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Celanese so Christian works on new business development with the focus on the EVA and LDPA material product lines.
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At Celanese, he's responsible for customer focus development in medical and pharmaceutical applications in EMEA.
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Chris has over 12 years of experience in research and product development of polymers and polymer polaroids.
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Kim's functional expertise includes research, product and application development, analytical method development and customer tech support.
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So it's my pleasure to introduce him and he's going to be delivering the talk on innovating parenteral sustained release of peptides, antibodies and RNA.
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Thank you.
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Thank you.
0:36
First of all, welcome to FMD from My Side.
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Hope you have a great show.
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Good to see you all here.
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Thanks for joining us session and panel.
0:45
Thanks for the nice introduction.
0:46
So this talk is about our platform by the dose EVA for long acting parenteral delivery.
0:51
This is really the theme of the presentation.
0:54
So before I go into any details about EVA that will come of the next slides, let me spend some time on outlining the value propositions of long acting those forms in general a little bit.
1:05
Again, long acting dose forms really are not nothing new.
1:09
They are around since many almost decades actually, not only on EVA, but also another like degradable excipients.
1:16
EVA was there right from the start since 2030 years.
1:19
So it's very established.
1:21
So what do long acting dose forms of in terms of value?
1:24
I think the clear value is that production in treatment burden, right?
1:28
They have the opportunity to basically substitute daily pills or daily injections to a dose form that you place once and then doses the drug for like weeks, months or even years and years of commercially established products.
1:42
They can do this.
1:43
So this is all nothing new.
1:44
This is very established.
1:46
Also with a reduction treatment burden also comes an increase of patient comfort.
1:52
Obviously nobody likes to get no get frequent injections daily.
1:56
And also of course in many products, which is very important, for example for addiction therapies, it also increases patient compliance.
2:04
These are the clear value props for long acting.
2:07
There are new kind of strategies to utilise from acting dose forms.
2:11
And this is for example by utilising them to crossing physical barriers like enabling targeted localised delivery, for example in oncology or also in pain, also seen as to the brain, for example, but crossing the blood brain barrier basically.
2:27
But it also offers the possibility, for example, to effectively or artificially, for example, increase the half-life of drugs, for example, peptide drugs, which very often have short half lives in the body.
2:39
You can actually formulating them into long acting dose forms.
2:42
And so again, get rid of a lot of frequent injections and efficiently and effectively extend the half-lives of these drugs.
2:50
So it's coming to EVA.
2:52
As I said, it was very established in long acting since many decades.
2:56
It had multiple routes of administration are available of products that are using EVA.
3:02
They're all inactive ingredients database.
3:05
There are ocular products, there're subcutaneous products, implants, for example, intravaginal rings.
3:09
There's also transdermal patches available.
3:12
There also has been an IoD, for example, gotten to market in the US many years ago.
3:17
Right now people looking at long acting also combining them with other, you know, drug dosings for combination therapies and also what we found very exciting, what is actually the theme of this talk is that EVA is a great platform to enable delivery of biologic molecules, peptides, proteins and also RNA.
3:38
We believe and lots of data out there which we basically show.
3:43
So the I think the patient centric value prop for acting I think established this just right now.
3:49
So for EVA, what can we achieve in terms of release time scales?
3:54
There are products out there that release for weeks, like almost a month.
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There are products out there that release for months, six months for example.
4:01
There are products out there that release for multiple years, like 3 years for example.
4:06
And that particular product is now I guess taken by the company to a five year product.
4:13
So this is really spending a very broad range of time scales that is possible with EVA.
4:19
Again, EVA is a very long use history.
4:21
So it's known new materials, very well known to the regulators all over the world, especially in Europe and the US And we provide pharmaceutical grade EVA and including of obviously also with a drug master file to for our EVAs. The therapeutic areas where the long actings are used that we are seeing historically there's a lot of activity on ophthalmic, in Women's Health and CNS.
4:47
But right now also big topic is utilising long acting in oncology and they come to this also later on.
4:55
Again, what I think already mentioned is that EVA is very compatible to wide variety of drugs commercially established are some small molecules, more hydrophobic ones, but also a little bit more hydrophilic ones.
5:09
And what data really clearly indicates a literature, but also our own data is that EVA is very well compatible to like peptide drugs, to larger proteins, to monoclonal antibodies and also to RNA based molecule drugs.
