0:01
OK, thank you very much for the kind introduction.
0:03
So it's my pleasure to give you the last presentation before the lunch break.
0:07
So I hope you're still all awake.
0:09
And yeah, let's jump into the topic of innovative formulations for targeted oral drug delivery.
0:17
So what is the current situation?
0:19
So we already discussed it before.
0:20
Like we as a formulator, we are in the middle of deciding which direction we should go for.
0:27
On one hand, we are looking at conventional production processes.
0:31
We need to take care for cost effectiveness.
0:34
On the other hand, we would like to be innovative.
0:36
We would, yeah, make the best of out of our formulation.
0:39
And so it's our challenge to combine those two worlds and to find a proper solution both for our own company, but also for the patients.
0:49
So when it comes to oral drug delivery, so this is, I would say, yeah, the most accepted route of administration.
0:56
So for sure patients will prefer an oral formulation over others and especially when there is a bitter taste or for example also a strong odour associated with the API.
1:10
It really makes sense to have a look at formulation options to allow patient compliance.
1:15
Because in the end if the patient is not taking the medicine, it's all not worth the effort.
1:22
So when talking about, yeah, targeting of APIs into the GI tract, we need to ask ourselves, So what is the reason that we are doing this?
1:33
And so you can and principally divide it into two sectors.
1:36
So one would be either to protect the API from the harsh gastric environment.
1:41
So this is true especially also for enzymes and peptides.
1:45
So we had a talk about that yesterday already, but also for example for small molecules such as for example proton pump inhibitors, which is a well-known example for, yeah, protecting the active.
1:59
The other thing is that in some cases it is also true that the API itself has a strong effect on our gastrointestinal tract.
2:09
And this is true, for example, for diclofenac, which is very acidic in nature and therefore also causes irritation of the gastric mucosa.
2:17
So in this case we are protecting the body from the API.
2:22
So when talking about intestinal absorption, we are specifically interested in targeting the API to a specific site of action with the intention to increase the concentration of the active where it is actually being taken up, which is in most cases to duodenum we are looking for.
2:41
But it could also be that we have or we are willing to, yeah, expose the API locally.
2:47
For example, inflammatory bowel diseases is one example in which we are aiming for a local release of the active.
2:57
And in the end, if we increase the concentration of API at the site of absorption, we increase the bioavailability with which goes along for sure with a dose reduction, may go along also with a reduction of side effects and also has implications for of course for cost reduction because the API might be very expensive.
3:21
So as said, we're talking about innovations here.
3:25
But of course, yeah, we also have to look at what we already have.
3:29
So in this talk I will focus on conventional production processes which target for capsules, tablets or multi particulates and to see what we already have and where we can drive the innovation with those already existing technologies.
3:47
So we will focus on single or multiple layer coatings and to see how we can adjust the enteric properties of such a formulation to achieve very high concentrations at the site of absorption either via coating thickness.
4:02
Polymer combinations and process conditions might also have an impact, but this is not something I will focus on today.
4:11
So the polymers I would like to talk you through are called EUDRAGIT polymers and those polymers are able to be processed either in aqueous formulations or also in solvent-based formulations.
4:24
However, we see that the majority of our customers are working with aqueous based formulations.
4:30
And yeah, I will focus on coating applications in this talk.
4:34
But of course, it is also possible to process them in other technologies like granulation, direct compression, of course, but also hot melt extrusion, spray drying, 3D printing.
4:44
So everything is possible here.
4:49
So giving you a big bit of background to the polymer itself.
4:53
So EUDRAGIT is a polymer that is used for coating of solid oral dosage forms.
5:00
About the pronunciation, I just had a discussion yesterday about how to spell it.
5:05
So I am German, I'm saying EUDRAGIT but in English some people might say EUDRAGIT and we discussed it yesterday.
5:13
The French say EUDRAGIT.
5:16
I don't know if I said it correctly.
5:19
So in the end, however you spell it has a certain meaning behind.
5:23
So the term EU stands for the Greek word good, DRA for dragee which is a coated tablet and GIT stands for gastrointestinal tract.
5:33
So this already shows you what the polymers were designed for.
5:36
So these are coatings that should enable a solid dosage form to be delivered over the gastrointestinal tract.
5:45
So what is the chemistry behind it?
5:47
So in this slide you will find very complex chemical structure, but it is isn't that complex at all.
5:53
So in the middle you see the chemical backbone of the polymers, which is the poly-methacrylate polymer.
6:01
And you see there is a functional rest R, which describes the functionality of the polymer.
6:09
So on the upper left you can see an amino alkyl function.
6:14
So it is quite easily described why this one is leading to immediate release.
