Lecture 12 - Biomolecular Engineering: General Concepts (cont.)

Overview

Professor Saltzman reviews the pharmacokinetic first-order rate equation that can be used to model changes in drug concentration in the blood, as well as its derivation from the law of conservation of mass. The importance of maintaining a drug concentration that is sufficient for therapeutic purpose, but below a toxic level, is emphasized. Since this is directly affected by drug administration method, ways to localize and sustain therapeutic concentrations of drug, such as incorporating in slow-releasing, biocompatible polymers are introduced. Professor Saltzman gave some examples of clinical applications of controlled release drug delivery system, such as anti-restenosis drug incorporated into stents, and chemotherapeutic drugs in brain implants and microspheres.

Lecture Chapters

Model for Injected Drug Delivery
Model for Oral Drug Delivery
Drug as Implant: Potentials and Limits
Accessibility of New Drug Delivery Methods

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Transcript	Audio
html Frontiers of Biomedical Engineering BENG 100 - Lecture 12 - Biomolecular Engineering: General Concepts (cont.) Chapter 1. Model for Injected Drug Delivery [00:00:00] Professor Mark Saltzman: Welcome, so we're going to continue today talking about drug delivery. I want to pick up where I started last time, where at the end of the class I was trying to convince you that one way to think about drug delivery was to take what we know is a complex system, the human body, and represent in a simple way. This is a common approach to engineering, where you take a system that might be a complex system and you say, 'How could I represent it in the most simple way?' Then you ask the question, 'What comes out that simple description and does it fit experimental evidence, does it match what we know about how things work?' This simplification was to take the human body and represent it as a simple stirred vessel of water and to ask the question, 'If we introduce drugs into the body do they behave in the same was as if I introduced drugs into this well-stirred vessel full of water, are there things that match about it?' We made the vessel a little bit more complicated than a simple tank full of water in that we allow its volume to be variable. This is going to account for the fact that when we introduce drugs into the body, some of them are going to go to different compartments within the body. Some will remain confined to the blood plasma space, for example, while some will be distributed more widely. So, we'll adjust the volume of the vessel to match the drug some way and how it's distributed. And we'll assume that it's a magical vessel in another sense, and that drugs disappear and they disappear in a very orderly fashion. That is they--the rate of disappearance of the drugs is equal to some constant times the concentration. It's a first-order rate of elimination from this compartment. If we do that, I wrote on the board today the equations that are in the box at the end of the chapter, in Chapter 14. Just to review them very quickly, that if we have a system like this we know that mass has to be conserved. One way to write down the conservation of mass equation is like this. The amount that comes in minus the amount that goes out, plus any molecules that are generated inside, minus any molecules that are consumed inside the system has to be equal to accumulation. IN--OUT + GEN--CONS = ACC Accumulation is just the rate of change of concentration. If molecules are accumulating inside the vessel that means their concentration is either going up or down, and so accumulation is the rate of change with time of the total number of molecules inside the vessel: -kM = dM/dt. If we went through this analysis for the system that I drew up here, and the particular circumstance, that I'm going to inject drugs into the body or into this vessel at time t = 0. After time t = 0, no molecules are going to be introduced. This is when I'm just giving all the drug at once at the beginning, so I'm simulating an intravenous injection. There's nothing coming in and there's going out over the--in terms of drugs introduced over the time that I'm interested in. No molecules of drug are being generated inside the body but they are being consumed, they are disappearing in some way. They're disappearing by this first-order process where the rate of disappearance is equal to a constant times the number of molecules that are still available (-kM). I could solve this equation, this differential equation--I've told you if you don't know about solving differential equations, don't worry. Another way to think about it is here's the solution, you could convince yourself that this solution does match this equation, 'If I take the derivative of this and plug it back in here do I get the right answer?' That's another way to think about or you could just trust me that it is the right solution to the equation. We also have to know one more thing, how many molecules of drug we introduced at the beginning, and we're going to call that number M0 and so the final result isM = M0*e-kt. The amount of drug that I have within the body at any time is equal to the amount I had at time 0, times e-kt, where k is this rate constant. So, if I knew what the rate constant was, I knew how long after the injection, I knew how many molecules I'd injected at the beginning, I could calculate how many I have at any time. Another way to write this is to write not in terms of the total number of molecules in the body but in terms of the concentration. To get concentration, I just divide both sides by the volume. So, concentration in the body's function of time is equal to this expression. I've plotted that for you last time and that plot's shown here. If I looked on a simple plot of concentration versus time, concentration starts at a maximum and it drops, and it drops exponentially over time. Turns out this very simple model matches very well the way many drugs behave if you inject them into the body. If you inject them intravenously, in this case, in that the concentration immediately after the injection will be the highest and concentration will drop over time. For many drugs the way that they're eliminated from the body does result in first-order elimination like this, so you see this pattern. Now, another useful parameter to describe here is that--is what's called the half-life. How long do drugs remain in the body, what's the time course of that. The half-life is defined as the time that it takes for drug concentration to drop from one value to half of that value. It might drop from C = C0 down to ½C0, it might drop from ½C0 down to a ¼C0, from a 1/4 to an 1/8th. It doesn't matter where you start at, for processes where you have first-order elimination the time to get rid of half of the drugs that are remaining is always the same. That's a characteristic of first-order processes. That half-life is just equal to ln(2/k). What this plot over here shows you is how rapidly would drugs disappear for drugs that had different half-lives or different rates of elimination? It's plotted on a semi-log plot so this is the natural--this is the log10 actually of drug concentration in the body as a function of time. Here's a drug that has a half-life of 600 minutes; long half-life means it stays in the body for a long time you clear it--you get rid of it very slowly. A shorter half-life you get rid of more quickly; a very short half-life you get rid of very quickly. What's the result of that? That for drugs with a short half-life, drugs that the body gets rid of more rapidly, if the desired effect isn't achieved with one dose I have to give another dose. I'd have to give another dose if the drug had a half-life of six minutes, I'd have to give another dose when the drug concentration dropped down to a very low level if I want to maintain a high concentration. Knowing the half-life is really important and when you--we'll see in a minute here how this same factor is important for drugs, not just that are intravenously injected but for drugs that are taken by pills as well. This is something that if you're making a drug, or you're making it to sell, you need to know about because you need to tell people how frequently they can take the drug. That depends on how quickly your body gets rid of it. That'll be more clear in just a moment, I hope. Chapter 2. Model for Oral Drug Delivery [00:08:42] That's the simplest, possible model, and it matches very well the behavior of many drugs when they're injected intravenously. How could I extend this to talk about--to think about other situations as well? Well, what's different if I don't directly inject the molecules into the body but I take them by a pill? That means if this is most of your body, now when I take a pill I'm not introducing the drugs all at once, but I'm putting them into my intestinal system and they're being slowly absorbed into the body. One way to describe that is to add another compartment to the model. To add another compartment to this simple model and say, here is a dose, but it's a dose in form of a pill. The patient's going to swallow it and then that drug will be available in a particular sub-compartment of the body. Now, it's going to be in the intestine and it will be absorbed from the intestine into the bulk of the body, into the circulatory system where it can distribute. Now, I'm not going to write down the equations for this but you could do that, and you could solve this equation. What you would find is this curve here which matches your intuition, probably. That what happens if I swallow a pill and that pill dissolves in my intestinal tract and then molecules get absorbed slowly into the body, is that right after I take the pill the concentration hasn't changed inside my blood yet, inside the bulk of my body. The molecules are still outside your body, they're still in your intestinal tract. They slowly get absorbed and as they absorbed concentration rises, you can see concentration rising here. Now, what happens to those molecules that are circulating in your body? Well, the same thing happens to them as what would happen to them if they were injected, is that your body's trying to get rid of them. At this point here, the rate at which they're being