• Skip to primary navigation
  • Skip to main content
  • Skip to footer

Session 8: Controlled Drug Release Technology

Transcript of Part 1: Controlled Drug Release Technology

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.

This material is based upon work supported by the National Science Foundation and the National Institute of General Medical Sciences under Grant No. MCB-1052331. Any opinion, finding, conclusion, or recommendation expressed in these videos are solely those of the speaker and do not necessarily represent the views of iBiology, the National Science Foundation, the National Institutes of Health, or other iBiology funders.

© 2021 - 2006 iBiology · All content under CC BY-NC-ND 3.0 license · Privacy Policy · Terms of Use · Usage Policy
 

Power by iBiology