0:01
Hello, everyone.
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My name is Covadonga Pañeda.
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I'm Chief Operating Officer of Altamira therapeutics, and I'll be your chair for today's session.
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And it's my pleasure to start with the first talk of the morning.
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The talk will be delivered by Ivy Huang, Director at BioDuro.
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Ivy graduated from CHA University of Pharmacy and Science in Taiwan with a Master's degree in Pharmaceutical Sciences.
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She has over 17 years of experience in pharmaceutical research and has worked in R&D centres of the top tier and top tier pharmaceutical companies.
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She's been responsible for the development of NCE and genetic drugs, as well as SPURS and regulations such as FDA, AMA, ICH, and GMP.
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And she’s proficient in formulation research and dosage form development.
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She has led to development, registration, batch production, scale up and submissions of numerous products.
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She is currently the Director of the formulation department of BioDuro.
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And she is where she is responsible for feasibility assessment of product development, formulation design, process development, and scale up.
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She has provided solubility and viability enhancement services for poorly soluble compounds to various renowned domestic and international pharmaceutical companies.
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And over the years, she has led more than 50 projects.
1:33
Please welcome Ivy.
1:42
So good morning everyone.
1:44
Very nice to meet you and it's my pleasure to have to sharing some of our technology in my company and share of some of enabling technology with you to how to enhance a drug’s solubility and bioavailability as well.
1:59
My name is Ivy Huang, so we'll go through some of the sharing information later on if you have any further discussion.
2:08
If I cannot finish my presentation on time so you can find me in my booth we're in #18. So we're here for whole day.
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If you have any further question or you would like to discuss more about your project, we can discuss in our booth later on.
2:23
So today I will go through the some of these of my content of the presentation very beginning.
2:29
We'll give you a few slices of the introduction and our one of the very important platforms called Solution Engine, how we enhance our solubility and bioavailability of the pro soluble drug.
2:43
And there's some come with the some of the lipid-based system and permeability enhancer application as well.
2:50
And in the very end, I'll give a very short overview of our formulation capability in our company.
3:01
Yeah, so for the when you take the drug in the very beginning that you take the drug orally into your stomach, like first of all the drug has to be disintegrated and then you will dissolve in your GI tract.
3:15
So in this phase, this is how we consider about the solubility and when the drug has been dissolved and get into central circulation, this is how we consider about the permeability.
3:28
So consider about these two important factors.
3:31
We have classified the drug into a several classifications that we have called BCS classification.
3:41
Classification 1, is representing the high solubility, high permeability, and Class 2, we have a low solubility, high permeability.
3:52
Class 3, we have a high solubility and low permeability.
3:55
In Class 4, we have low solubility and low permeability as well.
3:59
So for the new candidate drug have the main problem is based on the poor solubility and the poor permeability as well.
4:09
So now we will focus on these two categories, and to discuss how we're going to improve solubility and bioavailability by our technology platform.
4:22
So for the issue of the newly discovered chemical entity for oral administration, there's several issue we have to be considered before we get we have this new compound.
4:33
So normally it has a low bioavailability because of their physical chemical property of the API itself.
4:41
So sometimes it has low solubility, sometimes it doesn't have a good stability of itself and sometimes it has low permeability.
4:49
So these factors will cause that the drug has the poor bioavailability in human being and some of the biological barrier it's been natural for our human body.
4:59
So like there's some GI transition, the pH environment difference and sometimes there's a transdermal membrane of the drug if loss.
5:09
So if your drug has been studied in the cargo to study and it’s been found that there’s efflux pumping out.
5:19
It might be an issue of the bioavailability as well.
5:25
And also there is a fast pass metabolism and it’s all will be a chronic during our natural human body.
5:34
And also for the development stage, there's a very limited of the API quantity because it's in very early stage and sometimes the synthesis of the API is going to be very difficult.
5:46
So the limitation of the API quantity is going to limit what formulation we can do because no API, there's no formulation we can do, right.
5:55
So that’s one of the issues in the early stage of the drug product development. And also for the development time, the limited development time, because for the new drug entity development.
6:09
How we're going to do it is, what we're trying to get into the IND submission, to try the first human body clinical trial as soon as possible.
6:19
So we can know what's actually has accept the issue in this, how we going to do? How's the efficacy? How has the drug performed in the human being?
6:28
So sometimes the development time is manner of the issue of the drug product development.
6:38
So how we improve the drug solubility here?
6:41
There's various of technology for the chemical approach.
6:45
We can try to build a soft form or maybe to form the prodrug.
6:49
That will be the easiest way.
6:50
If you can actually modify by your or let's say optimise your API structure by soft formation or prodrug, there will be more easier for the drug product development. As a formulator, I'll prefer in this way.
7:03
However, this is not going to happen for all the time.
