Controlled Drug Release Technology

Transcript of Part 1: Advances in Controlled Drug Release Technology: An Overview

00:00:07.14	So, my name is Bob Langer.
00:00:09.07	I'm a professor at MIT,
00:00:10.27	and I'm going to be discussing,
00:00:13.03	in this first lecture,
00:00:14.19	to give you an overview
00:00:16.10	of this area of controlled drug delivery technology,
00:00:20.18	and in the second lecture...
00:00:23.05	I've listed the lectures here...
00:00:25.01	I'll be talking about
00:00:27.00	some of our own work
00:00:29.27	that lead to some of these drug delivery systems
00:00:32.07	and also some future work
00:00:34.15	in nanotechnology and other areas
00:00:36.09	that I think will be exciting for the future of drug delivery.
00:00:38.23	And, in the third and final lecture,
00:00:40.08	I'll be talking about biomaterials and biotechnology
00:00:43.13	and I'll give an example, in particular,
00:00:46.06	of how one can create new materials,
00:00:48.02	and I also will discuss
00:00:49.29	how one can combine materials with cells,
00:00:52.07	which helped to lay the foundation
00:00:53.28	of tissue engineering.
00:00:56.03	So, I'll start out by just going over,
00:00:59.06	as is mentioned here,
00:01:01.04	this whole field of controlled release technology,
00:01:03.05	and it's a field that actually
00:01:05.02	now affects hundreds of millions of patients
00:01:08.09	around the world
00:01:10.01	and yet it's still a very new field.
00:01:11.22	Maybe the easiest way to start
00:01:13.12	is to just go over how people generally take drugs.
00:01:15.26	Generally, you take a pill
00:01:18.05	or you might take an injection,
00:01:21.05	but whenever you take any of these drugs
00:01:24.17	what happens is, as we can see in the slide...
00:01:28.14	there are these blue lines
00:01:30.14	which give you a desired range...
00:01:32.17	if you're above that range the drug could be toxic,
00:01:34.28	if you're below it's not effective.
00:01:37.13	One example I sometimes just use is a sleeping pill.
00:01:39.29	If somebody took too much
00:01:43.00	they would die - that's obviously toxic.
00:01:44.26	And, if you took too little then it doesn't work,
00:01:46.28	you don't fall asleep.
00:01:49.05	So, for any drug,
00:01:51.05	you have this desired range,
00:01:53.06	and what happens in a lot of cases
00:01:55.21	is you get this what I'll call peak-and-valley delivery
00:01:58.24	which you see here,
00:02:00.14	meaning that when you first take the drug
00:02:02.10	it starts out at a very low level,
00:02:04.04	then it keeps going up,
00:02:06.05	and then it goes down.
00:02:07.26	And so, you would have to take it again,
00:02:10.13	and there are really two or three problems with this.
00:02:12.13	One is the problem that I just mentioned,
00:02:14.08	that you could get these toxic effects
00:02:15.29	or it may not work.
00:02:17.28	The second effect, the big effect
00:02:20.00	is that people have what are called very poor compliance.
00:02:23.13	People usually don't do what they're supposed to do
00:02:25.23	and they often don't take the drugs
00:02:28.09	when they're supposed to,
00:02:30.07	and that has led to hospitalizations
00:02:32.07	and all kinds of other kinds of problems.
00:02:34.20	So, what somebody would like to do is,
00:02:37.28	when you look at those lines,
00:02:40.00	is to have a pill or an injection or whatever
00:02:43.29	that starts out low but then goes into the desired range.
00:02:47.19	In a way, people have tried to do this for over 100 years.
00:02:52.18	The earliest examples of these
00:02:54.28	are what we called sustained release.
00:02:57.08	Sustained release systems,
00:02:58.23	and people have heard about these probably,
00:03:00.14	are things like tiny time pills
00:03:02.04	and things like that,
00:03:04.00	so rather than what you might have seen in the last slide,
00:03:06.11	where you took, say, a pill maybe every four hours,
00:03:08.25	sustained release probably it lasts for twelve hours,
00:03:11.26	and it kind of blunts those peaks.
00:03:13.25	But, what happens is that you still...
00:03:18.20	you still have to keep taking them,
00:03:21.05	and also you really are not in the desired range.
00:03:24.28	I mean, you're in the desired range
00:03:26.16	maybe longer, but not long enough.
00:03:29.02	So, the way these have been achieve,
00:03:32.00	these sustained release systems,
00:03:34.01	involves different types of chemistry and chemical engineering,
00:03:37.20	like you can have what's called a complex.
00:03:39.23	For example,
00:03:41.20	you want to slow the release down,
00:03:43.13	and the way you might slow the release down
00:03:45.22	is by adding a salt or even complexing it
00:03:48.09	to what's called an ion-exchange resin.
00:03:50.20	Another way of slowing it down
00:03:52.26	is to put what are called slowly dissolving coatings around it.
00:03:55.21	For example, there's something called an enteric coating,
00:03:57.22	and if you have a pill with an enteric coating,
00:04:01.16	the stomach, which often has a lot of acid,
00:04:04.15	will not dissolve that coating,
00:04:07.04	so you won't get release until later...
00:04:10.15	wait until you go past the stomach
00:04:12.21	and the acidity is neutralized.
00:04:16.16	You can also do things like suspensions or emulsions,
00:04:19.25	that decreases the availability of the drug
00:04:22.22	to the body,
00:04:24.22	and even something as simple as a compressed tablet
00:04:26.23	slows release down because the drug
00:04:28.29	won't dissolve as fast.
00:04:30.24	Still, as we look at the bottom part of this slide,
00:04:34.01	what sustained release systems...
00:04:36.07	release drugs generally for short periods of time, like hours,
00:04:39.19	and they require repeated administration.
00:04:41.24	Also, the release rates are very strongly influenced
00:04:44.02	by your environmental conditions.
