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.