absorbed is much faster than the rate that your body is getting rid of them, and so the concentration is rising. It eventually reaches a peak, most of the drug has now been absorbed and concentrations start to fall. What's happening during this phase is that most of the drug has now been absorbed so the rate at which you're getting--it's coming into your body from the pill that's dissolving and the molecules being absorbed through the intestinal tract is being--that rate is less than the rate at which your body is getting rid of it, and so the concentration starts to drop. If you took Acetaminophen or if you took Ibuprofen, which is Advil or Motrin, what's happening in your body is that over some period of time, usually ten minutes to half an hour, the molecules are being absorbed from your intestine; the concentration in your blood is starting to rise. If you took a pill and then you measured concentrations in your blood, you'd see those concentrations start to rise. They reach a peak, say half an hour after you take it, and hopefully whatever aches or pains, or whatever the reason you're taking the medication for, you start to feel an effect of it after some of period of time and then concentrations start to fall. Now, eventually they'll fall to such a low level that the drug doesn't have its desired effect anymore. In the event that your pain hasn't gone away you'll take another dose, in which case the same events will repeat; drug will be absorbed, concentration will go up and then it'll start to fall again. What you would see on repeated doses, here I show the effect of getting one dose at time 0, giving another dose at 120 minutes, giving a third dose at 240 minutes, so this would be taking a drug--taking pills every two hours. Each one of the pills you take yields the same behavior. The total concentration in your blood is just the sum of each of those--the effect of each those doses. Each of those doses would have produced what are the dotted lines here; the total effect that you would see is this purple line. Let's say this drug is effective when the concentration is 0.1. Well, that means after 20 minutes or so, after the first dose, I get a level that's above 0.1 and I start to feel some relief from the symptoms. Concentrations peak, I'm feeling good, they start to drop. I know because I read the bottle, it said take a dose every two hours. I take another dose at two hours, the concentration rises again. So, by repeating these doses every two hours I maintain the concentration over 0.1 and I have an effect from the drug that lasts a long time. What if at 0.3, what if at a concentration of 0.3 you begin to see side effects? What if at a concentration 0.3 you begin to see side effects? Well, no problem after the first dose, after the second dose I've slipped into the range where I might start to see side effects. After the third dose I'm clearly up into the range where side effects might happen. So your--there's some danger as you repeat doses that because drug is accumulating that you could slip into a range where you start to see side effects. Now, the reason why you can--I mentioned this last time but it should be more clear now when you look at this picture, the reason why you can take some drugs like Ibuprofen or aspirin, or drugs that you typically buy over the counter without a doctor's prescription, and therefore without a doctor's guidance on taking them. The reason why you can buy those and use them yourself is because toxic levels don't occur until high on this chart; side effects don't occur until high on this chart. You can safely take it and without much risk that side effects are going to occur. For many drugs, however, the side effects occur at lower concentrations. Concentrations that are closer to the dose you need in order to have a useful response. Those are ones that you have to be more careful with; those are ones that physicians don't want to prescribe unless they're seeing you frequently enough that they can monitor how well you're doing with the drug. This should give you some idea about why that happens. Chapter 3. Drug as Implant: Potentials and Limits [00:16:09] People have been thinking for a long time, we've talked about why different modes of administration. Oral administration is the preferred mode for almost all kinds of drugs because it can be self-administered, it's very convenient and people don't mind taking drugs that way. But there are problems with it, for example, this problem of how do you maintain constant levels within this safe range over long periods of time. This just shows that same plot again, with the levels rising and falling, with the minimum effective and the maximum tolerated concentrations shown explicitly here. What's shown by the blue line is sort of what you might prefer, some kind of a drug delivery system that gives you long lasting concentrations but concentrations that don't rise and fall in the way that they do when you're taking individual doses repeatedly. Now, could you do this with an oral--with a pill? Could you achieve this sort of long lasting constant concentration with a pill? Well, you could in some rare circumstances, right? Think about--how would that happen? Well, maybe a drug has a very long half-life. If you could design a drug that had a very, very long half-life you could maintain concentrations for a long time. Nate do you have a question? Student: Aren't there now these time release capsules? Professor Mark Saltzman: Yes, so let me get to that in just a minute, but that's a really good point. An alternate to that would be what if I had a drug that had a long half-life, well that would naturally have this kind of a pattern. Instead of that, what if I design a pill that releases it slowly? Thinking back a couple slides ago what if I designed a pill that was absorbed very slowly from the intestine? If I make it absorb so slowly that drug is continually coming into your body over a long period of time. The peak in this diagram occurs after only 30 minutes or so. What if I designed a pill such that the drug was absorbed over five hours? Then I could extend this period here and I could have drug concentrations that remain long a long time, this would be five hours instead of 60 minutes down here where the peak occurs. What's the limit of that? Why is there a limit on how far you can go with that approach? Justin? Student: There's only so much drug. Professor Mark Saltzman: There's only so much drug, so it might be that if you do that then your pill is getting larger and larger presumably. There's only so big a pill you could swallow, so that could be a problem. Most compounds fairly potent, if you had something that was potent you could still put several days worth into a pill that was of a reasonable size. That might not be the limitation for every drug but that's a really good point. What's another limitation? Yeah Ilya? Student: Safety, I think that if put a [inaudible]. Professor Mark Saltzman: So that's a real--safety is a really good point. What I've been talking about here is how these things behave in an average person. What if you happen to absorb drug much more quickly than the average person? You've got several days worth of drug you're taking in one pill but it gets absorbed more quickly, you go into this toxic or side effect range, so safety is certainly an issue. One more, how often do you eat? Why? Why don't we only eat once a day? Student: [inaudible] Professor Mark Saltzman: Sorry? Student: The breakdown of food [inaudible]. Professor Mark Saltzman: Because that's the rate at which you absorbed foot and that's the rate at which your intestinal system works. Things pass through at a certain rate. You can't really slow that down, you can't really--you can eat more and feel full for a period of time, feel satisfied but you can--you won't continue to be absorbing more drugs because whatever you take into your intestine passes through in a matter of hours. There is a transit rate through your intestinal system that is not very changeable. A pill that you take is only going to be there as long as it's still in your intestinal tract and there's a limit to how long it will last. It's not going to last forever. We know this from our experience with food and eliminating the waste products of food, that there's a time course there that can't be altered very much. There's a limit to how much you can do in terms of sustaining or prolonging release with an oral system so people have designed other methods. As I mentioned, this is my research lab, this is my specialty so I'm going to talk about some things that we've designed to try to get around these barriers for certain kinds of drugs and certain situations. One way that you could get around it is by designing, not something that's taken orally, but by designing a delivery system that's implanted. Now, when you start thinking about 'this is not a pill but an implant', you're automatically limiting it to certain kinds of conditions. You wouldn't want to get an implant for a headache or something that you know is going to go away. You're talking about serious medical problems that are ongoing. This might be for something like treating diabetes where you need to take drugs everyday, multiple times a day. It might be for treating something like cancer where a course of chemotherapy could last for several weeks or several months. It might be for treating long term disorders like hemophilia where you're deficient in factor 8, a protein in the blood and you need to have injections of factor 8 continuously. So, it's only for certain kinds of things but you could imagine that there are those kinds of medical problems that you could treat. Well, here's one way to achieve long release of drug into the body from an implant. To make implants out of biocompatible materials like polymers. What's shown on the bottom of this slide here is an implant that's made of a gray substance, which is a polymer, a biocompatible polymer. Imagine it's something like the contact lenses that you would put in contact with your eye. These are materials that are synthetic materials but they're--your body doesn't respond to them as foreign objects very strongly. You can put some polymers in contact with one of the most sensitive areas of your body, your eye, and it can remain there for a long