0:01
Thank you.
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So when it comes to pharmaceutical development and bringing a product from discovery all the way to market, years of work, hundreds and hundreds of people, at times thousands of patients that are involved with that kind of product development.
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It's essential that we figure out ways to make the transition from concept to clinic smooth.
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And how that can be done depends on the experience and partners that you have in your development process, of course.
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So here's the agenda.
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We are going to talk about challenges that are currently with the NCEs.
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You know what is solubility versus dissolution?
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One solution in there is amorphous solid dispersion.
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We have seen rise in utilisation of amorphous solid dispersion in increasing solubility and bioavailability of poorly soluble drugs.
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And also we will look at our approach at Biodura Sundia.
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Biodura Sundia is a CRDMO, you know all of the above, you know you have CDMO, you have CMO, you have CRO we are CRDMO.
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So all the aspects are in one place.
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So when it comes to developing products, of course we are talking about tens of thousands of compounds that have to be discovered for few of them maybe 250 to go into preclinic, maybe five of them go to actual clinical studies.
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And I have personally seen in Big Pharma where I was working in the past that you can spend a billion dollars, bring a product all the way to phase three with three, five, 10,000 patients globally.
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You know, all the colours of the, you know, people in the world, all types of ages and stuff.
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And still FDA can come back and say, no, you don't have enough evidence that this drug is safe and effective and efficient.
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So let's reject what you have brought all the way to phase three.
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So you can imagine that if this is the American Idol or whatever that is for drugs, that's how you select the singer at the end that is going to become that blockbuster that you know some of them are $16 billion.
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There is a drug in the market that is 16 or $15 billion by itself that is being utilised there.
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So at the end of the day, we are looking at bringing these discovered drugs as soon as possible to these different stages, bring it to FDA and get approval.
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Our objective is always, you know, at least in my team, we always look at the fact that who is the end user?
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What is the patient?
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We usually have our, you know, meetings where we talk not only about the fact that we have a product and we have a job and we have timelines to meet or whatever, but also there is certain patients that are going to be benefiting from this drug at the end of the life cycle of the drug and bringing it to the market.
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So it's essential to understand who is doing your discovery, who is doing your clinical manufacturing and how you can accelerate your time to get to the patients.
3:34
But someone has to pay the bills.
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You know, you're not going to be able to sustain a business, ou are going to not be able to sustain a discovery system if no one is able to pay the bills.
3:47
And at the end, you know, we have patients in mind, but we have to go there as fast as possible.
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So having a business in mind plus the patient, you can imagine that if someone can help you to bring a drug that is $365 million a year a day earlier to market, that's one day and $1 million back into the revenues of that company.
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If it is a billion, you know, you multiply by that by three and so on and so forth.
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So it's essential to understand how we can bridge the gap between discovery and development.
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Often time we are able to discover we have compounds that are there, but the decision to go to the next step is stuck with the fact that I have created a dust brick sand.
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And actually, you know, some people they like to call theirs diamond because actually what I had a client when I said your drug is like dust and sand, he was like, no, this drug is expensive.
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What are you talking about?
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I was like, OK, it's diamond.
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So it's even less soluble.
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So even if your drug is diamond very expensive, less soluble then going from discovery to formulation, often time there is that gap you have to create enough material, enough evidence that you can go to the next step.
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By the time you do that if you are a small mid-sized company, your investors, they're gone.
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They don't have patience.
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They are looking at you to show that this drug is soluble, bioavailable and that can be utilised.
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So it's important to figure out how we can close that gap and that is what I would like to talk about today specifically about ways to do this the most efficient way.
5:44
So the idea is that you don't have a lot of drug.
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You have 100 milligrams, 200 milligrams of active in whole world that you have manufactured.
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You have already spent maybe half a million, a million to get to that point to screen thousands of compounds and show that yes, this specific drug has certain capability and it is able to provide the effectiveness that you are looking for in the models that you have created.
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Yet you don't have enough drug to show that this drug is viable based on the fact that you have limited amount of material and the drug is not soluble.