5:24
This is because EVA is very inert.
5:27
It's super inert.
5:27
It doesn't have any degradation site products that can interfere with the drug.
5:31
And it's a very easy, convenient way to produce this those forms and it offers a lot of ways to modulate the release.
5:37
And then we come to this later and then the next slides.
5:40
Also because of what EVA is a thermoplastic material easy to form in a melt based process, you can really create different product concepts and designs like what is shown here on the left hand side, this core membrane layout.
5:55
This core membrane layout really enables to create very highly loaded systems that release very continuously over a long period of time.
6:03
It is pretty unique to the durable excipient like EVA.
6:06
And also what is now creeping up in our customers pipelines is that the customers designed different segments of an EVA based long acting dose form and then combine them into one product like what is shown here on the This is also now creeping up in our customers pipeline.
6:26
Again, a little more data about the compatibility of EVA with various drugs.
6:30
You can see on the left hand side you have the graph.
6:32
This is molecular weight on the X axis and water solubility on the Y axis.
6:35
And you can really see that this is just internal data that was generated by us where we basically formulated these drugs into EVA, and they come out in a very controlled manner and stable.
6:47
And so you can see that you're looking at small molecules, hydrophobic ones, but also very hydrophilic ones like niacin, just a model system, right?
6:56
This is like small hydrophilic molecules is where other kind of carrier systems like degradable solution you struggle with because of poor retention properties.
7:03
EVA can handle them very well and if you go up, then a molecular weight usually only find like hydrophilic drugs, ASOs for example and other proteins.
7:13
And again, EVA is very competitive to these and there's numerous data out there which shows that the EVA can release drugs, these drugs very well.
7:21
The only limitation that we actually can see from a drug perspective to incorporate into EVA is actually this that the drug needs to be able to be converted into a powder, lyophilized powder or spray dried powder.
7:37
And this has to do that EVA is a solid excipient.
7:41
So you're creating solid dose forms and that means you usually run an enhancement extrusion process.
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And for that you need to have a solid drug and utilise a liquid drug.
7:50
That's the only limitation that we can see.
7:54
So what is EVA from a chemical side is shown on the left hand side top.
7:58
It's a copolymer out of ethylene vinyl acetate.
8:01
So not really anything exciting, but it's very stable, it's very well established.
8:05
It's basically a polyethylene derivative.
8:07
And if now and this side is a little bit about how to tune the release rate for small molecules and how EVA works.
8:14
So you can see that if you're assuming a polyethylene is really a semi crystalline polymer roughly 50% crystallinity.
8:22
The polyethylene segments they tend to form into crystals.
8:25
And what is now different with EVA is that you have to buy an acetate side group, right?
8:29
This is more [bikey] than the typical ethylene repeat unit, right?
8:39
And that basically inhibits the crystallisation of the polyethylene segments.
8:42
And what you then have is that you get smaller crystallites and you get an overall decrease in crystallinity of the semi crystalline polymer.
8:50
That means you make basically the polyethylene more and more of this so to speak.
8:54
And this, like this decrease of crystallinity is actually very consistent and very efficient.
9:00
So here we go.
9:03
So if you now plot different EVAs, and different vinyl acetate Co polymer contents, this is on the X axis and the right hand side versus the crystallinity, you can see there's a clear linear relationship.
9:12
So vinyl acetate Co polymer content is really the most important driver for the crystallinity of the EVA.
9:19
We always say like for 90%, obviously this is just a, you know, over the thumb figure, but it's really the major driving force.
9:27
And so why is that important for drug release?
9:29
Now, if you're looking at the drug release mechanism from EVA, they're basically 2 main different mechanism that we differentiate usually the one shown on the top.
9:40
This is basically where a lot of commercial products how they work.
9:43
You have like small molecule distributed into the, in the EVA matrix at a pretty low loadings, let's say far below 20%.
9:53
And there what you have is that the small molecules basically dissolve on a molecular level and then dissolve through the EVA, through the free volume in the EVA to the outside.
10:04
And so that there you need diffusion pathways in the polymer and crystallites block the diffusion pathways.
10:10
The amorphous parts are responsible for having the volume, the free volume for the small molecules you choose through.