7:06
So what we're going to do here is we can try some of the other approaches like we can try if there is other crystalline form or they can optimise the crystalline structure here.
7:17
Sometimes we can do the particle size reduction.
7:19
For the particle size reduction, you can actually increase your surface area to your when your drug dissolving the GI tract
7:28
That could be sometimes helpful with your bioavailability improvement as well.
7:32
We can change the pH modification to create a microenvironment which is the pH relative to preferable to the drug itself.
7:42
It could be one of the approach we could use the solubilizer.
7:47
I think that would be the most common for the formulator, we can add some of the cyclodextrin, some of the surfactant.
7:56
It will be the approach of the adding some of the solubilizer, and that will be the easiest way as well because you can go through the very conventional dosage form and you can help with the drug bioavailability as well.
8:11
More complex way we will go for the lipid based formulation and sometimes the liquid oil completely liquid oil can actually help with the solubility of the lipophobic drug.
8:24
However sometimes it may not help with the to increase the bioavailability itself because it can actually just dissolve in the oil.
8:34
It’s challenging for the drug product manufacturing process because sometimes you will require for the softer gel capture dosage form and it's very unique production line actually.
8:44
So sometimes because some of the challenge for the manufacturing process. And the complex section, we will add some of the cyclodextrin to make the gel formation to improve or modify their phase of the drug.
9:05
And the other one we could do the solid dispersion as well.
9:08
So there is a very interesting statistics graph here that shows that they count about 200 drugs have been approved from 2000 to 2020 to launch in the US, EU, and Japan for marketing with the poor solubility drug.
9:34
As you can see that the highest priority of the technology being used in here is amorphous dispersion.
9:41
So which means this technology is very mature for the rest of the years and very applicable for this kind of the approach to help with the poor solubility and bioavailability drug as well.
9:55
Yeah, so next one I'll go to the solution.
9:57
And, how we're going to do for the amorphous solid dispersion platform? How we going to do in our company?
10:06
So what is amorphous solid dispersion?
10:09
The ASD is solid dispersion in which the active ingredient is dispersed in a polymer matrix in a subcutaneous amorphous form and the molecular level.
10:19
So when your API was actually dispersed in the molecule, it will actually increase leading to a high transcendence solubility here, and the polymer we're presenting a substance of super saturation of the drug itself.
10:34
So it can actually maintain a high level of the solubility level and you were easy to put water for your ASD matrix.
10:43
So this is how they improve their solubility and also they have the high energy status of the amorphous drug, and you will come with easily be wettable for the mixture of the ASD.
10:58
So and the molecular solubility will follow the concept of the like dissolves like, so which means that the polymer and API will have a high miscibility with each other and then come with the like dissolves like to help with the mixture and maintain their stability and to give a higher solubility performance as well.
11:26
So what's the key consideration of the development of the ASD?
11:31
First of all, we have to consider about the drug property, whether he has a pH dependent solubility, whether it has heat sensitivity or the acidic sensitivity etcetera.
11:44
So that will come after how we're going to apply for the manufacturing technology, which is good for the SDDs, spray dried dispersion, or the hot melt extrusion at that we call HME.
11:56
And sometimes you have to select your polymer just like we said before, we have to find out the most miscible polymer with the drug substance.
12:06
So the polymer selection will be a key issue how you improve your ASD formulation to improve your solubility.
12:15
So sometimes, also sometimes we will add some of the surfactant.
12:20
It's not just about the miscibility of this of the polymer and drug substance itself.
12:26
Sometimes some of the effect will be come from the surfactant as well.
12:31
So the combination could be more complex, but it could be easier.
12:36
However, if it is necessary, the surfactant can also be added.
12:43
For example, if your drug substance is easily efflux pumping out. In a surfactant, we can add some of the PGP inhibitor into the formulation to actually help with the to reduce the pumping out ratio.
12:58
So you can actually to remaining your drug substance in your absorption area.
13:04
It could actually increase your bioavailability as well.
13:07
And for your polymer selection, there's a different kind of selection.
13:12
Listed here in the right corner.
13:14
So you can see there's a different kind.
13:16
They have a different function.
13:17
If your substance is kind of like has higher solubility in acidic conditions but has the low solubility in base condition, we probably focus some of the polymer like Eudragit that has some enteric performance properties.
13:34
It could be actually improved or focus the improvement in the intestinal environment.
13:41
So that will release your drug above the pH above pH 5.5 or even higher.
13:48
So that's one of the options.
13:49
So we can consider about your property of the API and choose the most suitable polymer for your ASD prototype.
13:56
So what we're going to evaluate here is we will check out the physical, chemical properties of the API itself and then we will check their chemical physical stability as well.
14:07
Because we know the amorphous form usually have a high energy status, easy to be transitioned to the crystalline form.
14:14
So that makes the ASD will be lower physical stability of itself.