period of time without very much response of your body to the material. Well, what if you took that material embedded within it drug molecules? That's what's shown here. In fact, it's not just molecules of drug, its solid particles of drug which are shown as the orange dots here, so that this whole thing is maybe the size of a coin, maybe the size of a dime. What I'm showing you here is a cross-section of that dime, dime laying flat, I cut it like this, you're looking at it from the side. It's a millimeter or so in depth; several millimeters in diameter. It's a solid polymer, but inside of it are particles of the drug that you want to deliver. What these graphs show are experiments that we did - this was back in the late 1980s, where we put drug molecules into these polymers and then just dropped them into a test tube and ask the question, 'Could we release drugs slowly from these implants so we could make a long lasting pill essentially, make a long lasting implant that slowly released drugs?' This shows for a drug that is used to treat Parkinson's disease, another sort of chronic indication, where patients have to take drugs everyday for the rest of their life. This shows that when you drop these implants into a test tube full of water, the Dopamine is released and it's released for a fairly long period of time. This is days here, so this point here is 30 days, about a month. One of these systems released a drug for a period of a month. One released for almost three months here, a sort of continuous and reliable source of drug, so you can make implants that release drug molecules over long periods of time. The rest of these curves just show you that you could do this with drugs like Dopamine that are small in molecular weight and water soluble. You could do it with proteins, which are higher in molecular weight, and also water soluble. You could even do it with gene therapy vectors, with plasmids we talked about several weeks ago. Plasmid DNA, these are big molecules; very difficult to administer. We talked about how hard it is to get plasmid DNA inside of cells, but you can put them into these polymers and they'll slowly be released from the polymer over a long period of time. So, one could potentially make a long lasting gene therapy deliver system. One of the advantages of making these materials out of polymers is that we now know how to--you can make all kinds of things out of polymers. That's one of the nice features of plastics or polymers, is that you can mold them and shape them into all sorts of kinds of devices. Here, this is that same kind of material, but instead of making a coin out of it, we coated it onto the surface of a wire. This is a bare wire, and it's the kind of wire that you can put into the brain and you can measure recordings of what's happening in the brain extracellular space. You can measure action potentials and electrical activity in the brain by putting electrodes in. Physicians do this all the time to measure activity in the brain in patients that have epilepsy, for example. One of the problems with these materials is that when you put them into the brain they're not completely biocompatible. The brain does respond to them. It will form a scar around them and eventually the electrode won't work anymore. We coated these electrodes with a polymer that contained drug. In this case it's a drug, dexamethasone. It's a steroid that prevents scar formation locally. So, you make a wire that's able to record, but it's also able to deliver a drug. Now, when this is placed in the brain you not only can make the recordings, but the drug is slowly being released and it prevents scar formation around the outside of the electrode, and the electrode will function for a longer period of time inside the patient. This is an example of taking a medical device, the kind of devices we've been talking about, and will continue to talk about, and making it safer and better by adding drug delivery. The other advantage to this is that I didn't have to deliver steroids all over the body in order to accomplish this effect. We put the steroids right on the device and they act locally when they're needed. You don't have steroids delivered all over the body but only at the site where you're doing the intervention. Well, this has become a very big business in--around the world, and that's because several companies took this kind of technology that had been developed and used it in a very clinically important application. What this shows you here is a stent, it's made of a metal. This is one kind of it, there are many sort of versions of this. Imagine this is a stent that's expanded over this tube that's inside. You can imagine this design here which looks like a--kind of chicken wire fence could be collapsed because the wires are--would bend and you could collapse this into a smaller form. What they do is they collapse this into a form around the end of a tube called a catheter. A shrunken version of this stent, shrunken only in its diameter being reduced, is then put into your body. The catheter is a long narrow plastic tube that can be inserted into a distal artery like your femoral artery in your leg. Physicians know how to move this catheter up into your body and actually into the blood vessels of your heart. They put this tube up into your coronary artery. One of the manifestations of heart disease is that coronary arteries become sclerotic, they become narrowed because you get atherosclerotic plaques there. If the vessel becomes narrow then blood can't flow through very easily. That can lead to pain in your chest because your heart is not getting enough blood and can lead to a heart attack, or loss of blood flow to the heart and death of that tissue. When that process starts to happen, what if you put one of these catheters in? I didn't tell you that the catheter also has a balloon on the tip and the balloon is underneath this stent. So, once you've got it in place, you blow up the balloon, the stent becomes larger, it forces the blood vessel to become open. Then you deflate the balloon, and because this is made of metal it doesn't deflate when the balloon deflates. It stays there inside your blood vessel, holding the blood vessel open so now blood flow can continue. This is a very common medical therapy that's done as an alternative to heart bypass. We'll talk about heart bypass operations in a few weeks. Instead of having a new blood vessel put into your heart, which is a major operation, you can put this stent in, blow up the balloon, inflate the vessel, and the stent is left behind in order to keep the vessel open. Well you could imagine that this is not a normal circumstance. Your blood vessels were not designed to have a piece of metal inserted in them to hold them open. In fact, they respond to this. They respond in the way that your body responds to having foreign objects put into it, it tries to form a scar around it. Often that scar formation will occur so aggressively that scar tissue starts to fill in the vessel where--that you've opened, and this process is called restenosis. What these companies did was took these stents, which were known to be very effective, and physicians are very capable and able to put these into the body, into the coronary vascular system now readily. They coated the wires with a polymer and that's what's shown in this cartoon here. The yellow is a wire and this gray is a polymer like the polymers I've been describing, and why coat it with a polymer? Because now you can put drugs inside the polymer and the drugs will be slowly released from this polymer coating. This becomes not just a stent, but what they call in the industry a drug-eluting stent. It releases drugs that prevent scar formation locally. A patient that has heart disease gets one of these stents put in their vascular system, they open up the artery, and now that stent not only holds the artery open but it contains enough drug molecules that are released slowly over time that prevents this restenosis and the vessel stays open for, hopefully, the rest of their life. We're going to talk more about stents and mechanical objects like this that are used for medical therapy later. The important part here is the coating on the stent which releases drugs very slowly. It's really just an extension of what I showed you in the last couple of slides. These were released into the--approved by the FDA in 2002 or so, a few years ago, and became one of the biggest selling drug products ever in U.S. history, which tells you something about sort of the clinical need for things like this. Again, like that other system, one of the advantages is you're not delivering drugs over the whole body but only in the vessel where you need it, only in the vessel where the scar is going to form. You can deliver drugs locally, you can prevent side effects that would happen in other places. One more example, and in that example I just showed you, that you have a stent which is going to remain in the patient for a long period of time. There's a good reason to put the stent there, to hold this vessel open so that you can get good blood flow. In other situations you might want to introduce an implant but you don't want the implant to last forever. Because it's not a natural material, you might like the implant to go away. There are some polymers like this that can be made into devices like this implant here, which is again about the size of a coin. It's made of a very special polymer that's different than the kinds that are used in contact lenses, in that it slowly dissolves. If I implant this coin made of this kind of material into the body it will slowly dissolve. If I implant it into the skin and then I go back and I look several months later, the implant itself is totally disappeared. Of course you can't do this without any--with just any kind of material. It has to be a very special material that's both biocompatible, that your body doesn't respond to, and that dissolves down to molecules that are not toxic. It's not so easy to design these things, but there are some materials that are available now. What we did in this experiment was showed that you could load these polymers with chemotherapy drugs. These are just three different chemotherapy drugs. You could load them in such a way that if you put this material into water that