00:04:46.15	For example, I mentioned,
00:04:48.09	you know, release in the stomach.
00:04:50.05	Well, your stomach pH
00:04:52.03	is very dependent on when you ate your last meal,
00:04:53.25	so there's a lot of variability
00:04:55.23	when you take these kinds of systems.
00:04:57.17	And, with that in mind,
00:04:59.05	what's happened over the last 40 years
00:05:01.04	is the advent of what we now call
00:05:03.02	controlled release formulations.
00:05:04.22	These are often polymers or pumps.
00:05:08.08	They can release the drug
00:05:09.27	for really long periods of times,
00:05:11.23	like not only days but in some cases, as I 'll go over,
00:05:14.19	up to 5 years from a single tiny system.
00:05:17.16	Also, the release rates are only weakly
00:05:19.28	or not at all influenced by the environmental conditions,
00:05:23.01	so you get a fixed predetermined release pattern
00:05:28.05	for a definite period of time.
00:05:30.23	This is just a graph
00:05:32.23	that shows you an idealized case of that.
00:05:35.03	So, rather than getting this kind of peak-and-valley delivery
00:05:38.10	that I mentioned before,
00:05:40.07	what you can get is the drug starts out
00:05:42.15	in a low range, then it goes to the desired range,
00:05:45.09	and it stays there for as long as you want.
00:05:47.24	This is kind of the ideal case.
00:05:50.02	One other thing that I wanted to mention,
00:05:53.08	that's very exciting in this area of drug delivery,
00:05:56.08	is not only the idea of controlling the duration
00:05:59.00	of the drug and controlling its level,
00:06:02.10	but actually in some cases
00:06:04.09	targeting it right to where you want it to go,
00:06:06.17	and there's a lot of research going on in that area.
00:06:10.05	It's still very early,
00:06:11.24	but I'll mention some of this in my second talk,
00:06:15.06	but what people are doing
00:06:17.29	is they're looking at the little fatty particles called liposomes
00:06:21.09	that you can direct to certain cell types.
00:06:24.12	They're also looking at microspheres and microcarriers
00:06:28.00	that you can decorate in certain ways
00:06:30.12	to target them to specific places in the body.
00:06:33.04	And finally,
00:06:35.03	you can attach a drug to a carrier,
00:06:36.28	which might be an antibody or a polymer,
00:06:38.18	to hopefully, again,
00:06:40.12	target it to where you want to go.
00:06:42.12	So, all these are very exciting areas of
00:06:45.04	how you can take drugs
00:06:47.12	and make them do things they could never do before.
00:06:50.13	I thought in this lecture
00:06:52.13	what I want to do is go over
00:06:56.01	the general mechanisms by which this takes place,
00:06:58.13	and generally there's three mechanisms.
00:07:00.26	Diffusion is the first one,
00:07:02.13	and there are two geometries that people often use.
00:07:05.02	What's called a reservoir,
00:07:06.22	and I'll show you a picture of that in a minute,
00:07:08.18	and what's called matrix.
00:07:10.05	The second mechanism involves a chemical reaction,
00:07:14.00	and in the case of the chemical reaction
00:07:15.25	it might cause the polymer to erode, bioerode,
00:07:18.22	which will enable the drug to come out,
00:07:20.20	or you might have what we call a pendant chain system,
00:07:23.22	where the drug is attached to a polymer,
00:07:26.05	let's say,
00:07:28.08	and something comes along and cleaves it off.
00:07:30.14	The third mechanism is the solvent does something.
00:07:33.04	The solvent might cause the polymer to swell,
00:07:36.04	so the drug might be locked into place,
00:07:37.29	but when it swells,
00:07:39.19	now the drug comes out.
00:07:41.06	Or, as I'll show you,
00:07:42.14	there's some very clever ways using what's called osmosis
00:07:44.19	to actually deliver drugs.
00:07:47.04	Finally, and on top of all that,
00:07:49.23	you can actually in some cases
00:07:51.12	make even a smart delivery system,
00:07:53.07	where you can activate it externally
00:07:55.05	and make more drug come out at certain periods of time,
00:07:57.27	and I'll go over that...
00:08:02.08	a little bit of an example of that in my second lecture.
00:08:04.11	So, I'll just go over each of these three fundamental mechanisms.
00:08:08.19	First, diffusion,
00:08:11.11	and the most common way that people set up drug delivery
00:08:14.19	by diffusion is what's shown here,
00:08:16.16	a reservoir.
00:08:18.03	A reservoir,
00:08:19.18	and people have probably seen these,
00:08:21.06	could be a capsule, could be a microcapsule,
00:08:23.23	could be hollow fibers,
00:08:25.13	or the drug could be placed in between two membranes,
00:08:27.29	but basically what we see,
00:08:29.16	and the little dots in this slide
00:08:31.17	illustrate the drug,
00:08:33.03	the blue illustrates the membrane, let's say,
00:08:35.26	or the capsule,
00:08:37.15	and this is just a cross-section.
00:08:39.05	So, what you see is if you go
00:08:47.00	from the left-hand one to the right-hand one
00:08:49.14	is that the little dots...
00:08:52.13	the left-hand one is the system at time 0,
00:08:57.04	but what happens is over time,
00:08:59.07	the dots keep coming out by diffusion.
00:09:01.01	They diffuse through the polymer,
00:09:02.26	and that will keep coming out over really long periods of time.
00:09:06.27	There are a number of polymers that are very commonly
00:09:09.17	used to make these systems,
00:09:11.07	like silicone rubber, EVA,
00:09:12.20	which is ethylene-vinyl acetate copolymer,
00:09:15.09	or different hydrogels.
00:09:17.19	For polymer chemists,
00:09:19.08	one good example would be
00:09:21.12	poly(2-hydroxyethyl methacrylate),
00:09:23.10	but just in general, hydrogels are materials
00:09:25.15	that are used in soft contact lenses
00:09:27.15	and they're very biocompatible.