6:18
You have to imagine that once you swallow, for example, a tablet that is being coated with that polymer, the tablet gets into the stomach where we have acidic environment.
6:27
So what happens here is that the amino function gets protonated and therefore triggers the dissolution of the polymer.
6:34
So it is, yeah, targeted for the stomach, therefore showing an immediate release.
6:41
So these polymers are used, for example, for taste and odour masking.
6:45
On the upper right you will see a carboxylic function.
6:50
So these polymers are used for enteric formulations.
6:54
So same principle again, the tablet is being swallowed.
6:58
In the stomach, we have the sitting environment, the carboxylic function stays intact, nothing happens.
7:03
But once it gets into the intestine where we have basic conditions, the carboxylic function will dissociate and therefore polymer will dissolve.
7:11
So we have achieved here an enteric protection followed by a fast release in the intestinal environment.
7:20
So on the lower left and lower right, you will see the sustained release polymers.
7:26
So those polymers are not soluble at all, but they will swell over time releasing the active through diffusion.
7:34
So that's why these polymers are used for retard formulations and will be also excreted completely intact.
7:46
So the basis for our polymers is the pH in the gastrointestinal tract.
7:51
And so here we have just an overview that is taken from some literature that is shown below showing the very acidic conditions in stomach, followed by the more basic conditions coming into the duodenum and jejunum and finally neutral conditions, yeah, in the Ileo colonic region.
8:15
So this is what we make use of with the EUDRAGIT polymers targeting the specific regions in the GI tract.
8:24
As said, many APIs is are best absorbed in the small intestine, especially in the proximal part of the small intestine.
8:32
And yeah, our target is really to ensure a fast and homogeneous release of the active at the site of absorption for the reasons as shown before.
8:45
So just a quick introduction to the immediate release polymers.
8:49
So you have here the brand names and actually the brand name, it might look a bit complicated with the letter and the number code, but it's quite simple.
8:57
So you have a letter in the beginning which tells you something about the functionality, followed by a number code which gives you the product form.
9:05
So EUDRAGIT E for example in this case stands for the German word [unclear] which is the final coating which is being applied.
9:13
So it's an immediate release coating and it goes along with different product forms.
9:19
So as said before, this is a polymer that is being dissolved in acidic conditions, so below a pH of 5.0 and it is therefore used for taste and odour masking, but may also be used for light protection for coloured formulations or also for solubility enhancement with thinking about spray drying or hot melt extrusion.
9:42
So coming to the gastrointestinal targeting polymers.
9:46
So the number of polymers here is a bit broader.
9:50
So we have on one hand the polymers targeting the mid to upper small intestine which is the EUDRAGIT L type or EUDRAGIT FL which is the more flexible form of the EUDRAGIT L And the letter code stands for light or easy and fast dissolution in intestinal conditions.
10:10
So it will start dissolving above a pH of 5.5 and we have the Ileum and colonic delivery by the polymer EUDRAGIT S or FS for the more flexible form which starts dissolving as of a pH of 7.0.
10:26
And those polymers are used either alone or in combinations to target specific regions of the intestine.
10:35
And last but not least, the sustained release polymers, EUDRAGIT RL and RS as well as EUDRAGIT NM.
10:43
So these are the ones that are not dissolving at all, but they have different permeabilities based on their swelling capabilities and are therefore used for sustained release formulations that could either be coded multi particulates metrics tablets, for example, aiming for homogeneous release and constant blood levels.
11:04
OK, so that was a short introduction about the polymer.
11:08
So let's jump now into the case studies.
11:10
And in the following, I would like to show you a case study where capsules were being coated and assessed both in vitro and in vivo in volunteers.
11:20
And the idea was to show the efficacy for intestinal and colonic delivery.
11:26
So I would like to focus here on the capsules and especially on the weak part of the capsule when it comes to enteric formulations.
11:34
So you see here a scanning electron microscopy picture of capsule body and cap.
11:38
And yeah, mind the gap.
11:40
So in between, you see that's the weak point.
11:42
That's the point where either the acidic media could enter the formulation or also the API could be released through.
11:50
So that was the uncoated capsule.
11:52
And here we have now a bad example of an enteric coated capsule where still the gap is existing.
11:58
So this one would not be enteric.
12:02
And finally, a very good example of a banded capsule showing that the gap is really closed and the enteric properties can be fulfilled because there is no way for the API to escape the capsule.
12:15
So the complete surface coverage is really key for the enteric properties.
12:22
So what was done here was that HPMC capsules were filled with paracetamol and samarium oxide as a labelling agent and were then subsequently coated in the pen coater.
12:35
So we had two formulations that were tested.
12:37
One was with EUDRAGIT L 30 D-55 for intestinal targeting and the second one was EUDRAGIT FS 30 D for colonic targeting.