10:16
So that means the more crystalline than an EVA is, the less permeable is for drug and vice versa.
10:22
And in this way, the crystallinity of the polymer and that is driven by the vinyl acetate copolymer content drives really the permeability of the EVA to the small molecules.
10:33
And this is how a lot of commercial products work, how they modulate the release rate of their drugs.
10:41
What is small molecule, we have data that obviously, you know, and things like that.
10:47
These are these are commercial products.
10:49
These differs through the EVA and obviously doesn't that's one point an upper molecular weight, right?
10:54
That can't go through the available free volume of EVA anymore.
10:58
We know that peptides like cyclosporine and leuprolide also still diffuse through EVA and like an efficient high enough, let's say diffusion rate.
11:08
But at one point it will end, and they are it basically you need to have to switch from a purely EVA base those forms to something where the releases is enabled through a porous network.
11:20
This is shown on the lower side.
11:22
So they're basically this you always get when you have high loadings like 20% and also for small molecules where basically the release then is driven by the porous network because the release that happens out of the porous network and not through the EVA matrix per se anymore.
11:39
And this is really a requirement for very large molecules like proteins, monoclonal antibodies, they're so large, they don't go through EVA in at a high enough rate and they need to have this porous network.
11:50
And then the release is driven by the porous network morphology, by particle size distribution of the drug, by the amounts of loading and things like that.
11:58
It's also in that regards, it's a pretty well defined and very easy to control system to control the release rate.
12:06
You can also apply a membrane, for example, in the same bed as for small molecules that will come later to this.
12:12
So very convenient formulation pathways for EVA and a very broad compatibility to a variety of drugs.
12:20
So how do people manufacture EVA based those forms in like I would say 90% again, over the thumb a little bit, people employ hot melt extrusion process.
12:30
So you basically mix a dry powder of the drug with like a with like EPA either in a powdered state or in with the pellets.
12:37
Do you do the dry blending and then you feed them into a twin screw extraction process to get to melt blend them and create a homogeneous blending structure.
12:46
And then you can actually either, I mean either you use the filament you extrude directly as an implant as a stun, right?
12:52
But also you can use them the extrudate and another step for further shaping.
12:58
Running a Co extrusion process to create a core membrane design.
13:03
Auto injection moulding for ring.
13:05
Also any other shapes.
13:07
Also EVA is 3D printable for example.
13:09
You can do this as well if you want to.
13:12
And again here, this is the limitation that the drug needs to be in a solid-state.
13:17
It should not melt through the in the hot melt extrusion process, this is usually not an issue because EVA has a pretty low melting point.
13:23
So you can run an equipment extrusion process between let's say 60 and 70° C with EVA, depending a little bit on the loading and the EVA obviously.
13:33
And this is usually a range where a lot of molecules don't actually melt, especially also the smaller ones.
13:38
But there are some and this is then the challenge that you run into.
13:43
So just showing some in vitro release data over the next slides.
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Left hand side niacin, very hydrophilic small molecule.
13:50
You can see here that what is shown is basically the time on the X axis and the amount released, not the release rate, but the amount, the total amount released on the Y axis.
14:00
You can see here that the three different curves are shown as shown for three different EVAs.
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40% vinyl acetate containing EVA 28 and a nine percent.
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And you can see that the amounts released are really driven by the vinyl acetate Co polymer content of the EVA.
14:15
That basically means by the crystallinity and by the permeability.
14:18
You can see that a 9%, which is a very crystalline EVA has a low permeability, releases the drug very slowly, whereas the 40% for example, has a very low crystallinity and releases the drug very, pretty fast.
14:30
And then the 28 fits neatly in the middle.
14:33
And this is what we never saw any exceptions to be honest to this rule.
14:37
So it's always a very straightforward relationship.
14:39
Very often Cyclosporine on the right hand side, it's the same thing.
14:44
Cyclosporine is a like 1000 Dalton peptide, rather cyclic peptide.
14:49
Again, the release is driven by the vinyl acetate copolymer content.
14:53
The loadings in both cases are actually very low, 5% plus minus each.
14:56
So no porous network released through the EVA really.
14:59
And you can see on the right hand side that also the amount that you load into an EVA matrix drives the release rate, right.
15:05
So higher amount of drug gives a higher release rate and a lower amount of drug or lower one.