00:09:29.21	These systems have a number of advantages,
00:09:32.08	you can make them release at relatively constant rates,
00:09:35.24	but one possible disadvantage
00:09:38.02	is if you had a leak,
00:09:39.23	let's say there was a tear in the blue,
00:09:41.23	the drug could dump out.
00:09:43.24	So, what that might mean is if you had a potentially toxic drug
00:09:46.13	like a cancer drug or insulin,
00:09:48.28	you wouldn't probably use a reservoir system,
00:09:51.16	but if you were delivering...
00:09:53.14	let's say you were delivering human growth hormone,
00:09:55.14	or things like that,
00:09:57.13	this would probably be fine.
00:09:59.12	The second system
00:10:01.11	that's also diffusion-based
00:10:03.25	is what we call a matrix system,
00:10:05.20	and again the blue dots represent the drug,
00:10:09.14	and the yellow that you see there,
00:10:12.08	the yellow-green,
00:10:14.22	that's the outside of the polymer matrix.
00:10:17.14	So, in the case of a non-erodible matrix,
00:10:20.08	the drug is uniformly distributed through that matrix,
00:10:23.09	and we see that on the top,
00:10:25.01	but then when we go to the bottom
00:10:27.01	we see the drug diffusing out.
00:10:29.11	And again,
00:10:31.15	it diffuses out through the polymer,
00:10:33.10	but now, because this geometry is different,
00:10:35.11	other things happen.
00:10:37.04	For example, this is not as easy to get steady release,
00:10:39.24	but on the positive side,
00:10:41.24	let's say there was a tear in this matrix...
00:10:44.26	not much more drug would come out
00:10:46.27	because it's embedded throughout this entire matrix.
00:10:49.27	So, this is the first mechanism, is diffusion.
00:10:52.04	The second mechanism, as I mentioned,
00:10:53.25	is a chemical reaction,
00:10:56.06	and one of the very common ways of doing this
00:10:58.20	is a bioerodible system.
00:11:01.15	So, in the case of a bioerodible system,
00:11:04.15	it basically would look, in the beginning,
00:11:06.25	essentially identical to what I showed you on the matrix,
00:11:10.25	but now the yellow, rather than staying the same,
00:11:16.14	in other words, rather than the matrix staying the same size,
00:11:19.26	it actually shrinks and ultimately completely dissolves,
00:11:23.01	and as it dissolves
00:11:25.00	what we see is all those blue dots come out and are released.
00:11:27.22	So, bioerosion
00:11:30.01	provides a whole second mechanism of being released,
00:11:32.13	and the big advantage of bioerosion,
00:11:34.13	thinking about it from the patient's standpoint,
00:11:36.15	if you had an implant and it didn't dissolve,
00:11:40.04	you have to go in and take it out.
00:11:42.24	That's gonna be done in some cases,
00:11:44.05	as I'll mention later,
00:11:46.19	but that's still a disadvantage.
00:11:48.18	It certainly would be preferable for the patient
00:11:50.11	to just have one injection or one implant
00:11:52.10	and never have to worry about it again.
00:11:54.26	So, one mechanism for chemical reaction is erosion.
00:12:00.20	The second mechanism is the idea of the polymer
00:12:03.14	containing a pendant chain,
00:12:05.23	and now what happens is the drug is attached
00:12:08.03	to the polymer backbone,
00:12:10.03	but water or enzyme, as we see in the bottom,
00:12:12.28	comes along and basically breaks the bond
00:12:15.26	and then the drug is released.
00:12:18.06	One of the advantages of this
00:12:19.26	is that you can add a lot of drug to these,
00:12:22.29	but a possible disadvantage
00:12:25.17	is that these are what are called new chemical entities.
00:12:28.13	We've chemically modified the drug by attaching it,
00:12:30.29	so it's a new chemical entity,
00:12:32.14	so you'd have to do a lot more toxicology
00:12:34.13	to eventually get approval,
00:12:36.06	whereas the earlier systems that I talked about,
00:12:38.10	there is no change in the drug,
00:12:39.27	it's just physically embedded.
00:12:42.15	The third mechanism
00:12:44.26	is the solvent does something,
00:12:47.14	and so here we're looking at swelling having an effect,
00:12:50.08	and the idea of swelling is you,
00:12:53.20	again, if we look at the left-hand panel,
00:12:56.18	the drug is dissolved in the polymer
00:12:58.23	and we see it just looking blue,
00:13:00.27	but now, as we go the right-hand panel,
00:13:04.28	what happens is the water goes in
00:13:08.15	and the outer part of the matrix actually swells.
00:13:11.27	So, the drug was locked into place,
00:13:14.02	but now since it's swelling, it can come out,
00:13:18.02	and that takes place over time
00:13:20.15	and that gives you the opportunity
00:13:25.06	to deliver the drug simply based on water.
00:13:27.13	Also, one of the other things
00:13:29.07	that people have sometimes done in the case of swelling systems
00:13:31.17	is make them swell so much
00:13:33.21	that they might stay in the stomach a little longer,
00:13:35.21	and that might also give you a way, if you took an oral system,
00:13:38.25	of maybe making it act longer as well.
00:13:42.07	And, the final mechanism for solvents,
00:13:45.07	and of the one's I'm gonna talk about,
00:13:48.08	is osmotic pressure.
00:13:50.09	And, the idea of osmosis is that what happens is,
00:13:53.04	if you have... let's just say I had two sites,
00:13:58.22	I have site 1 where I have water and a lot of salt in it,
00:14:02.08	like table salt,
00:14:04.16	and I have site 2 that just has water in it,
00:14:07.26	and then they're connected by a membrane.
