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So I'm what I'm going to present today is about CMC.
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It's a bit late stage.
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It's about drug delivery.
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And I'm going to show you 3 examples of drug delivery for peptides, antisense oligonucleotide and monoclonal antibodies with a DelSiTech silica matrix drug delivery.
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And I will explain first how the technology is working and then we will see the example.
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So just quickly about the company, we are a small pharmaceutical stage drug delivery company based in Finland, and we are operating with our partners bringing them solution for drug delivery.
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But also, we have the same goal internally where we also have our own pipeline that we are developing around the technology.
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We work with various partners in different fields.
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We work with ocular disease, a lot of biological oncology and so on.
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So our technology is a bit different from all the other technology that normally is known.
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We work with silica and it's a biodegradable silica.
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So what we can do is we can have a physical encapsulation of different APIs being small molecules, peptides, antisense oligonucleotide, large biologic proteins, even vaccines, and we're going to encapsulate these into silica.
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This is what you see on the top right here at the silica microparticles.
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The silica microparticles also further combined with silica hydrogel.
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By doing this kind of design, we have long acting control release that we can have from 24 hours let's say to few weeks to few months, even to one year essentially through parenteral injection, mainly subcutaneous injection, intramuscular, intraarticular for instance.
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But also, we have topical eye delivery.
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For instance for top of the eye, the API do not really matter if it is very soluble or very insoluble.
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We can still encapsulate these, and the release is not directed by the API solubility through diffusion.
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But it's really related to the erosion of the matrix.
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So this is most important parameter of the technology.
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It's just through erosion that we can release the APIs, and I heard about today, we heard about aggregation of peptides.
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There is also aggregation of proteins.
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We can work with high loading capability from higher than 100 milligrams, 200 milligrams or even 400 milligrams per millilitre without aggregation.
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And the reason for this is because peptides or protein are decorated with silica around it, which prevents the aggregation later on.
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So we can work with quite high drug loading.
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So this is what I was explaining a bit before.
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What we first have is we're going to have the encapsulation of the API in one single silica microparticles that you see here on top, right, that's been broken to see what is inside.
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It's basically it's just silica and the API.
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Once we have formed this, we then further combine this with the silica hydrogel.
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And the silica hydrogel is meant here to be able to inject later on the product subcutaneously, for instance, and also to control even more even fine, more finely release of the API in the subcutaneous space.
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A quick chemistry about phase.
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So we start with Tetraethyl orthosilicate.
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It's this kind of silicon atom with a four OR silic groups that you see on the left side.
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It's a liquid that spontaneously degrades into water and start to form silica oligomers, and the silica oligomers in sorry in water, they will start to aggregate by themselves into what we call nanostructures of silica.
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When we have those nanostructures of silica being formed into the solution, we're going to combine it with the peptide or the proteins and through van der Waals forces for weak interactions, we're going to have an encapsulation of the API that's going to be aggregating around the silica oligomers.
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And further we continue this polymerization of this oligomerization, the further there is the creation of the silica oligomers around the API.
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Hence we can work very quickly with very high concentration of peptides or proteins.
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And you arrive to the last stage here where you have your API being encapsulated in the silica oligomers, and then we're going to spray dry it in order to remove all the solvent.
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So there's nice small microparticles that you saw earlier on.
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It's just basically a water droplet where the water has been evaporated.
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And then you just have the silica and the API in a dry form.
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Yeah.
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So the API here is in the dry form inside the silica microparticles after this, as I was explaining before, we combined the silica microparticles together with silica hydrogel.
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And we're going to have this mixed and put directly into a syringe to have a readily ready to use syringe for the final product.
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And it means that it's ready to use because the microparticles do not sediment.
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They are still in this kind of gel form.
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So there is no need to shake or redisperse or anything like this.
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It's a ready to use formulation that can be in syringes but also auto injectors.
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After this we can inject directly in the subcutaneous space.
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So the hydrogel that we are using is a sheer thinning hydrogel, which means that as soon as you push the plunger, serology drops down very quickly and it's able to go through needle kind of quite thin.
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For some volumes we can achieve 30 gauge needle for instance.
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We are working also with intraocular long acting injectable and it's very important to have very thin needles in that sense.
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So once we have the subcutaneous gel depot being implanted, the walled silica is going to dissolve just with body fluids into silicic acid.
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And the mechanism here is just like a surface erosion from outside outwards inward.
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So if you have 1ML in the depot obviously, but if you have one ML volume it's going to go down to 0.9, 0.8, 0.7 ML from outside inwards.
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And every tiny bit of silica that is dissolving to silicic acid, it will also release the API, the peptide or the protein.
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And we can adapt the release of the API by just changing the hydroxyl group on the silica.
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If there is a lot of hydroxyl group, the silica is more readily hydrolysed into silicic acid.
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By the way, silicic acid is something that is already circulating in your body right now.
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It's endemic and it's normally eliminated through kidneys and urine.
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The formulation is very simple because at the end it only contains 3 different ingredients, the API the silica sorry and water, residual water that is there.
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So water is not bound sorry.
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The water is not free water inside the microparticle, it's bound water.
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So the water activity is close to 0.
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So in a quick summary, we've got a simple silica sol-gel chemistry that is very well described in the literature.
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No toxic solvent, catalyst or excipients.
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We can add excipients if it's needed if we wanted to have something specific to that, but normally we don't use additional excipients.
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We can choose a release from 24 hours to basically one year.
