약물 전달 제어: 메커니즘 및 애플리케이션

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MIT 교수인 밥 랭거가 약물 전달 기술이 환자 순응도와 약물 방출 메커니즘 제어에 미치는 영향에 대해 설명합니다.

So, my name is Bob Langer. I'm a professor at MIT, and I'm going to be discussing, in this first lecture, to give you an overview of this area of controlled drug delivery technology, and in the second lecture... I've listed the lectures here... I'll be talking about some of our own work that lead to some of these drug delivery systems and also some future work in nanotechnology and other areas that I think will be exciting for the future of drug delivery. And, in the third and final lecture, I'll be talking about biomaterials and biotechnology, and I'll give an example, in particular, of how one can create new materials, and I also will discuss how one can combine materials with cells, which helped to lay the foundation of tissue engineering. So, I'll start out by just going over, as is mentioned here, this whole field of controlled release technology, and it's a field that actually now affects hundreds of millions of patients around the world.

and yet it's still a very new field. Maybe the easiest way to start is to just go over how people generally take drugs. Generally, you take a pill or you might take an injection, but whenever you take any of these drugs what happens is, as we can see in the slide... there are these blue lines which give you a desired range... if you're above that range the drug could be toxic, if you're below it's not effective. One example I sometimes just use is a sleeping pill. If somebody took too much they would die - that's obviously toxic. And, if you took too little then it doesn't work, you don't fall asleep. So, for any drug, you have this desired range, and what happens in a lot of cases is you get this what I'll call peak-and-valley delivery which you see here, meaning that when you first take the drug it starts out at a very low level, then it keeps going up, and then it goes down.

And so, you would have to take it again, and there are really two or three problems with this. One is the problem that I just mentioned, that you could get these toxic effects, or it may not work. The second effect, the big effect, is that people have what are called very poor compliance. People usually don't do what they're supposed to do, and they often don't take the drugs when they're supposed to, and that has led to hospitalizations and all kinds of other kinds of problems. So, what somebody would like to do is, when you look at those lines, is to have a pill or an injection or whatever that starts out low but then goes into the desired range. In a way, people have tried to do this for over 100 years. The earliest examples of these are what we called sustained release. Sustained release systems, and people have heard about these probably, are things like tiny time pills and things like that, so rather than what you might have seen in the last slide.

where you took, say, a pill maybe every four hours. Sustained release, probably it lasts for twelve hours, and it kind of blunts those peaks. But what happens is that you still... you still have to keep taking them, and also you really are not in the desired range. I mean, you're in the desired range maybe longer, but not long enough. So, the way these have been achieved, these sustained release systems, involves different types of chemistry and chemical engineering. Like you can have what's called a complex. For example, you want to slow the release down, and the way you might slow the release down is by adding a salt or even complexing it to what's called an ion-exchange resin. Another way of slowing it down is to put what are called slowly dissolving coatings around it. For example, there's something called an enteric coating, and if you have a pill with an enteric coating, the stomach, which often has a lot of acid.

will not dissolve that coating, so you won't get release until later. Wait until you go past the stomach and the acidity is neutralized. You can also do things like suspensions or emulsions, that decreases the availability of the drug to the body, and even something as simple as a compressed tablet slows release down because the drug won't dissolve as fast. Still, as we look at the bottom part of this slide, what sustained release systems release drugs generally for short periods of time, like hours, and they require repeated administration. Also, the release rates are very strongly influenced by your environmental conditions. For example, I mentioned, you know, release in the stomach. Well, your stomach pH is very dependent on when you ate your last meal, so there's a lot of variability when you take these kinds of systems. And, with that in mind, what's happened over the last 40 years is the advent of what we now call controlled release formulations. These are often polymers or pumps.