00:14:10.04	There's a whole field called thermodynamics
00:14:12.20	where what happens is,
00:14:14.16	if you have these two sites
00:14:16.10	and they're separated by the membrane
00:14:18.11	and water can permeate,
00:14:20.03	what they wanna do is have what's called
00:14:22.03	the same thermodynamic activity,
00:14:23.14	so what happens is water will actually
00:14:26.24	rush in from one to the other to actually dilute it,
00:14:29.04	so you'll actually hopefully someday
00:14:31.06	have the same salt concentration on both sides.
00:14:34.12	But, when that happens,
00:14:35.29	that is what leads to osmotic pressure,
00:14:39.21	because water is actually rushing in
00:14:41.18	and there's a certain amount of pressure
00:14:43.23	that is caused by that.
00:14:45.21	That same thing is manifested here in this final mechanism
00:14:48.12	of osmosis,
00:14:50.23	where the drug is dissolved in the polymer,
00:14:53.07	but now water rushes in
00:14:55.08	because the drugs not on the outside and water wants to...
00:14:58.24	the water wants to come in to dilute that drug,
00:15:01.04	and you see these cracks form, these porous openings,
00:15:04.00	and those permit release.
00:15:05.26	Now, one of the issues with this particular system
00:15:08.27	is it's not so reproducible.
00:15:12.07	It's getting cracks...
00:15:13.24	it's not easy to make reproducible cracks,
00:15:15.28	but I want to show you what I think is a very clever approach
00:15:19.06	that has been done
00:15:21.18	where you can actually make an osmotic pump,
00:15:23.26	and what's interesting about this pump...
00:15:25.21	I think when people generally think about pumps
00:15:27.28	you think about pumps that involve mechanical parts
00:15:31.28	and electricity and things like that.
00:15:34.03	The pump I'm gonna show you here
00:15:35.25	has none of that.
00:15:37.15	It's a totally-driven pump,
00:15:39.24	and it can actually give you very, very precise release rates.
00:15:42.12	So, when we look at this slide,
00:15:45.06	let's take a look first at the top left,
00:15:47.23	that's a front cross-section,
00:15:50.03	and the way this has been designed
00:15:52.19	is you've got an outer membrane
00:15:55.02	that's rigid but it's water permeable,
00:15:57.13	so water can go through it
00:15:59.08	and yet the system won't expand.
00:16:01.20	Immediately below that
00:16:04.12	there's another chamber where you see the salt.
00:16:06.17	That salt could be like sodium chloride or potassium chloride.
00:16:10.08	That salt is, again,
00:16:12.11	what's going to cause the osmotic pressure,
00:16:14.10	because there's not much salt on the outside,
00:16:16.03	so water is going to want to rush in to that salt.
00:16:19.17	And, actually you load the salt
00:16:21.18	at a pretty high level
00:16:23.18	so that it's always going to be above it's solubility level,
00:16:26.17	so water will actually rush in at a constant rate.
00:16:29.22	Now, the next chamber,
00:16:31.24	as we keep going to the inside,
00:16:33.29	is a compressible membrane,
00:16:35.24	but that compressible membrane is exactly the opposite
00:16:38.06	of the rigid membrane on the outside.
00:16:40.18	That compressible membrane is water impermeable,
00:16:42.23	in other words water can't get through it,
00:16:44.27	and yet it's compressible, it's not rigid.
00:16:47.17	You might of it like a balloon.
00:16:49.27	And, inside that chamber,
00:16:53.15	you have the dissolved drug.
00:16:55.23	So, the only other thing
00:16:57.23	that I wanted to point out as we look at this top section
00:17:01.20	is now if we looked at a side view,
00:17:03.20	there's actually a laser-drilled hole
00:17:05.13	in the very front of this system,
00:17:07.11	and that is how the drug's gonna come out.
00:17:09.19	But, let me just now go over how it works,
00:17:11.14	and it's really going to be looking at the bottom part
00:17:14.18	of this slide that shows you how that happens.
00:17:18.03	So, what happens is,
00:17:20.12	as I mentioned before, water is going to want to rush in
00:17:23.06	at a constant rate through that rigid membrane
00:17:25.27	and what happens is,
00:17:27.19	as water rushes in at a constant rate,
00:17:30.25	the outer membrane doesn't expand,
00:17:32.14	the whole system doesn't expand, but...
00:17:35.29	so the only thing that can happen
00:17:38.08	is the chamber where we have the salt,
00:17:40.07	that does expand inward
00:17:42.25	because that's the only place the water can go.
00:17:45.16	So, water rushes in at a constant rate,
00:17:48.11	diluting the salt,
00:17:50.13	and it compresses that compressible membrane.
00:17:52.17	It can't get inside that membrane, but it can compress it,
00:17:55.07	and it gets smaller and smaller,
00:17:57.15	and it's kind of almost like squishing a tube of toothpaste,
00:18:00.06	and as you squish it
00:18:02.07	the only thing that can happen
00:18:04.08	is the contents in the center, the solution,
00:18:06.08	go out that laser-drilled hole
00:18:08.16	where you see the drug coming out at the bottom.
00:18:11.02	So, you squish this by osmotic pressure
00:18:13.03	at an exactly constant rate,
00:18:14.21	the drug comes out at an exactly constant rate,
00:18:17.25	and the patient gets steady delivery.
00:18:22.19	So, what's novel about this is
00:18:24.25	this is I think a very interesting example of
00:18:27.13	where different chemical and physical principles
00:18:29.24	are used to design a steady delivery system,
00:18:34.04	and it's actually been widely used.
00:18:36.06	These kinds of systems are used for delivery systems
00:18:38.25	and studying different biological things in animals,
00:18:41.26	and actually variations of it
00:18:43.28	are pills that most people probably take.
00:18:46.09	They may not realize it,
00:18:47.29	but sometimes if you look down
00:18:50.06	very carefully at the pill, you can see a little laser-drilled hole right
00:18:52.26	where they have the label.