14:20
So sometimes we will check about the stability whether it can actually maintain amorphous form for a certain period.
14:26
For our drug product, for example, it has to be maintained for at least 24 months for the drug product summation, right.
14:35
So this is how we're going to study for the evaluation as well. And we will check out the in vitro in vivo evaluation, in vitro one we will check whether it's actually the solubility has been improved or not, in vivo we will combine with the PK performance.
14:51
So when you combine the in vitro in vivo study, you can actually know the prototype is actually suitable for your drug product.
14:56
You can actually improve not just only for the solubility but also for the bioavailability as well.
15:05
So for the ASD form, the main question is come to our client is how do we design the manufacturing approach whether it's go for the SDD or for the HME.
15:15
First of all, both technologies have advantages and disadvantage as well. For the SDD, it's been widely used, it's very friendly for the heat sensitivity drug.
15:25
So, but it will require a lot of organic solvent, it has to be recycling.
15:30
It has some, you know, when we consider about the Environment Protection, it comes about the issue of that.
15:37
But most of the drug has a heat sensitivity issue.
15:41
So it has widely been applied for the ASD dosage form actually. For hot metal extrusion, it's actually organic solvent free process.
15:52
So it's very, it could be called like a green process of the drug product production.
15:59
However, just like I said before, it requires a high heat stability of the drug substance itself.
16:07
So there's both of the advantage disadvantage of these two technologies.
16:14
How are we going to select the technology, once we will check the compound itself can be actually dissolved has the organic solubility.
16:24
What we suggest is greater than 5 milligramme per millilitre.
16:28
If you can get higher, that's even better.
16:30
But at least we will try to reach out if they can achieve five milligramme per millilitre.
16:36
Because as you know for the drop product, what we can use the organic solvent is very limited.
16:40
We are not like the chemical chemist, right?
16:45
When you're doing the drug substances, you can use plenty of the organic solvent you can use.
16:51
You can use DMSO, you can use the other organic solvent.
16:54
However, for the drug product development, there's a limited amount of the solvent you can use, which is only human being friendly and its low toxicology solvent you can use.
17:04
So what we're going to do here is we will try to screen your drug substance, whether it can be dissolved in this organic solvent or not.
17:15
The ideally we will get like a 5 milligramme per millilitre.
17:18
But really some of our case we actually have the solubility with the lower than 5 milligramme per millilitre.
17:27
But we actually go for the SDD process because the drug substance has a heat sensitivity issue.
17:33
So we can use alternative way to increase the capability of the manufacturing process.
17:43
So that's some of the really case.
17:45
But for the assumption. For the SDD, we can do the screening by micro evaporation process.
17:52
You can actually identify the polymer system that can actually enhance your solubility, and you evaluate by the kinetic solubility.
18:00
You can check your amorphous form of your API status by XRPD, MDSC, etcetera.
18:05
You can actually check your particle size of itself.
18:08
Generally for the particle size of being spray dried powder is around 10 micrometre or even less.
18:14
Somehow some of the system or some of the combination might cause a little bit larger particle size.
18:21
So when you're doing the dissolution sometimes it might affect your dissolution performance.
18:27
So what we're going to do is for the particular project, if there's really sensitivity of your particle size of the spray dried powder, we will evaluate the particle size as well. And stability definitely we will check of the kinetic solubility.
18:43
What we're going to do differently here is when we're doing the conventional dosage form development, we usually check the dynamic solubility, which is what's the actual solubility at the equilibrium status, right?
18:57
However, for the amorphous status form, because it cannot be maintain in the solution status for like 24-48 hours, it could only be sustained for a while, especially you dissolve your mixture into a solvent system.
19:15
So what we're going to do is we'll try to evaluate the kinetic solubility to see if the ASD itself can maintain in a like say biomim for a certain period.
19:28
For example, the most the period was to do is up to six hours, because it's the primary limitation transition period of your GI tract.
19:38
So that's why we choose the six hours the most.
19:40
If they can maintain at least for six hours, it can actually help with the bioavailability or yield in vivo performance as well.
19:49
So that's what we're going to do there.
19:51
For the HME, we will check your thermal stability.
19:55
If your decomposition temperature, it will be better above 200°.
20:02
Your melting point will be ideally to less than 160°.
20:06
So when you're adding some of the polymer into it, you will actually adjust your melting temperature range, even be a lower such if you combine with the surplus, there will be lowered transition temperature as well.
20:21
So your melting point is going to be lower.
20:24
So it's how we're going to do for this process.
20:33
So what's the importance of the stability, we will consider about the drug polymer miscibility.
20:38
Like we mentioned before, we have to consider about the drug polymer interaction with each other.
20:44
If there's a surfactant, we also have to consider about interaction as well and the solubility of the drug in polymer.
20:50
That's definitely the main screening candidate.