They can release the drug for really long periods of times, like not only days, but in some cases, as I'll go over, up to 5 years from a single tiny system. Also, the release rates are only weakly or not at all influenced by the environmental conditions, so you get a fixed predetermined release pattern for a definite period of time. This is just a graph that shows you an idealized case of that. So, rather than getting this kind of peak-and-valley delivery that I mentioned before, what you can get is the drug starts out in a low range, then it goes to the desired range, and it stays there for as long as you want. This is kind of the ideal case. One other thing that I wanted to mention, that's very exciting in this area of drug delivery, is not only the idea of controlling the duration of the drug and controlling its level, but actually in some cases targeting it right to where you want it to go.

and there's a lot of research going on in that area. It's still very early, but I'll mention some of this in my second talk. But what people are doing is they're looking at the little fatty particles called liposomes that you can direct to certain cell types. They're also looking at microspheres and microcarriers that you can decorate in certain ways to target them to specific places in the body. And finally, you can attach a drug to a carrier, which might be an antibody or a polymer, to hopefully, again, target it to where you want to go. So, all these are very exciting areas of how you can take drugs and make them do things they could never do before. I thought in this lecture what I want to do is go over the general mechanisms by which this takes place, and generally there's three mechanisms. Diffusion is the first one, and there are two geometries that people often use. What's called a reservoir, and I'll show you a picture of that in a minute.

and what's called matrix. The second mechanism involves a chemical reaction, and in the case of the chemical reaction, it might cause the polymer to erode, bioerode, which will enable the drug to come out, or you might have what we call a pendant chain system, where the drug is attached to a polymer, let's say, and something comes along and cleaves it off. The third mechanism is the solvent does something. The solvent might cause the polymer to swell, so the drug might be locked into place, but when it swells, now the drug comes out. Or, as I'll show you, there's some very clever ways using what's called osmosis to actually deliver drugs. Finally, and on top of all that, you can actually in some cases make even a smart delivery system, where you can activate it externally and make more drug come out at certain periods of time, and I'll go over that... a little bit of an example of that in my second lecture.

So, I'll just go over each of these three fundamental mechanisms. First, diffusion, and the most common way that people set up drug delivery by diffusion is what's shown here, a reservoir. A reservoir, and people have probably seen these, could be a capsule, could be a microcapsule, could be hollow fibers, or the drug could be placed in between two membranes, but basically what we see, and the little dots in this slide illustrate the drug. The blue illustrates the membrane, let's say, or the capsule, and this is just a cross-section. So, what you see is if you go from the left-hand one to the right-hand one is that the little dots... the left-hand one is the system at time 0, but what happens is over time, the dots keep coming out by diffusion. They diffuse through the polymer, and that will keep coming out over really long periods of time. There are a number of polymers that are very commonly

used to make these systems, like silicone rubber, EVA, which is ethylene-vinyl acetate copolymer, or different hydrogels. For polymer chemists, one good example would be poly(2-hydroxyethyl methacrylate), but just in general, hydrogels are materials that are used in soft contact lenses, and they're very biocompatible. These systems have a number of advantages. You can make them release at relatively constant rates, but one possible disadvantage is if you had a leak. Let's say there was a tear in the blue, the drug could dump out. So, what that might mean is if you had a potentially toxic drug like a cancer drug or insulin, you wouldn't probably use a reservoir system. But if you were delivering... let's say you were delivering human growth hormone, or things like that, this would probably be fine. The second system that's also diffusion-based is what we call a matrix system, and again the blue dots represent the drug.

and the yellow that you see there, the yellow-green, that's the outside of the polymer matrix. So, in the case of a non-erodible matrix, the drug is uniformly distributed through that matrix, and we see that on the top, but then when we go to the bottom, we see the drug diffusing out. And again, it diffuses out through the polymer, but now, because this geometry is different, other things happen. For example, this is not as easy to get steady release, but on the positive side, let's say there was a tear in this matrix... not much more drug would come out because it's embedded throughout this entire matrix. So, this is the first mechanism, is diffusion. The second mechanism, as I mentioned, is a chemical reaction, and one of the very common ways of doing this is a bioerodible system. So, in the case of a bioerodible system, it basically would look, in the beginning,