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High shear thinning composite means that we can use like quite thin needles.
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And of course, if we're talking about long acting injectable, they need to be sterile, and we can sterilise a matrix through different ways like my irritation, heat and filtration.
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So lots of talking and now I'm going to the example.
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So we start with a pramlintide.
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Here we have a small polypeptide hormone.
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It's pramlintide.
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It's a low molecular mass, about 4K Dalton.
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The target release was three months, and we have an example just after phase where we have injected a subcutaneous laser rat with one single dose and the samples, plasma samples were collected for the two next month.
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And the formulation that was chosen for this was as a normal formulation that we normally have, which means that we have encapsulated the API into the microparticle and combined the microparticle with the silica hydrogel and then gave one shot.
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And what we can see here on the left side is a peptide concentration in logarithmic scale.
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So you can see that there is a quite high concentration at the very beginning and decrease quickly to a plateau.
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So high concentration is not a burst release.
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We don't have typically burst release and if we start to graph the cumulated release of the API with time on the right side, you can see that the amount is pretty linear, which means that basically you have the same dose the day before and the day after.
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So here we have an example with a stable peptide concentration for more than two months with a 0.
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The release profile it's typical from this is a non-confidential slide deck.
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It's pretty typical from peptide release that we have obtained in different projects.
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Here it's an example of antisense oligonucleotide.
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What was interesting here, it was a work carried out with AstraZeneca.
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The interesting part here was that we were looking at 20% of drug loading of the API in the microparticles, so quite high, ending up at 100 milligrams of peptide per millilitre, sorry of ASO per millilitre, a quite soluble also molecule.
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Here the idea was to have a one month's release or even more for the ASO.
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The formulation strategy was again the same, which is basically encapsulating the ASO with his microparticle and combining base with the silica hydrogel.
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Again, we gave one shot in the subcutaneous space for rats as animal model.
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Here you see we have a less linear release and then the previous example for instance where we see the concentration building up quite quickly to a kind of plateau, descending plateau.
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But we have still sustained plasma concentration for more than 28 days.
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And then as a concentration here as more than 100 milligrams per millilitre.
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We have tried to put this even higher, but in this example, we have 140 milligrams per millilitre.
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But we start to be at the limit where the release start to be not controlled and we start to have a high concentration from the very beginning.
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So everything has got a limit.
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In the next example, we have a protein which is here an antibody.
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So it's an anti-CD40L MR1 antibody, molecular weight is roughly around 150 kilodalton.
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This one was not very soluble compared to the other one for instance.
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So target release was six months after subcutaneous injection.
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And again the same scenario where we put the antibody that survives it will process by the way everything survives the process, and we put this into the micro particles and the micro particle are further combined with the silica hydrogel.
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And I will come back to the stability because it's something that we have, we are asked quite often the plasma profiles are like these.
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So you can see here on the left in blue, the blue curve is monoclonal antibody concentration, again quite flat plasma concentration in logarithmic scale, where you can see that we have a plateau with plasma concentration being stable for at least two months.
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The black curve on the left is the same amount, the same dose of the Mab being injected.
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And you can see that it decreased very quickly.
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And again, if we plot the total concentration, cumulative concentration, we can see that it's again a close to 0, the release profile.
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And I would like to come back about stability because it's something that we have been asked quite often if we can have let's say three months or a six months long acting injectable.
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How do you ensure that one, it is stable in your package and two, it is stable in human when you have injected it?
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And one of the chances of the technology that we have is that the APIs are into a solid form.
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They are dry inside the microparticle.
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So they don't see the enzyme of the external environment, they don't see the oxidative environment, they don't see the pH and anything like this.
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If you think that you have a, let's say a protein that will be released in six months up to the six last month, the protein that's not seen the environment, it's only when it's released, when there is erosion that it's finally start to see the environment.
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And if there is some degradation coming from the environment, it will start just when it is released, not before.
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So here we had, sorry, here we had a bevacizumab that was encapsulated in a microparticles and depot.
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And the depot was left for four months at 37 Celsius degrees in physiological condition or let's say in a buffer mimicking the physiological condition, a buffer with 50 million molar arteries buffer at pH 7.4 under agitation.
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And after four months, we retrieved what was left from the depot but was not yet dissolved because it was for a six months.
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And we dissolved everything.
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And for the assay.
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And we looked at the binding activity of bevacizumab after four months and we compared it to the control, and we saw that the binding activity was the same.
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We also checked the effect on the proliferation cells with Vivek cells and it was the same also than the bevacizumab control.
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So binding activity or biological activities maintained in that sense for proteins if we encapsulate this and it's not a miracle, it's just because they are completely dry.
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Yeah, that's my last slide.
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So I just wanted to summarise here what we can do with the technology.
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We have a biodegradable silica matrix that is combined microparticles and hydrogel that's really help us to fine tune the release in vitro and in vivo.
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We can achieve a high concentration of APIs 200 milligrams or even higher.
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We've got two examples at 400 milligrams for proteins for instance, we have a true control of the API release that is based only on erosion.
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So it's not an enzymatic degradation or a dissolution or diffusion.
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It's really just erosion of the matrix, typically no burst release.
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And we can adapt the technology to small molecules, to very large molecules with good stability because the silica chemistry does not really react with a carbon chemistry.
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So from the chemical point of view, we've never seen any degradation from chemistry point of view.
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But the question remains on the biological activity for some proteins, yeah.