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So even you know, you cannot expose people to tens of grammes of drug in the hope that a few microgram of that is going to be absorbed by human body.
6:36
So in those cases it's essential to go back to the drawing board.
6:40
You know, of course everybody's familiar with these predictive tools, but the idea of these predictive tools was how we can do this paper exercise early on, do some analytical work early on, do some predictive tools before we bring these into animals.
6:59
Of course, before going into humans, there must be some kind of test in animals to be done.
7:08
But yet, you know, you don't want to throw everything into the animals either.
7:12
Yes, you know, you want to make sure that there is some due diligence done before that you go into the animal study work.
7:18
So of course many of those drugs fall in, you know, in the NCE world, fall into the poorly soluble, poorly bioavailable categories, at times they are also poorly permeable.
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Interestingly enough, amorphous solid dispersion has been utilised to address both poor permeability and poor solubility.
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If you look at the case of Kaletra was a soft gel with, you know, lipid based, you know of course, Lipinski's rule of five.
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If you look at them, you know that was the classic case where you know they were able to enhance the solubility and bioavailability of that drug through lipid formulations and soft gels.
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Later on when the amorphous solid dispersion was utilised for the same work, they were able to not only do the solubility enhancement using amorphous solid dispersion, but you look at inactive ingredients in that product, you will see that they kept the surfactant inside there as well in the hot melt extruded product.
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Interestingly enough, you can utilise lipids that are helping you to create your emulsion or whatever that you need from that lipid as far as digestion goes in into an amorphous solid system as a plasticizer.
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As a matter of fact, you know the many of these surfactants can be utilised as a process aid.
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Then further to that to original theory that you know was provided by Amidon and his team, Butler and Dresman came back with process selection.
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When you are at these early stages of development and you don't know which way to go, again, this DCS classification can allow you to decide is really lipid based formulation the right venue for me to enhance solubility and bioavailability or amorphous solid dispersion is a better one or just simple micronisation can help you.
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So that is the DCS classification that can allow you to do that.
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And that is based on, you know, of course, the data that was published already in literature and they classified that rather than going ahead and selecting randomly and trying everything based on the solubility and permeability that you have and the fact that is your product’s dissolution limited.
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And you need to bring this into a higher level of super saturation or your drug is going to be completely dissolved but it needs more surface area.
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So in order to increase the surface area, if your drug is only the dissolution rate limited, then micronization is going to be your way to go.
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If your dissolution in general overall solubility is limited then amorphous solid dispersion lipids based systems can be utilised.
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If your drug is DCS 1, everything is good so you are lucky, you hit the jackpot, you have a DCS1 you can just use active encapsuled, you know, direct compression, direct capsule filling of a blend and you are good to go to next step.
10:49
So again, if you look at that literature, you will see that there is evidence from what has already been published in that field.
10:59
Another area that is important to understand is that at the early stages of development one other factor that plays an important role in bioavailability of a drug in addition to solubility or permeability and everything else that we hear is also the site where you are delivering the drug.
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So if you there are you know many compounds, there are evidence for that.
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You know you can see in the literature that if you deliver certain peptides to duodenum to colon you get completely different bioavailability from that system.
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If your drug is a PPI and you have you know limited amount of that available right now we have you are creating the next generation of PPIs that are going to be more reliable and that the drug degrades in the acidic conditions of the stomach and you have only milligrams amount of that drug.
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Then also miniaturisation is going to be an important factor for you at these early stages to your to do your development.
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So it's all about how I can early on decide where in the GI tract for certain drugs the product is going to be delivered or in a sustained manner as a matter of fact.
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And that can be done later on in animals.
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Find the right evidence that your drug is efficient and efficacious and then go back to investors to invest more and scale up and make bigger batches and go to the next step.
12:28
So in order to do that, I will talk about later on the way that we do this at early stages when it is at the discovery level, we utilise mini tablets.
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As a matter of fact, you know mini tablets you can coat them even with sustained release polymer.
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The they are basically like multi particulates.
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They can be coated with a placebo as a bulking agent and then handpick the active that is coated properly there is spherical insides.