essentially identical to what I showed you on the matrix. But now the yellow, rather than staying the same. In other words, rather than the matrix staying the same size, it actually shrinks and ultimately completely dissolves. And as it dissolves, what we see is all those blue dots come out and are released. So, bioerosion provides a whole second mechanism of being released, and the big advantage of bioerosion, thinking about it from the patient's standpoint. If you had an implant and it didn't dissolve, you have to go in and take it out. That's gonna be done in some cases, as I'll mention later, but that's still a disadvantage. It certainly would be preferable for the patient to just have one injection or one implant and never have to worry about it again. So, one mechanism for chemical reaction is erosion. The second mechanism is the idea of the polymer containing a pendant chain, and now what happens is the drug is attached.

to the polymer backbone. But water or enzyme, as we see in the bottom, comes along and basically breaks the bond, and then the drug is released. One of the advantages of this is that you can add a lot of drug to these. But a possible disadvantage is that these are what are called new chemical entities. We've chemically modified the drug by attaching it, so it's a new chemical entity. So you'd have to do a lot more toxicology to eventually get approval. Whereas the earlier systems that I talked about, there is no change in the drug, it's just physically embedded. The third mechanism is the solvent does something. And so here we're looking at swelling having an effect, and the idea of swelling is, you again, if we look at the left-hand panel, the drug is dissolved in the polymer, and we see it just looking blue. But now, as we go to the right-hand panel, what happens is the water goes in, and the outer part of the matrix actually swells.

So, the drug was locked into place, but now since it's swelling, it can come out, and that takes place over time, and that gives you the opportunity to deliver the drug simply based on water. Also, one of the other things that people have sometimes done in the case of swelling systems is make them swell so much that they might stay in the stomach a little longer, and that might also give you a way, if you took an oral system, of maybe making it act longer as well. And the final mechanism for solvents, and of the ones I'm gonna talk about, is osmotic pressure. And the idea of osmosis is that what happens is, if you have... let's just say I had two sites, I have site 1 where I have water and a lot of salt in it, like table salt, and I have site 2 that just has water in it, and then they're connected by a membrane. There's a whole field called thermodynamics

where what happens is, if you have these two sites, and they're separated by the membrane, and water can permeate. What they wanna do is have what's called the same thermodynamic activity. So what happens is water will actually rush in from one to the other to actually dilute it, so you'll actually hopefully someday have the same salt concentration on both sides. But when that happens, that is what leads to osmotic pressure, because water is actually rushing in, and there's a certain amount of pressure that is caused by that. That same thing is manifested here in this final mechanism of osmosis, where the drug is dissolved in the polymer, but now water rushes in because the drug's not on the outside, and water wants to... the water wants to come in to dilute that drug, and you see these cracks form, these porous openings, and those permit release. Now, one of the issues with this particular system is it's not so reproducible. It's getting cracks...

it's not easy to make reproducible cracks, but I want to show you what I think is a very clever approach that has been done. Where you can actually make an osmotic pump, and what's interesting about this pump... I think when people generally think about pumps, you think about pumps that involve mechanical parts and electricity and things like that. The pump I'm gonna show you here has none of that. It's a totally-driven pump, and it can actually give you very, very precise release rates. So, when we look at this slide, let's take a look first at the top left. That's a front cross-section, and the way this has been designed is you've got an outer membrane that's rigid but it's water permeable. So, water can go through it and yet the system won't expand. Immediately below that, there's another chamber where you see the salt. That salt could be like sodium chloride or potassium chloride. That salt is, again, what's going to cause the osmotic pressure.

because there's not much salt on the outside, so water is going to want to rush in to that salt. And, actually you load the salt at a pretty high level so that it's always going to be above its solubility level, so water will actually rush in at a constant rate. Now, the next chamber, as we keep going to the inside, is a compressible membrane, but that compressible membrane is exactly the opposite of the rigid membrane on the outside. That compressible membrane is water impermeable, in other words water can't get through it, and yet it's compressible, it's not rigid. You might of it like a balloon. And, inside that chamber, you have the dissolved drug. So, the only other thing that I wanted to point out as we look at this top section is now if we looked at a side view, there's actually a laser-drilled hole in the very front of this system, and that is how the drug's gonna come out.