chemotherapy drugs would be slowly released. That's what's shown here. This is with the drug BCNU, it's a drug that's commonly used to treat--or at least it was in the 1990s, commonly used to treat brain cancer. It's released over a period of seven days; 90% of the drug is released and then the last 10% comes out over a period of several months. If we look longer than that, all the drug is gone now and then the polymer itself starts to dissolve. By three months later, or four months later, the whole device has disappeared. It disappears in an orderly fashion. In fact, we engineered it to work just this way, such that most of the drug would be released rapidly over a period of a week, 10% of the drug would be released more slowly over a period of several months, and then the device itself would be completely gone in a period of six months or so. What would you use this for? Well, this was designed as a device that you would give to neurosurgeons so that they could improve therapy of brain tumors. You probably know that tumors of the brain are among the most difficult to treat. If you get a tumor in the central nervous system they have very poor prognosis or life expectancy. People that get aggressive brain tumors die within a very short time after it's diagnosed, unfortunately. That situation hasn't changed much over the last 100 years. One of the reasons is what we mentioned earlier, that the brain is protected from chemical entry by the blood brain barrier. Capillaries in your brain don't allow molecules to move across them. There's good reasons for that, so that your brain chemistry can remain constant throughout the day. Because of that blood brain barrier, if you give drugs the normal way by taking pills or injections, you get high doses everywhere else but not very much gets into the brain. We thought that when they do neurosurgery to remove a tumor, which is commonly done, the brain is exposed. The surgeon has an opportunity, then, to do something extraordinary. That is to, after the surgery, they remove the tumor then they could place these wafers inside the surgical resection cavity. Where the tumor used to be, you place these coins that are made of this degradable polymer that released these drugs very slowly. The patient leaves the operating room with most of their tumor gone, and in addition, these drug delivery systems which are releasing drugs slowly to kill any tumor cells that remain in the vicinity of the surgical site. This is a different strategy for drug delivery. It's a very specialized strategy for delivering drugs. It's one that takes advantage of the fact that you're having a medical procedure already. Can we design something that's going to make that procedure even more effective? This was approved by the FDA; it's now the standard of care for treating brain tumors at--most countries in the world. Chapter 4. Accessibility of New Drug Delivery Methods [00:38:48] How could you make this more--how could you make this kind of technology, or this kind of engineering, more accessible? Like here was an example, actually several examples, of very specialized applications of this different form of drug delivery. Well, one way you could do it is by shrinking these devices down, so that they're so small they could be introduced through a needle. Those wafers I showed you before could be used by surgeons because they--the tissue is exposed and you could implant things in. That's not the case for many other indications; surgery isn't done in every medical situation. If you could put a needle into the body and introduce these delivery systems through needles, then maybe that would make it better for other forms of disease. These are micro-particles, they're made of the same kinds of degradable polymers but they're very tiny particles now. In section this afternoon we'll talk about how you make these kinds of particles, and you'll actually be able to make some. These particular ones are made of the same kind of polymer that slowly degrades, but they're very small, they're a micron or so in diameter. They're much, much smaller than a needle and they can be injected through a needle. You just imagine suspending these particles which look like dust in water, and then injecting them through a needle. They also have the property that you can put drugs in them at fairly high concentration and the drugs are released slowly over time. If I put a needle into a tissue and introduce these particles, the particles will sit there at the tissue site and they'll release the drug molecules for a long period time just like the implants do. Just to show that this works and how tiny you might be able to make the particles and how locally you might be able to deliver them, we made some particles like this and we injected them into the eye of an animal that had retinal disease. The animal had a disease of the retina such that would cause blindness. Ordinarily there are many drugs that are known to prevent this kind of blindness, but they have short half-lives. If I inject the drug directly into the eye it disappears within a day. So, here's a drug that works, here's a condition that it works in. It's a condition that causes a very serious medical problem, blindness but in order to use the drug you have to get an injection in the eye everyday. That's the only way to get concentrations high enough for it to be effective. If you put it into the particles that I showed you before, you put the same drug into the particles, you inject the particles into the eye, the particles stay there in the eye. They stay there for a long time, and drug concentration now lasts for 30 days instead of one day. This takes what would be an unthinkable therapy, difficult to think even if blind--if you want to avoid blindness, difficult to think about getting an injection in your eye once a day for the rest of the time you want to remain eyesight, but you might think about it once a month if it meant the difference between being able to see and not being able to see. If we could make the particles better, such that they worked for three months, that makes it even more possible. If they work for a year--then once a year, and you can see that's a therapy that would be acceptable to most people. It's an example of an approach but it also shows the constraints of the approach. So far we can do a month; we'd like to be able to do longer. As we do longer this will become a more--a therapy that's more likely to be adopted into clinical practice. You can imagine that making it longer requires better engineering of these particles. It's hard to make particles that are really small but hold onto drugs for a long time. That's a hard thing to make particles that are really small but hold onto drugs for a long time. What we've gotten good at so far is making particles that are really, really small. These are the--these are sort of the state-of-the-art. These are particles that are made of a degradable polymer. They're only 150 nanometers in size, so now much smaller than a micron even; these are the size of a virus. We were talking about smallpox virus before, a naturally occurring pathogen. These are synthetic polymers made totally in the laboratory that are the same size as a virus and they're made of a polymer that's well known to be safe and they also contain drug. These particular particles were made by a graduate student who worked with named Amarilys Sanchez, and Amarilys was able to put 20% by weight of a chemotherapy drug inside these very tiny particles, particles the size of a virus. Even though the particles are very tiny the drug comes out relatively slowly over a period of about a week. Now, why make particles so small? Well, it turns out that these particles are so small that they can actually enter cells. Like viruses they can infect cells, only they don't infect in the same way that a virus does because they're totally synthetic. They don't reproduce, they just sit inside the cells and they release chemotherapy drugs, in this case. Well, that's--makes possible a totally different strategy for treating cancer. One of the problems with treating cancer is that cancer drugs have to get deep inside the cell in order to work. Most of them work by inhibiting cell division and most of the targets for inhibiting cell division are not just within cells, they're within the nucleus inside the cell. The approach for chemotherapy is to deliver these toxic drugs all over the body and hope that they get into tumor cells. Hope that they get into tumor cells at high enough concentrations that they can reach these targets deep in the nucleus. What is possible, we think, with this approach is that you can design not just long release of drugs, but you can design particles that will specifically recognize tumor cells in the same way that viruses recognize tumor cells or specific cells that will enter only certain cells, and that they'll release their drugs only when they've entered the correct cell. That would be potentially a much safer, more effective form of chemotherapy. I've taken, in this lecture, and covered a lot of material, but the important things I hope are to--which I've emphasized, I hoped, are to think about ordinary forms or common forms of drug administration like pills and injections, and understand a little bit about how those forms of administration lead to concentration changes within the body as a function of time, and how those forms are limited in some ways. Now, even with those limitations, obviously medical therapy has advanced tremendously because of the availability of drugs. Antibiotics have changed our lifespan. People don't die of infectious diseases because of vaccines and because there are antibiotics that you can take, sometimes orally. We all have taken them. You've taken antibiotics and you got better, so drug therapy has been an incredible advance. The second part I want you to think about is how sort of engineering of materials, in the case I've described here, could allow you to think about making systems for drug delivery that are even better. That can take existing drugs and expose them to the body in different ways such they're safer and more effective at treating certain kinds of diseases. We'll meet at section this afternoon; any questions? Great, see you this afternoon. [end of transcript] Back to Top	mp3