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They are not going to get stuck in the stomach of if you are using rodent.
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As a matter of fact you can utilise one mini tablet if needed.
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For dogs and others you can put multiple mini tablets into a capsule and utilise for that purpose.
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So basically you decide with modified release like lunar Landers where on the surface of your GI tract the capsule or tablet is going to land and at which rate is going to release.
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So we don't have a lot of drug.
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We may have a lot of drug, but it is expensive.
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We have a cheap drug, we have a lot of drug, but no one has time, who has patients, who has time.
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So it is important to see how we can start from really microgram milligram and scale it up to metric tonnes in the fastest way, quickest way, yet not skipping steps and not undermining the quality of development.
14:05
So the partner that you choose to work with is important when it comes to developing these products and screening them properly and doing the right job and as far as screening process goes.
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So make sure that you don't have a false negative or as a matter of fact the false positive at times from the development that you are doing.
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So before that you go in the lab and do anything.
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Of course, I highly recommend utilise the paper exercise.
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Look at the log P, look at the, you know, the usual stuff that everybody's doing as far as developability of a drug goes.
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Then when it comes to us specifically, we believe in the fact that there is a science behind, you know, everything that we do.
14:53
The material science plays an important role when we do formulations specifically for amorphous solid dispersion that is trending, you know, heavily in the industry right now, in the pharmaceutical industry in general, we are breaking the crystal lattice of the drug, dispersing it within the polymer.
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The myth about the amorphous solid dispersion is that the polymer that you choose has to have a high TG so it can keep the drug amorphous.
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That is true if there is no interaction whatsoever between the drug and the polymer.
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If you have interactions between the drug and the polymer, then high TG is a good thing to have, but it is not a requirement.
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There are amorphous solid dispersions that have been made with T GS in the order of 60-70 with no problem.
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They are stable and they haven't had any issues with regards to re crystallisation of the system.
15:49
And that comes from a simple fact on the fact that if you look at the crystal lattice of sodium chloride, you know, simple example analogy that I give always in these talks is sodium chloride.
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Sodium chloride in order to break its crystal lattice, I need 801°C.
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That is, you know, well over 1000 Fahrenheit.
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You know, it's even a bigger number in United States.
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So you know, you have to get to those high temperatures in order to break that crystal lattice.
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But why I can take a sodium chloride and dump it inside water and crystal lattice immediately breaks because of ionic interactions between the water and the drug or the sodium chloride, my apologies, sodium chloride.
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So why that is happening because of ionic interactions.
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So if I have an ionic polymer and an ionic drug, why not to utilise that to our advantage?
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So if you take ibuprofen, you know, I worked 10 years at Ebonics, so I always give, you know, I'm a little bit biassed at times, but you know, I give the ibuprofen and [unclear]E example.
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If you take them and put them at room temperature together, they're going to dissolve into each other.
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Why is that?
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Because ibuprofen is an acid and [unclear] is basic and they dissolve into each other.
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So you can create these systems using these interactions.
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I take sugar, I put in water, it dissolved, everybody knows hydrogen bond.
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But when I tell people, oh, I can create hydrogen bond between the drug and the polymer and stabilise your systems, everybody thinks like, oh, this is science fiction, what are you talking about?
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How we can do hydrogen bonds?
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But you know, sugar does hydrogen bond, you can see it.
17:41
So polymer material science, we utilise obviously those equations already validated by chemical industry, they are using these equations to select how to mix polymers together to make the next generation of polymer by blending polymers, by blending or finding a solvent for a paint.
18:07
These equations, they are real, they are being utilised.
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Basically what we know in this equation is that the only thing that is unknown in this equation is the Ki can be calculated or measured, but once you have that, you can figure out at what concentration of drug and the polymer or paint and the solvent, the Gibbs free energy is minimised and that's where you start.
18:28
Does this answer every question out there about the right combination first time, right?
18:36
No, it's an estimation.
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It just puts you in the right design space where you want to do your screening study.
18:45
So the way that we work, again, like many companies, we do that due diligence at the beginning, do our screening paper exercise as far as categorization of the compound goes.