But let me just now go over how it works, and it's really going to be looking at the bottom part of this slide that shows you how that happens. So, what happens is, as I mentioned before, water is going to want to rush in at a constant rate through that rigid membrane. And what happens is, as water rushes in at a constant rate, the outer membrane doesn't expand, the whole system doesn't expand, but... so the only thing that can happen is the chamber where we have the salt. That does expand inward because that's the only place the water can go. So, water rushes in at a constant rate, diluting the salt, and it compresses that compressible membrane. It can't get inside that membrane, but it can compress it, and it gets smaller and smaller, and it's kind of almost like squishing a tube of toothpaste, and as you squish it, the only thing that can happen is the contents in the center, the solution.

go out that laser-drilled hole where you see the drug coming out at the bottom. So, you squish this by osmotic pressure at an exactly constant rate. The drug comes out at an exactly constant rate, and the patient gets steady delivery. So, what's novel about this is this is I think a very interesting example of where different chemical and physical principles are used to design a steady delivery system, and it's actually been widely used. These kinds of systems are used for delivery systems and studying different biological things in animals, and actually variations of it are pills that most people probably take. They may not realize it, but sometimes if you look down very carefully at the pill, you can see a little laser-drilled hole right where they have the label. So, what I've gone over so far are some of the different mechanisms by which these work. Now, I thought I'd turn and show you how they're actually used in different applications. Well, the eye was actually one of the earliest places

where people used controlled release. They used it in glaucoma, which is a leading cause of blindness, and in artificial tears, which is very uncomfortable. I’ll go over each of these. This was one of the earliest systems developed in controlled release. This was in the 70s, and it was called the Ocusert, and it's a little device that you just put into your eye. Which you see here, it's actually a reservoir system that lasts for one week. Normally, somebody, if they had this disease, would have had to take 28 eye drops. The way it's designed is shown here. It's a reservoir system, just like the very first thing that I went over on those three different types, so you have pilocarpine, that's the drug. It's surrounded by two membranes that really control the rate of diffusion, and what they've done, just so people can visualize it better, is they've put an annular ring right here.

that's got titanium dioxide in it, and that makes it easy for the patient to see. That's why when you looked at it on the last slide, it had this little ring around it on the bottom. So, depending on the thickness of those two membranes, that actually controls the rate of release. So, what's been done is to make one that releases at 40 µg/hour after an initial burst, and another that releases at 20 µg/hour after an initial burst. But really, again, by using engineering, you can make them release at any rate you want, just by controlling the thickness of those membranes. So, these are just two common ones that have been used. The next system I wanted to mention was artificial tears. If somebody had dry eye that can be very painful, and the goal is to put something in the eye that might last for a long time, rather than have somebody take eye drops, you know, really every 20 minutes sometimes. So, what's been done is to create an applicator.

shown here, which you can use to pick up a little polymer and then drop it in the eye, and basically, when you do, it might last for up to 18 hours and hold on to corneal moisture. It's not a perfect system by any means, because one of the things that happens sometimes for some patients is they get blurred vision, but it's an illustration of what you can do, and actually I think it's a challenge for the future to be able to do systems like this that will not have any change in visual acuity. Probably one of the biggest areas where this whole field of controlled release has been used worldwide is in contraceptive systems. There are a number of ways that people have done this: non-erodible subdermal implants, erodible ones, steroid-releasing intra-uterine devices, and vaginal rings. I'll go over them briefly. Probably the most widely-known system for contraception using controlled release is a system called the Norplant.