00:18:55.01	So, what I've gone over so far
00:18:57.01	are some of the different mechanisms by which these work.
00:19:00.08	Now, I thought I'd turn and show you how they're actually used
00:19:02.08	in different applications.
00:19:04.20	Well, the eye was actually one of the earliest places
00:19:07.21	where people used controlled release.
00:19:10.02	They used it in glaucoma,
00:19:12.19	which is a leading cause of blindness,
00:19:14.11	and in artificial tears, which is very uncomfortable.
00:19:17.06	I’ll go over each of these.
00:19:18.25	This was one of the earliest systems
00:19:20.25	developed in controlled release.
00:19:22.12	This was in the 70s, and it was called the Ocusert,
00:19:26.04	and it's a little device that you just put into your eye,
00:19:29.24	which you see here,
00:19:31.22	it's actually a reservoir system that lasts for one week.
00:19:38.04	Normally, somebody, it they had this disease,
00:19:40.10	would have had to take 28 eye drops.
00:19:44.21	The way it's designed is shown here.
00:19:47.01	It's a reservoir system,
00:19:48.27	just like the very first thing that I went over
00:19:50.28	on those three different types,
00:19:52.22	so you have pilocarpine, that's the drug.
00:19:55.01	It's surrounded by two membranes
00:19:57.00	that really control the rate of diffusion,
00:19:59.21	and what they've done,
00:20:01.09	just so people can visualize it better,
00:20:03.10	is they've put an annular ring right here
00:20:06.17	that's got titanium dioxide in it,
00:20:08.20	and that makes it easy for the patient to see.
00:20:11.03	That's why when you looked at it on the last slide
00:20:13.07	it had this little ring around it on the bottom.
00:20:16.18	So, depending on the thickness of those two membranes
00:20:20.25	that actually controls the rate of release,
00:20:22.22	so what's been done
00:20:24.24	is to make one that releases at 40 µg/hour
00:20:27.09	after an initial burst,
00:20:29.07	and another that releases at 20 µg/hour
00:20:31.17	after an initial burst.
00:20:33.06	But really, again, by using engineering
00:20:35.03	you can make them release at any rate you want,
00:20:37.00	just by controlling the thickness of those membranes,
00:20:39.18	so these are just two common ones that have been used.
00:20:43.17	The next system I wanted to mention was artificial tears.
00:20:46.09	If somebody had dry eye
00:20:48.07	that can be very painful,
00:20:50.12	and the goal is to put something in the eye
00:20:53.16	that might last for a long time,
00:20:55.12	rather than have somebody take eye drops, you know,
00:20:57.15	really every 20 minutes sometimes.
00:20:59.08	So, what's been done is to create an applicator,
00:21:01.24	shown here,
00:21:03.25	which you can use to pick up a little polymer
00:21:07.15	and then drop it in the eye
00:21:10.11	and basically, when you do,
00:21:13.18	it might last for up to 18 hours
00:21:15.23	and hold on to corneal moisture.
00:21:17.29	It's not a perfect system by any means,
00:21:19.28	because one of the things that happens sometimes
00:21:22.02	for some patients is they get blurred vision,
00:21:24.10	but it's an illustration of what you can do,
00:21:26.02	and actually I think it's a challenge for the future
00:21:28.21	to be able to do systems like this
00:21:32.01	that will not have any change in visual acuity.
00:21:36.19	Probably one of the biggest areas
00:21:38.11	where this whole field of controlled release
00:21:40.10	has been used worldwide
00:21:42.12	is in contraceptive systems.
00:21:44.06	There are a number of ways
00:21:46.01	that people have done this:
00:21:47.23	non-erodible subdermal implants, erodible ones,
00:21:52.01	steroid releasing intra-uterine devices,
00:21:53.22	and vaginal rings.
00:21:55.28	I'll go over them briefly.
00:21:57.27	Probably the most widely-known system
00:22:00.18	for contraception using controlled release
00:22:03.02	is a system called the Norplant.
00:22:05.12	It's actually shown here.
00:22:07.22	This is a woman's finger
00:22:09.20	and she has these six sticks,
00:22:11.17	now actually they've designed them so you can just have two of them,
00:22:14.28	but they're very small, they're like matchstick-size.
00:22:17.28	They can be placed underneath the skin
00:22:20.24	and they'll deliver the drug for 5 years.
00:22:22.24	It's just slow diffusion through the polymer,
00:22:25.08	through the reservoir system like I mentioned,
00:22:27.15	and it'll last for 5 years.
00:22:29.05	Here is an example of that,
00:22:31.00	where we're looking at release curves for different patients,
00:22:33.19	and it goes for 2000 days
00:22:35.26	even though it's as small as what I showed you.
00:22:38.16	Another system, also a reservoir system,
00:22:41.27	is what's called the Progestasert,
00:22:45.21	and this system...
00:22:47.22	again, very small, it's an intra-uterine device.
00:22:50.10	These again are a woman's fingers
00:22:52.16	and, again, you put the drug
00:22:55.22	in the center of the system,
00:22:57.29	just like I showed earlier
00:23:00.01	with the picture where the drug was the dots
00:23:03.10	and then it will diffuse out,
00:23:05.15	and here's an example of that,
00:23:07.19	where look at the core matrix.
00:23:09.17	The dots here, again, represent the drug,
00:23:11.19	and the drug will diffuse out
00:23:14.03	over a 365 day period.
00:23:17.01	This is just a curve, it's not exactly constant,
00:23:20.00	but it basically will vary from,
00:23:23.05	over a 400 day period,
00:23:26.05	it's pretty close to 50 µg/day over that period.
00:23:30.21	So, this is a second way that people do it,
00:23:33.14	and there are other controlled release systems as well
00:23:36.12	that have been worked on for contraception.
00:23:40.25	A third area that's been very important
00:23:43.14	is dentistry, actually,
00:23:45.18	that people use controlled release for.