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Frontiers of Biomedical Engineering

BENG 100 - Lecture 12 - Biomolecular Engineering: General Concepts (cont.)

Chapter 1. Model for Injected Drug Delivery [00:00:00]

Professor Mark Saltzman: Welcome, so we're going to continue today talking about drug delivery. I want to pick up where I started last time, where at the end of the class I was trying to convince you that one way to think about drug delivery was to take what we know is a complex system, the human body, and represent in a simple way. This is a common approach to engineering, where you take a system that might be a complex system and you say, 'How could I represent it in the most simple way?' Then you ask the question, 'What comes out that simple description and does it fit experimental evidence, does it match what we know about how things work?'

This simplification was to take the human body and represent it as a simple stirred vessel of water and to ask the question, 'If we introduce drugs into the body do they behave in the same was as if I introduced drugs into this well-stirred vessel full of water, are there things that match about it?' We made the vessel a little bit more complicated than a simple tank full of water in that we allow its volume to be variable. This is going to account for the fact that when we introduce drugs into the body, some of them are going to go to different compartments within the body. Some will remain confined to the blood plasma space, for example, while some will be distributed more widely. So, we'll adjust the volume of the vessel to match the drug some way and how it's distributed. And we'll assume that it's a magical vessel in another sense, and that drugs disappear and they disappear in a very orderly fashion. That is they--the rate of disappearance of the drugs is equal to some constant times the concentration. It's a first-order rate of elimination from this compartment.

If we do that, I wrote on the board today the equations that are in the box at the end of the chapter, in Chapter 14. Just to review them very quickly, that if we have a system like this we know that mass has to be conserved. One way to write down the conservation of mass equation is like this. The amount that comes in minus the amount that goes out, plus any molecules that are generated inside, minus any molecules that are consumed inside the system has to be equal to accumulation.

IN--OUT + GEN--CONS = ACC

Accumulation is just the rate of change of concentration. If molecules are accumulating inside the vessel that means their concentration is either going up or down, and so accumulation is the rate of change with time of the total number of molecules inside the vessel: -kM = dM/dt.

If we went through this analysis for the system that I drew up here, and the particular circumstance, that I'm going to inject drugs into the body or into this vessel at time t = 0. After time t = 0, no molecules are going to be introduced. This is when I'm just giving all the drug at once at the beginning, so I'm simulating an intravenous injection. There's nothing coming in and there's going out over the--in terms of drugs introduced over the time that I'm interested in. No molecules of drug are being generated inside the body but they are being consumed, they are disappearing in some way. They're disappearing by this first-order process where the rate of disappearance is equal to a constant times the number of molecules that are still available (-kM).

I could solve this equation, this differential equation--I've told you if you don't know about solving differential equations, don't worry. Another way to think about it is here's the solution, you could convince yourself that this solution does match this equation, 'If I take the derivative of this and plug it back in here do I get the right answer?' That's another way to think about or you could just trust me that it is the right solution to the equation. We also have to know one more thing, how many molecules of drug we introduced at the beginning, and we're going to call that number M0 and so the final result isM = M0*e-kt. The amount of drug that I have within the body at any time is equal to the amount I had at time 0, times e-kt, where k is this rate constant. So, if I knew what the rate constant was, I knew how long after the injection, I knew how many molecules I'd injected at the beginning, I could calculate how many I have at any time.

Another way to write this is to write not in terms of the total number of molecules in the body but in terms of the concentration. To get concentration, I just divide both sides by the volume. So, concentration in the body's function of time is equal to this expression. I've plotted that for you last time and that plot's shown here. If I looked on a simple plot of concentration versus time, concentration starts at a maximum and it drops, and it drops exponentially over time. Turns out this very simple model matches very well the way many drugs behave if you inject them into the body. If you inject them intravenously, in this case, in that the concentration immediately after the injection will be the highest and concentration will drop over time. For many drugs the way that they're eliminated from the body does result in first-order elimination like this, so you see this pattern.

Now, another useful parameter to describe here is that--is what's called the half-life. How long do drugs remain in the body, what's the time course of that. The half-life is defined as the time that it takes for drug concentration to drop from one value to half of that value. It might drop from C = C0 down to ½C0, it might drop from ½C0 down to a ¼C0, from a 1/4 to an 1/8th. It doesn't matter where you start at, for processes where you have first-order elimination the time to get rid of half of the drugs that are remaining is always the same. That's a characteristic of first-order processes. That half-life is just equal to ln(2/k). What this plot over here shows you is how rapidly would drugs disappear for drugs that had different half-lives or different rates of elimination? It's plotted on a semi-log plot so this is the natural--this is the log10 actually of drug concentration in the body as a function of time. Here's a drug that has a half-life of 600 minutes; long half-life means it stays in the body for a long time you clear it--you get rid of it very slowly. A shorter half-life you get rid of more quickly; a very short half-life you get rid of very quickly.

What's the result of that? That for drugs with a short half-life, drugs that the body gets rid of more rapidly, if the desired effect isn't achieved with one dose I have to give another dose. I'd have to give another dose if the drug had a half-life of six minutes, I'd have to give another dose when the drug concentration dropped down to a very low level if I want to maintain a high concentration. Knowing the half-life is really important and when you--we'll see in a minute here how this same factor is important for drugs, not just that are intravenously injected but for drugs that are taken by pills as well. This is something that if you're making a drug, or you're making it to sell, you need to know about because you need to tell people how frequently they can take the drug. That depends on how quickly your body gets rid of it. That'll be more clear in just a moment, I hope.

Chapter 2. Model for Oral Drug Delivery [00:08:42]

That's the simplest, possible model, and it matches very well the behavior of many drugs when they're injected intravenously. How could I extend this to talk about--to think about other situations as well? Well, what's different if I don't directly inject the molecules into the body but I take them by a pill? That means if this is most of your body, now when I take a pill I'm not introducing the drugs all at once, but I'm putting them into my intestinal system and they're being slowly absorbed into the body.

One way to describe that is to add another compartment to the model. To add another compartment to this simple model and say, here is a dose, but it's a dose in form of a pill. The patient's going to swallow it and then that drug will be available in a particular sub-compartment of the body. Now, it's going to be in the intestine and it will be absorbed from the intestine into the bulk of the body, into the circulatory system where it can distribute. Now, I'm not going to write down the equations for this but you could do that, and you could solve this equation. What you would find is this curve here which matches your intuition, probably. That what happens if I swallow a pill and that pill dissolves in my intestinal tract and then molecules get absorbed slowly into the body, is that right after I take the pill the concentration hasn't changed inside my blood yet, inside the bulk of my body.

The molecules are still outside your body, they're still in your intestinal tract. They slowly get absorbed and as they absorbed concentration rises, you can see concentration rising here. Now, what happens to those molecules that are circulating in your body? Well, the same thing happens to them as what would happen to them if they were injected, is that your body's trying to get rid of them. At this point here, the rate at which they're being absorbed is much faster than the rate that your body is getting rid of them, and so the concentration is rising. It eventually reaches a peak, most of the drug has now been absorbed and concentrations start to fall. What's happening during this phase is that most of the drug has now been absorbed so the rate at which you're getting--it's coming into your body from the pill that's dissolving and the molecules being absorbed through the intestinal tract is being--that rate is less than the rate at which your body is getting rid of it, and so the concentration starts to drop.