20:52
We are going to screen it for the micro liquid mobility will actually justify whether the physical stability of the ASD itself. Also the manufacturing technology are we consider about the STD or HME and environment storage of and condition as well.
21:13
So here's our platform.
21:15
I think I'll just quick to skip this one.
21:18
Let's go for the next one please.
21:23
So this is the actually how we're going to do for our solution engine process.
21:27
So first of all, when you receive the API, we're actually characterised, do the API characterised evaluation to check the melting point, to check their thermal stability, crystalline solubility, et cetera.
21:40
And then next one, we will go to the in vitro formulation screening.
21:44
We have our own in silico modelling calculation.
21:47
We've been developed nearly 30 years already.
21:50
So we can actually by calculating the miscibility by Hansen theory, Gibbs energy et cetera, to calculate the miscibility of your polymer with your drug substance as well.
22:01
And there’s no API required.
22:03
So this is a very helpful for the prediction.
22:08
However, there is some confidential consideration for the early stage of the drop product development.
22:14
The customer may not be able to provide the full structure of the compound itself.
22:19
So what we're going to do is we can skip that step and jump into the high throughput screening as well.
22:26
If you don't like, if you have some of the consideration and willing not to provide a structure of this of the compound, it's fine.
22:33
We can go through the high throughput screening.
22:35
We can also provide a very good prototype of the ASD formulation as well.
22:41
And now during the screening the polymer screening, the solvent screening, the surfactant screening will be all in included in our screening process.
22:51
We will do the micro evaporation process to limit the API quantity used.
22:55
We will do some optimization with the difference of the drug to the polymer or surfactant ratio.
23:01
And it's only required a few 100 milligrammes of the API.
23:04
So it's very efficient of your compound.
23:08
And then in vitro screening, we will check this kinetic solubility and maybe some of the stability evaluation as well in the early beginning. In parallel, when we doing when we got the prototype, we provide to prepare a PK sample for your PK study.
23:27
So actually you can compare in vivo in vitro data performance and to see whether it can actually improve your solubility or bioavailability as well.
23:38
So this is a summary slide of how our technology be going on.
23:43
It's particularly friendly for the BCS class two and class four compound.
23:47
It can limit the quantity of the API use and it's fast time frame, it because it takes only for the screening time.
23:53
We only take about two to three weeks in general for the screening time.
23:58
So it's going to be really fast.
23:59
Plus the PK study, if you go for the rodent, it will be less than five days for one round.
24:04
So even two round, they will take about four to six weeks.
24:07
And you can get your vivo in vitro performance data.
24:10
So it's very time consuming.
24:11
It's very time efficient for this platform as well.
24:15
And the prototype you'll be found can actually be applied for your clinical drug development as well.
24:24
I think this one is a very standard case study that the candidate has a poor solubility.
24:32
It's usually less than 10 microgram per millilitre. In silico modelling, we actually calculate the miscibility of the API with the polymer as well and we check the compound characteristic by XRPD, DSC, TJA, PLM, etcetera.
24:47
And then we go for the ASD formulation screening by micro evaporator method and we check the kinetic solubility we can actually measure by UV test.
24:56
So the data will come out really fast, and PK study will perform on mice as well.
25:04
So here's you can see the there's actually improve of the solubility by itself and the right graph here, right hand graph.
25:13
It can actually we can see we can we also add some of the surfactant into it like TBGS, like poloxamer 407 to further improve the saturation of solubility as well.
25:29
So eventually it got a 12 times higher improvement of the bioavailability compared to the pure candidate of the compound itself.
25:47
This one I would like to mention to you a very interesting case study is this case study has the low solubility in water and FaSSIF medium also.
25:55
But what the beginning the client has greater than 20% bioavailability in rat.
26:01
So in the very beginning, they think the performance for in vivo performance should be good for the new candidate.
26:07
Actually when they go to the dog PK study, the bioavailability, suddenly dropped down to the 10%.
26:14
So what we're going to do is we use this technology; we evaluate with more than 80 combinations of the prototype of the combination to find out a faster approach.
26:24
The combination of the prototype of the ASD itself within two weeks and the API quantity is only about 500 milligrammes.
26:32
Now catalytic solubility is about greater than 500 times higher than a crystalline form compound and the bioavailability you can see here is almost reached to 100%.
26:42
It's this is a very encouraging project and we really impressed ourselves as well.
26:48
So the data has really good effect by using this technology.
26:54
Let's go to the next one.
26:56
So this is another one as well because the this is the project, the main problem, the API itself has the low transition temperature as well.
27:04
So the low transition temperature usually cause the low physical stability.
27:10
So what we're trying to do here is we optimise the formulation by higher transition temperature polymer, and I think we are running out of time.
27:20
So this is the case study we're going to share with you guys.
27:24
And if you have any further in discussion would like to discuss with me, we can meet at #18.
27:31
Thank you very much today.
