Well, I think the key benefits
are pretty clear. Lay them on us. These technologies
allow us to optimize how drugs work in the body.
Okay. They help us minimize those unwanted side
effects. And in many cases, they can also make
it easier for patients to stick to their treatment
plans. Absolutely, because they often allow for
less frequent dosing. It is about making medicines
work smarter, not harder. And it all comes down
to a deep understanding of material science.
Polymers playing a big role there. Yes. And also
a thorough understanding of the amazing complexity
of the human body. It's a fascinating field.
It truly is. And it seems like we are just scratching
the surface of what's possible. Yeah, I think
the future is incredibly bright for controlled
release and targeted drug delivery. So here is
a thought for you to ponder as we end this episode.
I am listening. Given all the advances in nanotechnology
and our ever -growing knowledge of human biology,
what new breakthroughs do you think we might
see in this field? I can't wait to see what the
future holds. It's exciting to think about. It
really is. Thank you for joining me today for
this deep dive into the world of controlled release
and targeted drug delivery. It's been my pleasure.
Until next time, stay curious and keep exploring.