If you took Acetaminophen or if you took Ibuprofen, which is Advil or Motrin, what's happening in your body is that over some period of time, usually ten minutes to half an hour, the molecules are being absorbed from your intestine; the concentration in your blood is starting to rise. If you took a pill and then you measured concentrations in your blood, you'd see those concentrations start to rise. They reach a peak, say half an hour after you take it, and hopefully whatever aches or pains, or whatever the reason you're taking the medication for, you start to feel an effect of it after some of period of time and then concentrations start to fall.

Now, eventually they'll fall to such a low level that the drug doesn't have its desired effect anymore. In the event that your pain hasn't gone away you'll take another dose, in which case the same events will repeat; drug will be absorbed, concentration will go up and then it'll start to fall again. What you would see on repeated doses, here I show the effect of getting one dose at time 0, giving another dose at 120 minutes, giving a third dose at 240 minutes, so this would be taking a drug--taking pills every two hours. Each one of the pills you take yields the same behavior. The total concentration in your blood is just the sum of each of those--the effect of each those doses. Each of those doses would have produced what are the dotted lines here; the total effect that you would see is this purple line.

Let's say this drug is effective when the concentration is 0.1. Well, that means after 20 minutes or so, after the first dose, I get a level that's above 0.1 and I start to feel some relief from the symptoms. Concentrations peak, I'm feeling good, they start to drop. I know because I read the bottle, it said take a dose every two hours. I take another dose at two hours, the concentration rises again. So, by repeating these doses every two hours I maintain the concentration over 0.1 and I have an effect from the drug that lasts a long time. What if at 0.3, what if at a concentration of 0.3 you begin to see side effects? What if at a concentration 0.3 you begin to see side effects? Well, no problem after the first dose, after the second dose I've slipped into the range where I might start to see side effects. After the third dose I'm clearly up into the range where side effects might happen. So your--there's some danger as you repeat doses that because drug is accumulating that you could slip into a range where you start to see side effects.

Now, the reason why you can--I mentioned this last time but it should be more clear now when you look at this picture, the reason why you can take some drugs like Ibuprofen or aspirin, or drugs that you typically buy over the counter without a doctor's prescription, and therefore without a doctor's guidance on taking them. The reason why you can buy those and use them yourself is because toxic levels don't occur until high on this chart; side effects don't occur until high on this chart. You can safely take it and without much risk that side effects are going to occur. For many drugs, however, the side effects occur at lower concentrations. Concentrations that are closer to the dose you need in order to have a useful response. Those are ones that you have to be more careful with; those are ones that physicians don't want to prescribe unless they're seeing you frequently enough that they can monitor how well you're doing with the drug. This should give you some idea about why that happens.

Chapter 3. Drug as Implant: Potentials and Limits [00:16:09]

People have been thinking for a long time, we've talked about why different modes of administration. Oral administration is the preferred mode for almost all kinds of drugs because it can be self-administered, it's very convenient and people don't mind taking drugs that way. But there are problems with it, for example, this problem of how do you maintain constant levels within this safe range over long periods of time. This just shows that same plot again, with the levels rising and falling, with the minimum effective and the maximum tolerated concentrations shown explicitly here. What's shown by the blue line is sort of what you might prefer, some kind of a drug delivery system that gives you long lasting concentrations but concentrations that don't rise and fall in the way that they do when you're taking individual doses repeatedly.

Now, could you do this with an oral--with a pill? Could you achieve this sort of long lasting constant concentration with a pill? Well, you could in some rare circumstances, right? Think about--how would that happen? Well, maybe a drug has a very long half-life. If you could design a drug that had a very, very long half-life you could maintain concentrations for a long time. Nate do you have a question?

Student: Aren't there now these time release capsules?

Professor Mark Saltzman: Yes, so let me get to that in just a minute, but that's a really good point. An alternate to that would be what if I had a drug that had a long half-life, well that would naturally have this kind of a pattern. Instead of that, what if I design a pill that releases it slowly? Thinking back a couple slides ago what if I designed a pill that was absorbed very slowly from the intestine? If I make it absorb so slowly that drug is continually coming into your body over a long period of time. The peak in this diagram occurs after only 30 minutes or so. What if I designed a pill such that the drug was absorbed over five hours? Then I could extend this period here and I could have drug concentrations that remain long a long time, this would be five hours instead of 60 minutes down here where the peak occurs. What's the limit of that? Why is there a limit on how far you can go with that approach? Justin?

Student: There's only so much drug.

Professor Mark Saltzman: There's only so much drug, so it might be that if you do that then your pill is getting larger and larger presumably. There's only so big a pill you could swallow, so that could be a problem. Most compounds fairly potent, if you had something that was potent you could still put several days worth into a pill that was of a reasonable size. That might not be the limitation for every drug but that's a really good point. What's another limitation? Yeah Ilya?

Student: Safety, I think that if put a [inaudible].

Professor Mark Saltzman: So that's a real--safety is a really good point. What I've been talking about here is how these things behave in an average person. What if you happen to absorb drug much more quickly than the average person? You've got several days worth of drug you're taking in one pill but it gets absorbed more quickly, you go into this toxic or side effect range, so safety is certainly an issue. One more, how often do you eat? Why? Why don't we only eat once a day?

Student: [inaudible]

Professor Mark Saltzman: Sorry?

Student: The breakdown of food [inaudible].

Professor Mark Saltzman: Because that's the rate at which you absorbed foot and that's the rate at which your intestinal system works. Things pass through at a certain rate. You can't really slow that down, you can't really--you can eat more and feel full for a period of time, feel satisfied but you can--you won't continue to be absorbing more drugs because whatever you take into your intestine passes through in a matter of hours. There is a transit rate through your intestinal system that is not very changeable. A pill that you take is only going to be there as long as it's still in your intestinal tract and there's a limit to how long it will last. It's not going to last forever. We know this from our experience with food and eliminating the waste products of food, that there's a time course there that can't be altered very much. There's a limit to how much you can do in terms of sustaining or prolonging release with an oral system so people have designed other methods.

As I mentioned, this is my research lab, this is my specialty so I'm going to talk about some things that we've designed to try to get around these barriers for certain kinds of drugs and certain situations. One way that you could get around it is by designing, not something that's taken orally, but by designing a delivery system that's implanted. Now, when you start thinking about 'this is not a pill but an implant', you're automatically limiting it to certain kinds of conditions. You wouldn't want to get an implant for a headache or something that you know is going to go away. You're talking about serious medical problems that are ongoing. This might be for something like treating diabetes where you need to take drugs everyday, multiple times a day. It might be for treating something like cancer where a course of chemotherapy could last for several weeks or several months. It might be for treating long term disorders like hemophilia where you're deficient in factor 8, a protein in the blood and you need to have injections of factor 8 continuously. So, it's only for certain kinds of things but you could imagine that there are those kinds of medical problems that you could treat.

Well, here's one way to achieve long release of drug into the body from an implant. To make implants out of biocompatible materials like polymers. What's shown on the bottom of this slide here is an implant that's made of a gray substance, which is a polymer, a biocompatible polymer. Imagine it's something like the contact lenses that you would put in contact with your eye. These are materials that are synthetic materials but they're--your body doesn't respond to them as foreign objects very strongly. You can put some polymers in contact with one of the most sensitive areas of your body, your eye, and it can remain there for a long period of time without very much response of your body to the material.