00:23:47.22	If one looks at the percentage of patients
00:23:50.02	who have periodontal disease,
00:23:52.00	it's maybe 25% of the population.
00:23:55.13	To tell if you have periodontal disease,
00:23:57.07	the way I always know is if I go to the dentist
00:23:59.21	and, you know, they brush your teeth a lot harder
00:24:01.24	than we do, or I do at least,
00:24:03.20	and if they start bleeding
00:24:05.24	then you probably have some periodontal disease.
00:24:07.20	It's not pleasant, 2-3% of the people
00:24:10.02	who have periodontal disease require surgery.
00:24:12.19	If you have no treatment
00:24:14.25	the result is no teeth.
00:24:16.11	That's not a very good outcome.
00:24:18.03	If you do surgery, that's painful, it's expensive.
00:24:21.04	There are drugs that people use,
00:24:22.26	like tetracycline, but they make you incredibly sick
00:24:24.21	to your stomach.
00:24:26.20	So, what's been done
00:24:28.26	is to actually make fibers
00:24:32.04	with tetracycline or other drugs,
00:24:34.05	and here you're delivering the drug locally.
00:24:36.27	So, because you're delivering the drug locally,
00:24:38.24	rather than throughout the whole body,
00:24:40.16	the body doesn't get as much
00:24:42.24	and so it's effective,
00:24:45.03	but with much lower dosage,
00:24:46.24	like in this case it's effective with less than 1/1000-th the dose,
00:24:49.23	and the dentist can apply them very quickly,
00:24:51.22	like 3 minutes per tooth.
00:24:53.28	You can barely see them, I'll show you a picture.
00:24:55.26	They get rid of the problem, the spirochetes,
00:24:58.05	and they don't cause irritation.
00:24:59.24	I'll just show you a couple pictures.
00:25:01.26	Here is a picture of the general idea
00:25:05.15	of the hollow fiber in the bottom,
00:25:08.08	just covering the tooth,
00:25:10.12	and it will deliver the drug over time.
00:25:13.01	And, let me just even go further
00:25:15.01	and show you what was done.
00:25:17.06	Originally, they used a reservoir system,
00:25:19.15	this is a hollow fiber,
00:25:21.01	where the drug was placed in the center,
00:25:22.20	but they got some leaks.
00:25:24.13	So, then they went to the matrix system
00:25:26.02	where they uniformly distribute it,
00:25:27.29	and tetracycline is kind of a yellowish drug,
00:25:30.07	so now it's in these fibers
00:25:33.02	but they're uniformly distributed,
00:25:34.27	and what the dentist did,
00:25:37.00	and I'll just show you some pictures...
00:25:39.28	here's a patient with periodontal disease,
00:25:42.01	notice the red gums.
00:25:44.15	Then, what the dentist does
00:25:47.17	is he puts... she puts
00:25:50.13	the matrix systems that are on the teeth
00:25:54.00	like you see them here,
00:25:56.21	and so they are actually on several of the teeth,
00:25:59.12	and that will release the drug,
00:26:01.23	say, over a 10 day period,
00:26:03.12	and when you're done with that,
00:26:05.18	notice the difference in the gums.
00:26:07.17	The problem has gone away.
00:26:09.15	And, there have been many different variations
00:26:11.07	of these that people have used
00:26:13.06	to help people with this problem.
00:26:15.08	Another really powerful example of local delivery
00:26:18.10	is the drug-eluting stent.
00:26:20.26	If somebody has cardiovascular disease,
00:26:23.02	one of the most common ways
00:26:25.08	of treating cardiovascular disease today
00:26:27.19	is to basically prop open the blood vessel
00:26:29.21	with a system like this.
00:26:31.17	This is a stent,
00:26:33.10	and it basically looks like a Chinese finger puzzle.
00:26:35.18	It props open the blood vessel,
00:26:37.06	but unfortunately about 50% of the time
00:26:39.27	when you do this you get a lot of cells,
00:26:42.17	smooth muscle cells proliferating,
00:26:44.16	and they'll block off the blood vessel itself,
00:26:48.02	which isn't good and in the worst case somebody could die,
00:26:51.22	but even short of that
00:26:54.05	you'll have to go in and do another operation.
00:26:56.02	So, what's been done is to take some fairly toxic anti-cancer drugs
00:26:59.26	like Taxol,
00:27:01.27	coat them with a polymer on these stents,
00:27:05.07	and these anti-cancer drugs are anti-proliferative,
00:27:08.15	they prevent the smooth muscle cells
00:27:10.25	from dividing the same way,
00:27:13.26	and basically they keep the blood vessel open,
00:27:16.03	and probably close to a million patients use this every year.
00:27:20.26	Now, I'm gonna move a little bit
00:27:23.20	from local delivery like the teeth and stent
00:27:26.15	to systemic delivery,
00:27:28.20	and again go over a couple of examples.
00:27:31.04	One of the other I think really important areas
00:27:33.28	for controlled release
00:27:36.06	is a lot of times people have come up with new drugs
00:27:38.01	like peptides and proteins
00:27:40.01	in the last 20 or 30 years.
00:27:41.26	One of those was what's called
00:27:43.15	a luteinizing hormone-releasing hormone analog,
00:27:45.22	and that has been shown to be very effective
00:27:48.08	in treating certain diseases
00:27:50.05	like prostate cancer, endometriosis,
00:27:52.10	and other diseases.
00:27:53.24	The problem was,
00:27:55.17	since it's a peptide of 1200 molecular weight,
00:27:57.22	there was no good way to give it to the patient.
00:28:00.02	If the patient tried to swallow it,
00:28:02.02	it's destroyed in the stomach and the GI tract
00:28:05.14	by enzymes.
00:28:06.23	Also, it's too big to get absorbed.
00:28:08.25	They also tried to give it through the nasal passages
00:28:10.24	and other things but, again,
00:28:12.06	none got into the body.