12:48
So you see the formulations here.
12:50
So we had GMS as an anti-tacking agent, TSE as a plasticizer and Polysorbate 80 as an emulsifier.
12:58
And this was applied as an aqueous coating formulation and on a batch size of five kilogramme.
13:06
And maybe I should say before that the capsules were banded before we did the coating.
13:13
So these are the in vitro dissolution results showing the performance of the capsule.
13:19
So what we did was we tested the capsules 2 hours in hydrochloric acid, proving the enteric properties in vitro, followed by phosphate buffer 6.8.
13:28
And you see on the left graph is showing the L 30 D-55 which starts dissolving at pH 5.5 so at 6.8 it's quite fast here.
13:39
And then followed by incubation and phosphate buffer 7.4 showing the capsules being coated with FS 30 D to release the active yeah in a more basic condition.
13:54
So the capsules were then used for an in vivo evaluation.
13:58
So what was done that eight healthy volunteers received those capsules in a two-way randomised crossover study.
14:05
The volunteers were fasted and took 200 millilitres of water with themselves when they took the capsules and they had to stand in front of a camera every 10 minutes until 8 hours post dose then and every 20 minutes until the end of the imaging period which was 12 hours and then one additional image was taken 24 hours post dose and so the results look like the following.
14:32
So you see on the right the pictures that were taken.
14:35
So you see in white the stomach.
14:37
Here the capsule can easily be followed by the samarium oxide labelling.
14:43
So you see already after one hour in this one proband the capsule left the stomach and it started dissolving almost 1.5 hours post dose and after two hours the capsule was completely dissolved.
14:57
And so the graph on the left shows you the variation within the different pro bands.
15:03
So in all cases the capsules left the stomach quite fast and delivered the active either to the proximal or the mid small vowel.
15:18
So these are now the results for the colonic targeted capsules.
15:22
So again here you see the picture on the right where the capsules started dissolving 6 hours post dose and yeah, as you had a complete dissolution or disintegration almost 9 hours post dose in this one patient.
15:39
And on the left in the table you can see that in the mean.
15:43
So the mean value was around 7 hours post dose and in majority of cases the capsule was delivered either to the distal small bowel or the ascending colon.
15:57
So everyone who has already been working on capsule coding might know that really the process is not very easy, especially if you have very sensitive actives that you need to formulate.
16:08
Because you when you're thinking about both aqueous and solvent based processes, there are some APIs that are very difficult to formulate because they're very sensitive to these solvents.
16:20
So and that was the reason why have we have been thinking about a new product that we launched now two years ago.
16:28
And that is something I would like to show you now.
16:31
And this is actually already coated capsules, so a ready to fill capsule.
16:37
And the idea is really that you have a functionalized capsule that you can immediately use for your purposes and can fill the API inside and achieve intestinal targeting.
16:49
So how does it work?
16:51
So these are HPMC capsules that yeah, are delivered from the manufacturer in the pre-locked stage.
16:58
And we from EVONIK, we code those capsules with your ultra get polymers to achieve the intestinal targeting.
17:05
So when you receive the capsule, you will simply open them, fill your sensitive API inside, close the capsule completely and without any processing, you will have an enteric functionality.
17:17
And yeah, so the fillings could be either powder, it could be pellets or even granules.
17:25
So the capsule shows, yeah, enteric properties followed by a fast release in the Intestine.
17:31
It comes in size 0 and colour white.
17:34
And yeah, it's not a new excipient or new yeah product or how to say it does not consist of new excipients.
17:41
So all ingredients that are inside are really well described in the Pharmacopoeia that will be yeah, very good for you when you talk to your regulatory people.
17:51
And yeah, so the excipients are also listed in the inactive ingredient database.
17:59
So these are the SEM pictures of the capsules again.
18:02
So showing the magnification of the capsule gap, sorry.
18:08
So you see on the left the capsule in its pre locked stage.
18:11
So how you would receive them in the middle the open capsule, so you can clearly see, yeah, where the capsule work was coated and where it's not.
18:21
And once you close the capsule, the gap will be really the overlapping area where you have, yeah, I would say double the coating thickness of the initial coating.
18:31
So really ensuring that the capsule is dense and will not release the API too early.
18:39
So this is one example I would like to show you with omeprazole that was selected as an acid sensitive model and we filled that into the capsule and did some dissolution tests to ours in hydrochloric acid.
18:54
And as shown on the right, you can see that we had very low dissolution here.
18:59
It was below 5% even followed by a fast release and pH 6.8 and we had a good reproducibility over 3 batches that we tested.
19:12
Then we used caffeine as the model substance for highly water-soluble APIs again the same setup.