Well, what if you took that material embedded within it drug molecules? That's what's shown here. In fact, it's not just molecules of drug, its solid particles of drug which are shown as the orange dots here, so that this whole thing is maybe the size of a coin, maybe the size of a dime. What I'm showing you here is a cross-section of that dime, dime laying flat, I cut it like this, you're looking at it from the side. It's a millimeter or so in depth; several millimeters in diameter. It's a solid polymer, but inside of it are particles of the drug that you want to deliver. What these graphs show are experiments that we did - this was back in the late 1980s, where we put drug molecules into these polymers and then just dropped them into a test tube and ask the question, 'Could we release drugs slowly from these implants so we could make a long lasting pill essentially, make a long lasting implant that slowly released drugs?'

This shows for a drug that is used to treat Parkinson's disease, another sort of chronic indication, where patients have to take drugs everyday for the rest of their life. This shows that when you drop these implants into a test tube full of water, the Dopamine is released and it's released for a fairly long period of time. This is days here, so this point here is 30 days, about a month. One of these systems released a drug for a period of a month. One released for almost three months here, a sort of continuous and reliable source of drug, so you can make implants that release drug molecules over long periods of time.

The rest of these curves just show you that you could do this with drugs like Dopamine that are small in molecular weight and water soluble. You could do it with proteins, which are higher in molecular weight, and also water soluble. You could even do it with gene therapy vectors, with plasmids we talked about several weeks ago. Plasmid DNA, these are big molecules; very difficult to administer. We talked about how hard it is to get plasmid DNA inside of cells, but you can put them into these polymers and they'll slowly be released from the polymer over a long period of time. So, one could potentially make a long lasting gene therapy deliver system.

One of the advantages of making these materials out of polymers is that we now know how to--you can make all kinds of things out of polymers. That's one of the nice features of plastics or polymers, is that you can mold them and shape them into all sorts of kinds of devices. Here, this is that same kind of material, but instead of making a coin out of it, we coated it onto the surface of a wire. This is a bare wire, and it's the kind of wire that you can put into the brain and you can measure recordings of what's happening in the brain extracellular space. You can measure action potentials and electrical activity in the brain by putting electrodes in. Physicians do this all the time to measure activity in the brain in patients that have epilepsy, for example.

One of the problems with these materials is that when you put them into the brain they're not completely biocompatible. The brain does respond to them. It will form a scar around them and eventually the electrode won't work anymore. We coated these electrodes with a polymer that contained drug. In this case it's a drug, dexamethasone. It's a steroid that prevents scar formation locally. So, you make a wire that's able to record, but it's also able to deliver a drug. Now, when this is placed in the brain you not only can make the recordings, but the drug is slowly being released and it prevents scar formation around the outside of the electrode, and the electrode will function for a longer period of time inside the patient.

This is an example of taking a medical device, the kind of devices we've been talking about, and will continue to talk about, and making it safer and better by adding drug delivery. The other advantage to this is that I didn't have to deliver steroids all over the body in order to accomplish this effect. We put the steroids right on the device and they act locally when they're needed. You don't have steroids delivered all over the body but only at the site where you're doing the intervention. Well, this has become a very big business in--around the world, and that's because several companies took this kind of technology that had been developed and used it in a very clinically important application.

What this shows you here is a stent, it's made of a metal. This is one kind of it, there are many sort of versions of this. Imagine this is a stent that's expanded over this tube that's inside. You can imagine this design here which looks like a--kind of chicken wire fence could be collapsed because the wires are--would bend and you could collapse this into a smaller form. What they do is they collapse this into a form around the end of a tube called a catheter. A shrunken version of this stent, shrunken only in its diameter being reduced, is then put into your body. The catheter is a long narrow plastic tube that can be inserted into a distal artery like your femoral artery in your leg. Physicians know how to move this catheter up into your body and actually into the blood vessels of your heart. They put this tube up into your coronary artery.

One of the manifestations of heart disease is that coronary arteries become sclerotic, they become narrowed because you get atherosclerotic plaques there. If the vessel becomes narrow then blood can't flow through very easily. That can lead to pain in your chest because your heart is not getting enough blood and can lead to a heart attack, or loss of blood flow to the heart and death of that tissue. When that process starts to happen, what if you put one of these catheters in? I didn't tell you that the catheter also has a balloon on the tip and the balloon is underneath this stent. So, once you've got it in place, you blow up the balloon, the stent becomes larger, it forces the blood vessel to become open. Then you deflate the balloon, and because this is made of metal it doesn't deflate when the balloon deflates. It stays there inside your blood vessel, holding the blood vessel open so now blood flow can continue.

This is a very common medical therapy that's done as an alternative to heart bypass. We'll talk about heart bypass operations in a few weeks. Instead of having a new blood vessel put into your heart, which is a major operation, you can put this stent in, blow up the balloon, inflate the vessel, and the stent is left behind in order to keep the vessel open. Well you could imagine that this is not a normal circumstance. Your blood vessels were not designed to have a piece of metal inserted in them to hold them open. In fact, they respond to this. They respond in the way that your body responds to having foreign objects put into it, it tries to form a scar around it. Often that scar formation will occur so aggressively that scar tissue starts to fill in the vessel where--that you've opened, and this process is called restenosis.

What these companies did was took these stents, which were known to be very effective, and physicians are very capable and able to put these into the body, into the coronary vascular system now readily. They coated the wires with a polymer and that's what's shown in this cartoon here. The yellow is a wire and this gray is a polymer like the polymers I've been describing, and why coat it with a polymer? Because now you can put drugs inside the polymer and the drugs will be slowly released from this polymer coating. This becomes not just a stent, but what they call in the industry a drug-eluting stent. It releases drugs that prevent scar formation locally. A patient that has heart disease gets one of these stents put in their vascular system, they open up the artery, and now that stent not only holds the artery open but it contains enough drug molecules that are released slowly over time that prevents this restenosis and the vessel stays open for, hopefully, the rest of their life.

We're going to talk more about stents and mechanical objects like this that are used for medical therapy later. The important part here is the coating on the stent which releases drugs very slowly. It's really just an extension of what I showed you in the last couple of slides. These were released into the--approved by the FDA in 2002 or so, a few years ago, and became one of the biggest selling drug products ever in U.S. history, which tells you something about sort of the clinical need for things like this. Again, like that other system, one of the advantages is you're not delivering drugs over the whole body but only in the vessel where you need it, only in the vessel where the scar is going to form. You can deliver drugs locally, you can prevent side effects that would happen in other places.

One more example, and in that example I just showed you, that you have a stent which is going to remain in the patient for a long period of time. There's a good reason to put the stent there, to hold this vessel open so that you can get good blood flow. In other situations you might want to introduce an implant but you don't want the implant to last forever. Because it's not a natural material, you might like the implant to go away. There are some polymers like this that can be made into devices like this implant here, which is again about the size of a coin. It's made of a very special polymer that's different than the kinds that are used in contact lenses, in that it slowly dissolves. If I implant this coin made of this kind of material into the body it will slowly dissolve. If I implant it into the skin and then I go back and I look several months later, the implant itself is totally disappeared.

Of course you can't do this without any--with just any kind of material. It has to be a very special material that's both biocompatible, that your body doesn't respond to, and that dissolves down to molecules that are not toxic. It's not so easy to design these things, but there are some materials that are available now. What we did in this experiment was showed that you could load these polymers with chemotherapy drugs. These are just three different chemotherapy drugs. You could load them in such a way that if you put this material into water that chemotherapy drugs would be slowly released.