15:10
It's just really first order release kinetics.
15:12
But apart from that vinyl acetate copolymer content really drives the release rate.
15:19
Oh, sorry, over the next slide, I showed the, let's say the main focus of our work, which is like delivery of large molecules, proteins and RNA there we always employ A porous network release just because we have to, they're just too large to diffuse through the EVA.
15:39
And so again, it's driven by the porosity of the network, the release rate just as a basically repeating the information a couple of slides ago.
15:49
So this is now an antibody IgG, human derived antibody.
15:54
We run a hot Med extrusion process at around I think 60-70° C It's a monolithic design.
16:00
So it just was compounded into one EVA with other membrane and it's like a roughly 50% loading.
16:07
So not too high, but also not too low.
16:09
And you can see that the release is actually more or less 1st order.
16:12
You have a high release at the beginning and the things that they're sitting on the surface which are not very fast.
16:17
And then as the dose form depletes, you get a lower release.
16:21
Actually, it would kind of flatten off if you show what days. In this case, the IgG was shown to be very stable.
16:28
No kind of degradation or aggregation that we can detect after the hot melt extrusion process or even after like I don't know, but this is 160 days in an in vitro test.
16:41
All the things that can't come out of the implant at this time points are still very fine.
16:48
And you also utilise the real monoclonal antibody trastuzumab.
16:51
It's really hard to get your hands on monoclonal antibodies and I'm not sure if you ever tried Trastuzumab is one of the very few that is actually available.
16:59
So again, we run here really hot melt extrusion process, 45% loaded 45 is really just to save some drug, right?
17:06
You could do it, 60% you could do it whatever.
17:09
But 45 is just needs a very good indication and it's just saves drug amounts. In this case again, first order release rate basically very fast release at the beginning over the first kind of couple of weeks and then it flattens off. In this case up to three months after the hot melt extrusion process and putting in putting the specimen in an in vitro test, there was no stability issues detected.
17:32
So just do some up survives the hot man extrusion process very well.
17:36
But then small amounts of aggregates in this case are actually detected.
17:41
This is not super surprising.
17:44
Monoclonal antibodies, they, depending on the molecule, they show that they're not super stable for a very long time, even liquid formulation.
17:51
So that this kind of issues appears not surprising.
17:54
We have to say we didn't optimise the stability.
17:56
This was just trastuzumab as we received it and then put it into EVA, that's it.
18:00
So right now we're basically working on formulation strategies to stabilise trastuzumab in EVA. From the monolithic design that was shown over the last two slides.
18:15
You can't tune the release rate, for example, through the drug loading.
18:19
So low drug loading, low release rate, high drug loading, high release rate.
18:24
This is a way to tune the release rate.
18:26
I'm not a very big fan of that because usually in an implant you have you want to maximise to space available.
18:32
That means you want to get as high loading as possible to maximise the lifetime of the implant.
18:38
So tuning the release rate with like a loading is for me a little bit not ideal to be honest.
18:43
So what else can you basically do?
18:45
And as I already mentioned with EVA, you have really almost universal formulation strategy or design strategy to basically add a red control membrane around a drug loaded core layer.
18:57
And this is again commercially established with small molecules on the left hand side.
19:01
This is a study that we did on naproxen 10% loaded samples, so release through the EVA, you can see the monolithic specimens with three different EVAs on top.
19:11
This released pretty fast, again very consistent to what was shown before.
19:15
And then if you add like in this case, we added to the 28% specimens, we added the membrane again with three different EVAs 9, 28 and 40.
19:24
And you can see that the membrane specimens all release in a slower lower rate compared to monolithic designs.
19:31
And again, they all very consistently release based on the vinyl acetate copolymer content in the crystallinity of the polymer.
19:37
Also, the slope of the release rate changes a little bit.
19:40
It's flatter and a little bit more straight.
19:42
So what you do with a membrane, basically, if you look at the theory, you move away from a first order release kinetics more or less to not really a zero order since it is not really achievable even in theory.
19:54
But you really flatten your release profile and get it more constant and far more constant and independent on the actual drug amounts remaining in the dose form than with a monolithic design.