It's actually shown here. This is a woman's finger, and she has these six sticks. Now, actually, they've designed them so you can just have two of them, but they're very small. They're like matchstick-size. They can be placed underneath the skin, and they'll deliver the drug for 5 years. It's just slow diffusion through the polymer, through the reservoir system like I mentioned, and it'll last for 5 years. Here is an example of that, where we're looking at release curves for different patients, and it goes for 2000 days even though it's as small as what I showed you. Another system, also a reservoir system, is what's called the Progestasert, and this system... again, very small, it's an intra-uterine device. These again are a woman's fingers, and again, you put the drug in the center of the system, just like I showed earlier with the picture where the drug was the dots.

and then it will diffuse out. And here's an example of that. Where look at the core matrix. The dots here, again, represent the drug, and the drug will diffuse out over a 365-day period. This is just a curve. It's not exactly constant, but it basically will vary from over a 400-day period. It's pretty close to 50 µg/day over that period. So, this is a second way that people do it, and there are other controlled release systems as well that have been worked on for contraception. A third area that's been very important is dentistry, actually, that people use controlled release for. If one looks at the percentage of patients who have periodontal disease, it's maybe 25% of the population. To tell if you have periodontal disease, the way I always know is if I go to the dentist and, you know, they brush your teeth a lot harder than we do, or I do at least.

and if they start bleeding, then you probably have some periodontal disease. It's not pleasant. 2-3% of the people who have periodontal disease require surgery. If you have no treatment, the result is no teeth. That's not a very good outcome. If you do surgery, that's painful, it's expensive. There are drugs that people use, like tetracycline, but they make you incredibly sick to your stomach. So, what's been done is to actually make fibers with tetracycline or other drugs, and here you're delivering the drug locally. So, because you're delivering the drug locally, rather than throughout the whole body, the body doesn't get as much and so it's effective, but with much lower dosage, like in this case it's effective with less than 1/1000-th the dose, and the dentist can apply them very quickly, like 3 minutes per tooth. You can barely see them. I'll show you a picture.

They get rid of the problem, the spirochetes, and they don't cause irritation. I'll just show you a couple pictures. Here is a picture of the general idea of the hollow fiber in the bottom, just covering the tooth, and it will deliver the drug over time. And, let me just even go further and show you what was done. Originally, they used a reservoir system. This is a hollow fiber where the drug was placed in the center, but they got some leaks. So, then they went to the matrix system where they uniformly distribute it, and tetracycline is kind of a yellowish drug, so now it's in these fibers but they're uniformly distributed, and what the dentist did, and I'll just show you some pictures... here's a patient with periodontal disease, notice the red gums. Then, what the dentist does is he puts... she puts the matrix systems that are on the teeth like you see them here.

and so they are actually on several of the teeth, and that will release the drug, say, over a 10-day period, and when you're done with that, notice the difference in the gums. The problem has gone away. And there have been many different variations of these that people have used to help people with this problem. Another really powerful example of local delivery is the drug-eluting stent. If somebody has cardiovascular disease, one of the most common ways of treating cardiovascular disease today is to basically prop open the blood vessel with a system like this. This is a stent, and it basically looks like a Chinese finger puzzle. It props open the blood vessel, but unfortunately about 50% of the time when you do this you get a lot of cells, smooth muscle cells proliferating, and they'll block off the blood vessel itself, which isn't good, and in the worst case, somebody could die, but even short of that you'll have to go in and do another operation.

So, what's been done is to take some fairly toxic anti-cancer drugs like Taxol, coat them with a polymer on these stents, and these anti-cancer drugs are anti-proliferative. They prevent the smooth muscle cells from dividing the same way, and basically they keep the blood vessel open, and probably close to a million patients use this every year. Now, I'm gonna move a little bit from local delivery like the teeth and stent to systemic delivery, and again go over a couple of examples. One of the other I think really important areas for controlled release is a lot of times people have come up with new drugs like peptides and proteins in the last 20 or 30 years. One of those was what's called a luteinizing hormone-releasing hormone analog, and that has been shown to be very effective in treating certain diseases like prostate cancer, endometriosis, and other diseases. The problem was, since it's a peptide of 1200 molecular weight.