That's what's shown here. This is with the drug BCNU, it's a drug that's commonly used to treat--or at least it was in the 1990s, commonly used to treat brain cancer. It's released over a period of seven days; 90% of the drug is released and then the last 10% comes out over a period of several months. If we look longer than that, all the drug is gone now and then the polymer itself starts to dissolve. By three months later, or four months later, the whole device has disappeared. It disappears in an orderly fashion. In fact, we engineered it to work just this way, such that most of the drug would be released rapidly over a period of a week, 10% of the drug would be released more slowly over a period of several months, and then the device itself would be completely gone in a period of six months or so.

What would you use this for? Well, this was designed as a device that you would give to neurosurgeons so that they could improve therapy of brain tumors. You probably know that tumors of the brain are among the most difficult to treat. If you get a tumor in the central nervous system they have very poor prognosis or life expectancy. People that get aggressive brain tumors die within a very short time after it's diagnosed, unfortunately. That situation hasn't changed much over the last 100 years. One of the reasons is what we mentioned earlier, that the brain is protected from chemical entry by the blood brain barrier. Capillaries in your brain don't allow molecules to move across them. There's good reasons for that, so that your brain chemistry can remain constant throughout the day. Because of that blood brain barrier, if you give drugs the normal way by taking pills or injections, you get high doses everywhere else but not very much gets into the brain.

We thought that when they do neurosurgery to remove a tumor, which is commonly done, the brain is exposed. The surgeon has an opportunity, then, to do something extraordinary. That is to, after the surgery, they remove the tumor then they could place these wafers inside the surgical resection cavity. Where the tumor used to be, you place these coins that are made of this degradable polymer that released these drugs very slowly. The patient leaves the operating room with most of their tumor gone, and in addition, these drug delivery systems which are releasing drugs slowly to kill any tumor cells that remain in the vicinity of the surgical site. This is a different strategy for drug delivery. It's a very specialized strategy for delivering drugs. It's one that takes advantage of the fact that you're having a medical procedure already. Can we design something that's going to make that procedure even more effective? This was approved by the FDA; it's now the standard of care for treating brain tumors at--most countries in the world.

Chapter 4. Accessibility of New Drug Delivery Methods [00:38:48]

How could you make this more--how could you make this kind of technology, or this kind of engineering, more accessible? Like here was an example, actually several examples, of very specialized applications of this different form of drug delivery. Well, one way you could do it is by shrinking these devices down, so that they're so small they could be introduced through a needle. Those wafers I showed you before could be used by surgeons because they--the tissue is exposed and you could implant things in. That's not the case for many other indications; surgery isn't done in every medical situation. If you could put a needle into the body and introduce these delivery systems through needles, then maybe that would make it better for other forms of disease.

These are micro-particles, they're made of the same kinds of degradable polymers but they're very tiny particles now. In section this afternoon we'll talk about how you make these kinds of particles, and you'll actually be able to make some. These particular ones are made of the same kind of polymer that slowly degrades, but they're very small, they're a micron or so in diameter. They're much, much smaller than a needle and they can be injected through a needle. You just imagine suspending these particles which look like dust in water, and then injecting them through a needle. They also have the property that you can put drugs in them at fairly high concentration and the drugs are released slowly over time. If I put a needle into a tissue and introduce these particles, the particles will sit there at the tissue site and they'll release the drug molecules for a long period time just like the implants do.

Just to show that this works and how tiny you might be able to make the particles and how locally you might be able to deliver them, we made some particles like this and we injected them into the eye of an animal that had retinal disease. The animal had a disease of the retina such that would cause blindness. Ordinarily there are many drugs that are known to prevent this kind of blindness, but they have short half-lives. If I inject the drug directly into the eye it disappears within a day. So, here's a drug that works, here's a condition that it works in. It's a condition that causes a very serious medical problem, blindness but in order to use the drug you have to get an injection in the eye everyday. That's the only way to get concentrations high enough for it to be effective. If you put it into the particles that I showed you before, you put the same drug into the particles, you inject the particles into the eye, the particles stay there in the eye. They stay there for a long time, and drug concentration now lasts for 30 days instead of one day.

This takes what would be an unthinkable therapy, difficult to think even if blind--if you want to avoid blindness, difficult to think about getting an injection in your eye once a day for the rest of the time you want to remain eyesight, but you might think about it once a month if it meant the difference between being able to see and not being able to see. If we could make the particles better, such that they worked for three months, that makes it even more possible. If they work for a year--then once a year, and you can see that's a therapy that would be acceptable to most people. It's an example of an approach but it also shows the constraints of the approach. So far we can do a month; we'd like to be able to do longer. As we do longer this will become a more--a therapy that's more likely to be adopted into clinical practice.

You can imagine that making it longer requires better engineering of these particles. It's hard to make particles that are really small but hold onto drugs for a long time. That's a hard thing to make particles that are really small but hold onto drugs for a long time. What we've gotten good at so far is making particles that are really, really small. These are the--these are sort of the state-of-the-art. These are particles that are made of a degradable polymer. They're only 150 nanometers in size, so now much smaller than a micron even; these are the size of a virus.

We were talking about smallpox virus before, a naturally occurring pathogen. These are synthetic polymers made totally in the laboratory that are the same size as a virus and they're made of a polymer that's well known to be safe and they also contain drug. These particular particles were made by a graduate student who worked with named Amarilys Sanchez, and Amarilys was able to put 20% by weight of a chemotherapy drug inside these very tiny particles, particles the size of a virus. Even though the particles are very tiny the drug comes out relatively slowly over a period of about a week. Now, why make particles so small? Well, it turns out that these particles are so small that they can actually enter cells. Like viruses they can infect cells, only they don't infect in the same way that a virus does because they're totally synthetic. They don't reproduce, they just sit inside the cells and they release chemotherapy drugs, in this case.

Well, that's--makes possible a totally different strategy for treating cancer. One of the problems with treating cancer is that cancer drugs have to get deep inside the cell in order to work. Most of them work by inhibiting cell division and most of the targets for inhibiting cell division are not just within cells, they're within the nucleus inside the cell. The approach for chemotherapy is to deliver these toxic drugs all over the body and hope that they get into tumor cells. Hope that they get into tumor cells at high enough concentrations that they can reach these targets deep in the nucleus. What is possible, we think, with this approach is that you can design not just long release of drugs, but you can design particles that will specifically recognize tumor cells in the same way that viruses recognize tumor cells or specific cells that will enter only certain cells, and that they'll release their drugs only when they've entered the correct cell. That would be potentially a much safer, more effective form of chemotherapy.

I've taken, in this lecture, and covered a lot of material, but the important things I hope are to--which I've emphasized, I hoped, are to think about ordinary forms or common forms of drug administration like pills and injections, and understand a little bit about how those forms of administration lead to concentration changes within the body as a function of time, and how those forms are limited in some ways. Now, even with those limitations, obviously medical therapy has advanced tremendously because of the availability of drugs. Antibiotics have changed our lifespan. People don't die of infectious diseases because of vaccines and because there are antibiotics that you can take, sometimes orally. We all have taken them. You've taken antibiotics and you got better, so drug therapy has been an incredible advance.

The second part I want you to think about is how sort of engineering of materials, in the case I've described here, could allow you to think about making systems for drug delivery that are even better. That can take existing drugs and expose them to the body in different ways such they're safer and more effective at treating certain kinds of diseases. We'll meet at section this afternoon; any questions? Great, see you this afternoon.

[end of transcript]

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BENG 100: Frontiers of Biomedical Engineering