20:07
So if you want to actually have a, if you have a very therapeutic narrow window and you want to have a release rate over a long period of time, utilise the core membrane systems and this usually work very well. Again for small molecules, commercially established formulation strategy with EVA on the right hand side, you have now the large molecule study which we basically innovative in our labs.
20:27
You can see the monolithic designs on the left hand side.
20:29
Well, you can hardly see them.
20:31
This is lysozyme, a pretty small protein, 15,000 Daltons and so quickly, pretty quick diffusion times.
20:38
You can see that the monolithic highly loaded systems, they release in a matter of days and then they're just empty, right.
20:44
But what you can do now you can add rate control membranes with the right porosity to slow down the release rate.
20:49
And depending on the membrane porosity, if you design it currently, you can get to this nice different release curves than shown on the right hand side of the plot.
20:59
And again, this is just really by controlling the porosity of the membrane, which you can very easily do in reality.
21:08
So we also ran a co-extruded study.
21:10
So the same as before were not extruded that were manually assembled.
21:15
This is really a co-extrusion study for membrane design with a protein.
21:20
So this is Lysozyme.
21:21
You just use Lysozyme because you need quite some amount of drugs to run a co-extrusion process.
21:27
This is really a limitation.
21:29
And Lysozyme happens to be available, although I think we were for some weeks the world's largest user of Lysozyme.
21:36
I think so much we bought for this.
21:39
But anyhow, you can see the release rate here.
21:41
It's really different than the other ones.
21:44
You're looking at a little bit of a PEGylation kind of time, a breakthrough time at the beginning until the membrane is getting leached out and porous.
21:52
And then you're looking for some for quite some for almost two months of a very nice almost constant release.
21:58
And then it basically flattens out and the specimen is depleted.
22:02
So this is a very typical release behaviour.
22:04
And it was just a proof of principle for co-extruded sample with a protein drug.
22:10
Oh, not drug. The same principles you can be applied on larger peptides.
22:19
We're actually starting work on peptides very soon and so we hope that we have results there and end of this year, exciting results.
22:27
What we already did is looking at RNA based compounds in this case ASO.
22:32
This ASO compound that we utilised here was also around 15,000 Dalton.
22:35
So it's similar to lysozyme.
22:37
And so the release rate again this was just a monolithic design just to keep it simple.
22:41
We wanted just to show that the ASO comes out of the hot melt extrusion process unchanged.
22:48
And this is what we found even after 160 days of release of the ASO compound, we couldn't detect any aggregation or any fragmentation, which is actually not surprising because this ASO compound was optimised for stability.
23:01
So nothing really that is unknown to the industry.
23:04
And so this was also actually not unexpected.
23:06
So there's a lot of potential that we can see in RNA based, especially the oligos delivery with an EVA based system, they're really super stable and well behaved and there you can for example, optimise the release rate obviously by applying like a membrane to this.
23:24
So just some product concepts, what you, what we envision, what you can do with EVA and long acting and also what our customers envision, for example, I said overcoming the blood brain barrier.
23:38
That is something that people are looking at, for example, to treat or post treat brain tumours also to maybe treat directing the brain some central nervous disorders like Parkinson or Alzheimer.
23:51
People are kind of looking into this.
23:54
So this is 1 to overcome really the again, the physiological barriers.
24:01
On the other hand, subcutaneous delivery is still what time's up, OK, it’s people, what people, what are people looking at for various drugs.
24:11
Very interesting is actually oncology on the left hand side with targeted intratumoral delivery where long acting offers a good opportunity to improve on frequent injections.
24:23
Frequent injections in intratumoral have been really investigated for a very long time, but they have some drawbacks, a high treatment burden for example, and people are now looking into utilising solid dose forms for localised treatment of solid tumours with very promising results.
24:38
There's a study coming out from a team looking at solid using an animal model and video validating many value propositions for this dose forms and oncology.
24:53
Yeah, ophthalmic a lot of uses a very well established.
24:57
I'm not going through that in much detail in a lot of time, but we do, we offer a lab development services for people's APIs if they don't have in house capabilities, but we also provide pharma grade EVA for in house development.
25:12
So summary EVA is actually very versatile.
25:14
It's actually a great material.
25:15
So please use it.
25:16
We would be happy.
25:17
Otherwise.
25:18
We have a booth just out there right in front of the stall.
25:21
If you have any more question, we're happy to discuss.