18:56
Of course, everything that is about the log P and everything else that is in there.
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Early on we look at that Gibbs free energy equation from Flory Huggins.
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We decide which combinations we are going to mix and match.
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Sowe already narrowed down the 20 possibilities for the type of polymer to maybe two or one that have the highest chance.
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That equation also gives you where to start as far as concentration goes, what drug polymer combinations is going to give you the best approach as far as amorphous solid dispersion goes.
19:39
Once you mix and match those in these film casting tubes, you evaporate the solvent, put the dissolution media in, do actual dissolution and these tubes find which one has the best solubility.
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And then after you do that, you did that all due diligence.
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That's when you go to the animal.
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But the question is how long should it this take you know from?
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From in silico to that screening to that animal study PK.
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So the way that CRDMO can work in our favour right now for us is the fact that because we have our own animal study site and our own screening, the time between the time 0, as soon as we get the active to the animal study is 4 weeks.
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So your first PK profile after doing all that due diligence, paper exercise and everything else like everyone further, the advantage that we have is that we can do this internalise.
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So it is done in 4 weeks and then following that maybe we got the, you know, right profile, we got the right release.
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Now the client is happy and they can move on to the investors and go to the next step.
20:58
If it is not the case, we come back to the drawing board, do another 4 weeks, a second PK and often time that is the breaking point.
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You know if amorphous solid dispersion is not the right technology, then we have to find alternate options for you.
21:12
Then once we did that, of course the other advantage for CRDMO is that we have everything related to scale up process development, validation, registration, matches and filing.
21:27
All that can happen in very quick manner in our Irvine, CA facility.
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We have only one facility in United States, it's in Irvine, CA.
21:37
As I mentioned earlier, the miniaturised multi particulate at early stages of development is mini tablet.
21:46
You know, of course we can make mini tablets, these mini tablets.
21:48
As you can see, the active for this client was different colour than blue by itself or purple by itself.
21:56
And then we bulked it up with placebo, coated the whole thing and picked up the active, which was coloured and then utilised in, you know, next steps for animal studies.
22:08
So here's a case study, an actual programme where somebody came to us and said, OK, you know, let's do the initial screening with solution engine 2.0
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Then let's do also spray drying, hot melt extrusion, even nano suspension and all that in one place.
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So we did all this in our labs.
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At the time it was San Diego.
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Now we are in Irvine, CA and we looked at the dissolution profile of those samples of course in the in vitro using the UV method that we have and we identified which one works the best.
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That is the one that was selected for next step and used in animal studies.
22:55
And once they had more product, we were able to look at the non-sync dissolution.
22:59
Still, it prevailed that specific combination.
23:03
All those were tried in the animal studies and these are the PK profiles.
23:08
As you can see the STD formulation and the simulated tube formulation, they have the same release profiles.
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Interestingly enough, the nano suspension and the PEC solution had better bioavailability, but a tablet is often time more attractive.
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Despite that the client that we have decided to go with the tablet formulation rather than the other aspects.
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This is another example very recent one that we published at AEPS 2 years ago.
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We have another one that is published in CRS and another one that is coming to the AEPS in Orlando this year.
23:58
Again, you know, the same strategy with regards to screening, looking at the solubility in vitro and then in vivo profile.
24:07
And interestingly enough, our client from this work was a university.
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You know, many of these companies come from universities now it's a whole independent company because of the these results that were published by our team.
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Again, the concept of CRDMO for us is starting from early stage all the way to you know commercial.
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The very first company that provided hot melt extrusion as a service is our legacy company.
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So we are continuing that legacy in our site.
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We have commercial hot melt extruder right now in our labs in our commercial building, but also we are working on getting PSD 4 for our site in there.
24:57
Again, discovery drug, substance drug product and these are our sites throughout the world.
25:04
Again, anything that is oral solids, we love it.
25:07
The others are good too, but you know we are not a specialist in it.
25:11
So you know gel whatever topical we do in development, but we are not going to be able to scale it up for you in our labs by all means.
25:18
Again, thank you so much for your time.