there was no good way to give it to the patient. If the patient tried to swallow it, it's destroyed in the stomach and the GI tract by enzymes. Also, it's too big to get absorbed. They also tried to give it through the nasal passages and other things but, again, none got into the body. So, they injected it, but the problem when you inject it is that enzymes destroyed it right away, so what's now done is to put it in little microspheres like one of those matrix systems, actually a bioerodible matrix system, and what happens is you can actually release it for many days. This is a graph of it, but now Lupron Depot, which has been used by many, many millions of patients... most of these last for about four months. So, you give a single injection every four months for the patient and it will deliver the drug. Another example that's widely used is for patients that have schizophrenia. If somebody has schizophrenia

there are also drugs like Risperdal, which are quite good for the patient. But a lot of times, people forget to take them. And so what's been done is to put them in another type of microsphere, bioerodible system like I was talking about. And they're injected every two weeks. Now, actually, they've come up with one that will be injected every four weeks, again using these kind of principles that I mentioned earlier. And that's had a huge effect on helping patients that have schizophrenia. It's decreased the amounts of hospitalizations. It's decreased suicides. And probably about five million patients have taken these. Another example, recently approved, is another molecule that may be useful in this case for type 2 diabetes. This is a glucagon-like peptide. And what happened was when it came out, it was effective in terms of improving blood sugar after food intake. But you had to give injections twice a day. Now it's put into one of these microspheres.

again, one of these bioerodible systems that I mentioned, and it's given once a week from a degradable system called PLGA, which is poly(lactic-glycolic acid). The last area that I wanted to talk about to illustrate some of these points are what are called transdermal systems. For many years, people would have never thought that you could deliver drugs through the skin because you'd think that that might be... you know, if things could get through the skin easily that might be very bad, like somebody could get infected. But what's been found out is that some molecules can actually get through the skin, and what's been done is to make, again, another reservoir system, diffusion-based system, shown here, and the way this is designed is you've got a backing membrane, a drug reservoir which is shown in the middle, a rate controlling membrane, and finally an adhesive. And you just put this reservoir system, diffusion-controlled reservoir,

on the skin, and it will release the drug, and these may last anywhere from a day to a week. The key issue in terms of getting drugs through the skin is pretty much all the resistance in terms of getting the drugs through the skin is the outermost skin layer. It's called the stratum corneum, and actually, if you looked at it under a microscope, it looks like a brick wall. There are dead cells called keratinocytes, and then there are lipid bilayers in between them, and that provides a very tight barrier that makes it very hard for things to get through, but if some molecule has just the right characteristics, like the right molecular size and the right, let's say lipophilicity, meaning how fat-soluble it is, actually it can get through. So, I though I'd make a few general comments about transdermal systems. The skin, as I mentioned, is generally impenetrable, and the principle resistance is the stratum corneum.

which is actually dead skin. But it has this tight sheath, as I mentioned, of keratinocytes and lipid bilayers. The permeability of a drug correlates with its water solubility, its molecular weight. You'd like it to be fairly small, and its oil/water partition coefficient, because if the drug is more what's called lipid-like, it's more likely to, you know, if you take the principle like-dissolves-like, it's more likely to be able to penetrate through the lipid bilayers that I showed you in the last slide. And finally, it's useful. Transdermal systems are useful for drugs that have a low dose requirement, the lower the better because of this permeability issue, and also for drugs that have high skin permeability. One of the big areas of transdermal research is the fact that you can enhance permeability by using certain compounds, chemical compounds, and just to give an example, when people have put estradiol in a patch.

for postmenopausal women, the flux is not very high. But what they found is that you can take ethanol and you can put it in it, and that will increase the flux by a factor of 20. And what that means for the patient is that they can go from having this giant patch to a much smaller patch, a factor of 20 smaller, and that makes it practical. Also, these transdermal systems are easy to apply and easy to remove. One of the biggest advantages is the fact that when you do something transdermally, rather than orally, you really tremendously reduce the first pass effect. For example, there's lots of drugs that, when you take them orally, they're destroyed by the liver, and that leads to low amounts in the blood and also variability. But transdermal systems can reduce that tremendously. One possible drawback, however, of a transdermal system is that it takes time to reach a steady state, like maybe 2-6 hours in some cases.