00:28:14.08	So, they injected it,
00:28:16.04	but the problem when you inject it is that enzymes
00:28:18.08	destroyed it right away,
00:28:19.27	so what's now done
00:28:21.20	is to put it in little microspheres
00:28:23.10	like one of those matrix systems,
00:28:24.27	actually a bioerodible matrix system,
00:28:26.24	and what happens is you can actually release it for many days.
00:28:29.25	This is a graph of it,
00:28:31.23	but now Lupron Depot,
00:28:33.08	which has been used by many, many millions of patients...
00:28:36.15	most of these last for about four months.
00:28:39.02	So, you give a single injection every four months
00:28:41.20	for the patient and it will deliver the drug.
00:28:44.23	Another example that's widely used
00:28:48.09	is for patients that have schizophrenia.
00:28:50.19	If somebody has schizophrenia
00:28:52.07	there are also drugs like Risperdal
00:28:54.23	which are quite good for the patient,
00:28:56.29	but a lot of times people forget to take them,
00:29:00.26	and so what's been done
00:29:03.02	is to put them in another type of microsphere,
00:29:06.23	bioerodible system like I was talking about,
00:29:09.20	and they're injected every two weeks.
00:29:11.28	Now, actually, they've come up with one
00:29:14.01	that will be injected every four weeks,
00:29:15.24	again using these kind of principles
00:29:17.12	that I mentioned earlier.
00:29:19.01	And, that's had a huge effect
00:29:22.01	on helping patients that have schizophrenia.
00:29:25.23	It's decreased the amounts of hospitalizations,
00:29:29.21	it's decreased suicides,
00:29:32.08	and probably about five million patients have taken these.
00:29:37.00	Another example, recently approved,
00:29:39.02	is another molecule
00:29:41.08	that may be useful in this case for type 2 diabetes.
00:29:43.10	This is a glucagon-like peptide,
00:29:45.20	and what happened was when it came out
00:29:48.27	it was effective in terms of improving blood sugar
00:29:51.16	after food intake,
00:29:53.24	but you had to give injections twice a day.
00:29:56.05	Now it's put into one of these microspheres,
00:29:58.03	again, one of these bioerodible systems
00:29:59.27	that I mentioned,
00:30:01.23	and it's given once a week
00:30:03.20	from a degradable system called PLGA,
00:30:05.19	which is poly(lactic-glycolic acid).
00:30:10.02	The last area that I wanted to talk about
00:30:13.02	to illustrate some of these points
00:30:14.17	are what are called transdermal systems.
00:30:16.10	For many years, people would have never thought
00:30:18.17	that you could deliver drugs through the skin
00:30:20.22	because you'd think that that might be...
00:30:23.00	you know, if things could get through the skin easily
00:30:25.09	that might be very bad,
00:30:26.25	like somebody could get infected.
00:30:28.15	But what's been found out
00:30:30.28	is that some molecules can actually get through the skin,
00:30:32.22	and what's been done is to make, again,
00:30:35.29	another reservoir system,
00:30:37.15	diffusion-based system, shown here,
00:30:39.22	and the way this is designed
00:30:41.18	is you've got a backing membrane,
00:30:43.13	a drug reservoir which is shown in the middle,
00:30:45.27	a rate controlling membrane,
00:30:47.27	and finally an adhesive.
00:30:49.16	And you just put this reservoir system,
00:30:51.19	diffusion controlled reservoir,
00:30:53.22	on the skin and it will release the drug,
00:30:56.00	and these may last anywhere
00:30:58.11	from a day to a week.
00:31:00.20	The key issue in terms of getting drugs
00:31:03.13	through the skin
00:31:05.09	is pretty much all the resistance
00:31:07.05	in terms of getting the drugs through the skin
00:31:08.25	is the outermost skin layer.
00:31:10.09	It's called the stratum corneum,
00:31:12.10	and actually if you looked at it under a microscope
00:31:14.07	it looks like a brick wall.
00:31:16.09	There are dead cells called keratinocytes
00:31:18.05	and then there are lipid bilayers in between them,
00:31:20.28	and that provides a very tight barrier
00:31:23.10	that makes it very hard for things to get through,
00:31:26.04	but if some molecule has just the right characteristics,
00:31:29.10	like the right molecular size
00:31:31.06	and the right, let's say lipophilicity,
00:31:33.10	meaning how fat soluble it is,
00:31:35.05	actually it can get through.
00:31:37.10	So, I though I'd make a few general comments
00:31:39.12	about transdermal systems.
00:31:41.11	The skin, as I mentioned,
00:31:42.26	is generally impenetrable
00:31:44.20	and the principle resistance
00:31:46.27	is the stratum corneum,
00:31:49.03	which is actually dead skin,
00:31:51.03	but it has this tight sheath, as I mentioned,
00:31:53.19	of keratinocytes and lipid bilayers.
00:31:57.22	The permeability of a drug
00:32:01.16	correlates with its water solubility,
00:32:03.09	its molecular weight,
00:32:05.01	you'd like it to be fairly small,
00:32:06.24	and its oil/water partition coefficient,
00:32:09.07	because if the drug is more what's called lipid-like
00:32:11.09	it's more likely to, you know,
00:32:13.16	if you take the principle "like-dissolves-like",
00:32:15.19	it's more likely to be able to penetrate through the lipid bilayers
00:32:17.25	that I showed you in the last slide.
00:32:20.08	And finally, it's useful...
00:32:22.05	transdermal systems are useful for drugs
00:32:24.01	that have a low dose requirement,
00:32:26.04	the lower the better because of this permeability issue,
00:32:28.06	and also for drugs that have high skin permeability.