19:19
So in two hours we had no release of the active followed by a fast solution at pH 6.8.
19:27
And because it was so fast, we were interested to see what is actually the trigger dissolution pH.
19:31
So we did even more testing on that.
19:34
So we tested after the 2-hour hydrochloric acid phase, 30 minutes and pH 5.5 followed by one hour and pH 6.2.
19:44
And we could clearly see the dissolution properties of the polymer that we had been using.
19:49
So we had less than 5% release in the pH 5.5 and a fast release in pH 6.2.
19:57
So really proving that the capsule is delivering at the very early stage of the small intestinal environment, let's say.
20:07
So we further did some disintegration testing.
20:10
So again here you see the pictures on the right proving that the capsule was still intact after two hours of testing in hydrochloric acid, followed by very fast dissolution and disintegration in buffer stage pH 6.8.
20:25
So after 15 minutes, the capsule was completely gone.
20:33
So it is one thing to deliver the API to the right side, but the other thing is really to protect it from the gastric environment.
20:40
And that's one question we often get.
20:42
And that's why we did the following analyses.
20:44
So we used the capsule and filled it with a dye that is acid sensitive and changed its colour when in contact with hydrochloric acid.
20:54
So I see it on the upper picture.
20:55
So it turns really into dark purple.
20:58
We took the capsule, filled it with the dye and incubated this two and even 4 hours in hydrochloric acid.
21:05
And you see, yeah, after four hours, there were few dots on the outside.
21:10
But when we opened the capsule and yeah, I had a look at the powder was still white, showing that really there was no ingress of hydrochloric acid inside the capsule, proving that the capsule gap was really dense and tight.
21:25
So this has implications, for example, for companies working with biologicals, working on microbiomes, for example.
21:33
And yeah, really proves core strength of the product.
21:39
So as said, this is a product that comes in size 0 and with a specific release profile.
21:45
But we have customers that are looking for very specific release profiles or maybe other capsule sizes.
21:52
And this is what we from Evonic offer as a kind of service.
21:54
So we call that EUDRACAP Select.
21:57
So our customers can then directly select which capsule size and release profile they're looking for.
22:02
And we are then preparing the samples, both technical and GMP on a customised basis.
22:12
So another option to combine these conventional production processes with innovative formulations are our technologies.
22:21
And I would just briefly talk about that because of timing.
22:24
But if you're interested in that, just let us know.
22:28
So we have here three technologies I would just briefly mention, which are either single or double coating technologies to even accelerate or boost the performance of a coating.
22:39
The first one is EUDRATEC Fasteric.
22:42
And as the name already says, it's yeah, it is the intention to be very fast releasing in the upper small intestine.
22:50
You know, EUDRAGIT L 30 D55 starts dissolving as a pH of 5.5.
22:56
But we have some cases where this is already too late or too slow and we would like even to accelerate the release.
23:02
And that's where this double coating technology really makes sense.
23:06
So we can target dissolution pHs of 3 to 5.5, depending also on the composition of this formulation.
23:16
The second is dual coat, which is a double coating technology used for a rapid release either in the intestine or the colon.
23:24
So we're thinking, for example, on colonic formulations starting to dissolve as of a pH of 7.0, there is a need to speed up that release and that's where the DuoCoat comes into the game.
23:36
So again, a double coating technology that really, yeah, allows a faster dissolution of the polymer in this case.
23:45
And last but not least, Phloral, which is a single coating technology that combines an EUDRAGIT polymer with a polysaccharide.
23:54
And the idea is really behind that there are some patients, especially those with inflammatory bowel diseases that have an alteration in the pH value in the colon or in the late intestine.
24:07
This is due because of the inflammation that is taking place here.
24:11
So therefore it could be the case that the pH for colon targeting is never reached and we addressed this by this dual coating mechanism or dual action mechanism.
24:24
That is on one hand the pH value, but on the other hand also the degradation of the polymer with bacteria that existent in the colon.
24:32
So it's kind of a failsafe mechanism.
24:36
So in the end all of these technologies target for higher precision which goes along with fewer side effects and smaller doses.
24:46
So with this, I'm finished with my presentation.
24:50
I hope I could show you that there is a way to combine conventional processes, well known excipients with new formulations.
24:57
And yeah, so these polymers are really well described and the as they are from synthetic nature, they have very narrow specifications.
25:09
So they are very good reproducible in their yeah characteristics.
25:14
And in the end really the core strength of EUDRAGIT is really the long-term leadership we have here for the gastrointestinal targeting.
25:24
And with this me and also my colleagues, we are happy to answer your questions.
25:28
So if not here then also later on during lunch break at our booth.
25:32
Thank you very much.