and what that means is that probably, if you had an acute problem like say sudden pain, an oral system would be better than a transdermal system. But if you have a chronic situation, transdermal is actually quite good. This slide simply shows the flux of different drugs and melting points, but in particular what I wanted to note is if you look at the drug on the top like say nitroglycerin, scopolamine, fentanyl... all of which are used clinically in transdermal systems, their fluxes are pretty high. But if you go down closer to the bottom and you look at estradiol, estradiol has a lower flux. So the only way to really get that to become a useful transdermal system is you have to have a permeation enhancer, and that would move estradiol up higher so it would be more like the scopolamine, fentanyl, and nitroglycerin fluxes. On the final slide,

I just wanted to expand that point a little bit further and go over methods of enhancement. This is a big area probably for the future, because most drugs... right now there's only about 20-25 drugs or drug combinations that are given transdermally, even though they're used by millions of patients. We'd like to expand the numbers of drugs that could be given this way, so one way of doing it that people are looking at is electric fields like by iontophoresis. Could you actually take an electric field and apply it to a drug so that the drug could go through the hair follicles or sweat ducts? And, this is experimental, but may some time be useful for delivering peptides, for example, in patches. Electroporation, that's a second method, and it also involves electricity, but it involves creating new pathways, new pores in the skin that are just temporarily there, and even though it's an early stage it's shown very, very large increases.

like 10^4 increases in permeation and is in clinical trials in some situations. The third are is ultrasound. Ultrasound... actually there has already been an ultrasound system approved by the FDA for delivering pain medications, and one of things the ultrasound does is it gets rid of any type of lag time, but also tremendously increases permeation of drugs, and people are exploring it for different types of large molecules. For all of these three, iontophoresis, electroporation, and ultrasound, one of big challenges is engineering and miniaturizing and making less expensive the units, so that you could make a small patch that the patient could conveniently wear. In addition to these methods, there are chemical methods like making a drug more lipophilic by making what's called a prodrug, that means attaching something lipophilic to the drug and, as I mentioned, penetration enhancers. So, drug delivery, in summary, is actually a very, very broad area. It involves a lot of chemical

and physical and biological principles. It's been very, very important for delivering all kinds of drug up until now, and I believe it will probably be even more important in the future as we come up with... and the world comes up with new drugs like siRNA, mRNA, DNA, gene editing, all kinds of approaches where really I think the delivery will end up being critical to getting these important molecules into the cells where you want them. Thank you very much.

Robert S. Langer (MIT) Part 1: Advances in Controlled Drug Release Technology: An Overview

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- 제어 약물 전달 기술은 원하는 범위 내에서 약물을 제공하여 효과와 환자 순응도를 개선하는 것을 목표로 합니다.

- 서방형 시스템과 같은 초기 방법에서는 약물 방출 속도를 늦추기 위해 다양한 화학 공학적 접근 방식을 사용했지만 여전히 반복 투여가 필요했습니다.

- 지난 40년 동안 폴리머와 펌프를 포함한 제어 방출 제형의 등장으로 보다 정확하고 일관된 약물 전달이 가능해져 자주 투여할 필요성이 줄어들었습니다.

약물 전달 시스템은 이제 환경 조건에 영향을 받지 않고 미리 정해진 패턴으로 최대 5년 동안 약물을 방출할 수 있습니다.

흥미롭게도 리포좀, 마이크로스피어 및 기타 운반체를 사용하여 신체의 특정 부위에 약물을 표적화하는 연구가 활발히 진행되고 있습니다.

약물 전달의 세 가지 기본 메커니즘은 확산, 화학 반응 및 용매 효과로, 각각 약물 방출을 제어하는 고유한 방법을 제공합니다.

일반적인 확산 기반 약물 전달 시스템에는 일정한 속도로 약물을 방출할 수 있는 저장고와 장기 약물 방출에 대한 다른 접근 방식을 제공하는 매트릭스 시스템이 있습니다.