00:32:32.09	One of the big areas of transdermal research
00:32:35.10	is the fact that
00:32:37.27	you can enhance permeability by using certain compounds,
00:32:41.07	chemical compounds,
00:32:42.28	and just to give an example,
00:32:44.28	when people have put estradiol in a patch,
00:32:47.23	for postmenopausal women,
00:32:50.20	the flux is not very high,
00:32:52.11	but what they found is that you can take ethanol
00:32:55.10	and you can put it in it,
00:32:57.05	and that will increase the flux by a factor of 20,
00:32:59.13	and what that means for the patient
00:33:01.14	is that they can go from having this giant patch
00:33:03.14	to a much smaller patch,
00:33:05.06	a factor of 20 smaller,
00:33:07.00	and that makes it practical.
00:33:08.16	Also, these transdermal systems
00:33:11.06	are easy to apply and easy to remove.
00:33:15.12	One of the biggest advantages
00:33:17.05	is the fact that when you do something transdermally,
00:33:20.10	rather than orally,
00:33:22.09	you really tremendously reduce the first pass effect.
00:33:25.01	For example, there's lots of drugs that,
00:33:26.15	when you take them orally,
00:33:28.11	they're destroyed by the liver,
00:33:30.17	and that leads to low amounts in the blood
00:33:32.14	and also variability,
00:33:34.19	but transdermal systems can reduce that tremendously.
00:33:38.20	One possible drawback, however, of a transdermal system
00:33:41.26	is that it takes time to reach a steady state,
00:33:44.09	like maybe 2-6 hours in some cases,
00:33:47.17	and what that means is that
00:33:49.14	probably if you had an acute problem,
00:33:51.04	like say, sudden pain,
00:33:52.27	an oral system would be better than a transdermal system,
00:33:55.15	but if you have a chronic situation
00:33:58.03	transdermal is actually quite good.
00:34:01.04	This slide simply shows
00:34:04.13	the flux of different drugs
00:34:07.05	and melting points,
00:34:08.28	but in particular what I wanted to note
00:34:10.29	is if you look at the drug on the top,
00:34:12.19	like say nitroglycerin, scopolamine, fentanyl...
00:34:14.16	all of which are used clinically
00:34:17.21	in transdermal systems,
00:34:19.07	their fluxes are pretty high,
00:34:21.06	but if you go down closer to the bottom
00:34:23.14	and you look at estradiol,
00:34:25.15	estradiol has a lower flux,
00:34:27.11	so the only way to really get that to
00:34:29.24	become a useful transdermal system
00:34:31.18	is you have to have a permeation enhancer,
00:34:34.21	and that would move estradiol up higher
00:34:38.25	so it would be more like the scopolamine,
00:34:40.15	fentanyl, and nitroglycerin fluxes.
00:34:44.14	On the final slide,
00:34:46.04	I just wanted to expand that point a little bit further
00:34:48.18	and go over methods of enhancement.
00:34:51.03	This is a big area probably for the future,
00:34:54.16	because most drugs...
00:34:55.28	right now there's only about 20-25 drugs
00:34:57.21	or drug combinations
00:34:59.19	that are given transdermally,
00:35:01.17	even though they're used by millions of patients.
00:35:04.09	We'd like to expand the numbers of drugs
00:35:07.16	that could be given this way,
00:35:09.26	so one way of doing it
00:35:12.05	that people are looking at is electric fields
00:35:14.05	like by iontophoresis.
00:35:15.29	Could you actually take an electric field
00:35:18.21	and apply it to a drug
00:35:21.18	so that the drug could go through the hair follicles or sweat ducts?
00:35:24.29	And, this is experimental,
00:35:26.28	but may some time be useful for delivering peptides,
00:35:30.01	for example, in patches.
00:35:31.25	Electroporation, that's a second method,
00:35:34.11	and it also involves electricity,
00:35:36.06	but it involves creating new pathways,
00:35:37.29	new pores in the skin that are just temporarily there,
00:35:41.01	and even though it's an early stage
00:35:43.07	it's shown very, very large increases,
00:35:45.09	like 10^4 increases in permeation
00:35:48.08	and is in clinical trials in some situations.
00:35:51.06	The third are is ultrasound.
00:35:52.25	Ultrasound... actually
00:35:54.13	there has already been an ultrasound system approved by the FDA
00:35:57.07	for delivering pain medications,
00:35:59.08	and one of things the ultrasound does
00:36:01.21	is it gets rid of any type of lag time,
00:36:04.03	but also tremendously increases permeation of drugs,
00:36:07.24	and people are exploring it for
00:36:10.19	different types of large molecules.
00:36:13.02	For all of these three,
00:36:14.24	iontophoresis, electroporation,
00:36:16.05	and ultrasound,
00:36:18.08	one of big challenges is engineering
00:36:20.08	and miniaturizing
00:36:22.14	and making less expensive the units,
00:36:24.09	so that you could make a small patch
00:36:26.09	that the patient could conveniently wear.
00:36:28.17	In addition to these methods,
00:36:30.08	there are chemical methods like making a drug more lipophilic
00:36:33.27	by making what's called a prodrug,
00:36:35.23	that means attaching something lipophilic to the drug
00:36:38.18	and, as I mentioned, penetration enhancers.
00:36:41.00	So, drug delivery, in summary,
00:36:43.26	is actually a very, very broad area.
00:36:45.13	It involves a lot of chemical
00:36:47.22	and physical and biological principles.
00:36:49.15	It's been very, very important
00:36:51.01	for delivering all kinds of drug up until now,
00:36:54.09	and I believe it will probably be even more important
00:36:56.15	in the future as we come up with...
00:36:58.13	and the world comes up with new drugs
00:36:59.29	like siRNA, mRNA, DNA, gene editing,
00:37:05.21	all kinds of approaches
00:37:08.01	where really I think the delivery
00:37:10.03	will end up being critical
00:37:12.15	to getting these important molecules
00:37:14.10	into the cells where you want them.
00:37:16.10	Thank you very much.