고분자 매트릭스에서 약물 방출의 메커니즘

고분자 매트릭스는 확산, 화학 반응(생체 침식), 용매 팽창을 통해 약물을 방출할 수 있습니다.

생체 침식은 매트릭스가 용해되어 약물을 방출하여 환자 친화적인 솔루션을 제공합니다.

화학 반응은 또한 약물과 폴리머 사이의 결합을 끊어 약물을 방출할 수 있습니다.

용매 팽창은 매트릭스를 팽창시켜 물 섭취량에 따라 약물이 방출되도록 할 수 있으며 삼투압은 약물 방출을 위한 다공성 구멍을 만들 수 있지만 이 방법은 재현성이 떨어질 수 있습니다.

정밀한 약물 전달을 위한 삼투 펌프에 대한 독특한 접근 방식

삼투 펌프는 완전 구동식 시스템을 사용하여 개발되어 매우 정밀한 방출 속도를 구현할 수 있습니다.

펌프 설계에는 삼투압을 생성하는 소금이 들어 있는 챔버, 약물을 위한 압축성 및 불투수성 멤브레인, 약물이 방출되는 레이저 드릴 구멍이 포함됩니다.

이 혁신적인 펌프 디자인은 약물 전달 시스템에 널리 사용되어 왔으며, 녹내장 치료 및 눈의 인공 눈물에 일찍이 적용되었습니다.

이산화티타늄은 약물 방출 시스템을 가시화하기 위해 사용되며 방출 속도를 조절할 수 있습니다.

제어 방출 시스템은 건조한 눈에 오래 지속되는 수분을 공급하기 위해 인공 눈물을 위해 개발되었습니다.

이러한 시스템은 장기 약물 전달을 위한 노플랜트와 같은 피임 방법에도 널리 사용되었습니다.

또한, 제어 방출 시스템은 치주 질환 치료를 위한 국소 약물 전달을 위해 치과에 적용되어 기존 방법보다 더 효과적이고 효율적인 대안을 제공합니다.

중공 섬유 시스템은 치주 질환 치료 시 국소 약물 전달에 사용되며, 시간이 지남에 따라 약물이 방출되어 잇몸 상태를 개선합니다.

항암제로 코팅된 약물 용출 스텐트는 일반적으로 심혈관 질환 환자의 평활근 세포 증식을 방지하고 혈관을 열어두는 데 사용됩니다.

생분해성 마이크로스피어와 같은 제어 방출 시스템도 약물의 전신 전달에 활용되어 정신분열증이나 제2형 당뇨병과 같은 질환을 앓고 있는 환자에게 오래 지속되는 효과를 제공합니다.

약물 전달에서 경피 시스템의 역할

경피 시스템은 저장소 및 확산 기반 시스템을 사용하여 피부를 통해 약물을 전달하며, 하루에서 일주일까지 지속됩니다.

약물의 투과성은 수용성, 분자량, 유/수분 분할 계수 등의 특성에 의해 영향을 받습니다.

이러한 시스템은 용량이 적고 피부 투과성이 높은 약물에 유용하며, 안정 상태에 도달하는 데 시간이 걸릴 수 있지만 첫 번째 통과 효과를 줄일 수 있는 이점이 있습니다.

경피 약물 전달은 만성 질환에 더 효과적이기 때문에 낮은 플럭스를 가진 약물에 대한 투과 강화제가 필요합니다.

미래의 약물 전달 시스템에는 투과율을 높이기 위해 전기장, 전기 천공 및 초음파가 포함될 수 있지만, 환자가 편리하게 사용할 수 있도록 장치를 소형화하는 것이 주요 과제입니다.

또한 전구체 및 침투 강화제와 같은 화학적 방법은 약물 전달에 중요한 역할을 하며, 이는 siRNA, mRNA 및 유전자 편집 분자와 같은 새로운 약물을 포함한 다양한 약물의 효과에 필수적입니다.