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Good morning and thank you.
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And it's good to have opportunity here to presenting the topic of solution engine programme, which we offer to the many of our clients.
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It's a solution engine.
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It's a rapid formulation approach for the solubility enhancement using the Milligrams of API.
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I tried to get my time control in 20 minutes.
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I will do my best.
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So if we do have the questions and we cannot address here, you are welcome to stop by.
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We have the booth outside.
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So the outline for today is introduction, first introduction of the some of the background information and the solution engine, introduce the solution engine.
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What is the silicon modelling?
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What's the theory behind for those silicon modelling and also the intro and the in vivo screening?
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How do we do in house for those studies and the last one and we will share a couple case study afterwards.
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So that's information I think most people already know for the oral administration it's a most preferred drug delivery system.
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So for many reasons and easy administration and high patient and compliant etcetera.
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So we do have some issues for the oral dosage form such as the poor oral bioavailabilities and of the reasons is the drug itself.
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So it's a physical chemical, the property itself and some other common biological barrier.
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So it's for the new drug and especially and according to the literature report it's a 40% of the market drug on sale right now and the nearly 90% of the new drug under development have the solubility issues.
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So the main reason and it's for the poor oral bioavailability recent is we can find out it's mainly due to the solubility and the permeability issue.
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So that is the challenge we're facing now in the especially at the early stage of the drug development.
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Others is like such as an early phase of the development, we have the API the availability is really limited and the typically we're asking for the fast delivery time.
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So those are the challenge what we have for the oral administration at this day so at this time there's many technology available at this time to overcome the drug solubility issues.
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Listing some of them here, one is a chemical approach like salt formation prodrug that's basically fundamentally ordered the molecule, the structure, the nature of the molecule, the chemical molecules and what we do at the formulation formulators, we do a lot of the physical approach, try the physical approach such as crystal engineering, like maybe a lot of people are familiar with the polymer screening.
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So we find a suitable soluble a polymer for this particular compound and others such as the particle size reductions or the of the lipid base formulation recently get a lot of attention.
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But and the complexation such as the lab also, it's one of the way to improve solubility.
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Solid dispersion is the most popular among all of the technology available right now is the most popular technology and also the widely studied solubility enhancement technology so far.
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So you can see from this chart in the last two decade amorphous solid dispersions and attract a lot of importance for the from this chart 2000 to 2020, the 20 years there the over 40 market ASD based the drug product on the market.
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So all of the information I just share with us, share with everyone is time cost and achieving a higher drug exposure very important especially at early development stage.
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So BioDuro Sundia, we have been the pioneer service provider of the ASD amorphous solid dispersion technologies since 1996.
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A solution engine is really the rapid formulation development of the ASD by the combined the silicon modelling technology, silicon modelling and also the high throughput in vitro screening with in vivo PK studies using the milligram levels of the API.
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So it's basically instead of, a lot of time we're doing the random mixing and the matching, we use the silicon modelling for the polymer screenings.
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And then based on the silicon modelling result, we do the mutualize in vitro experiment.
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Our experiment can be finished in a very short period of time.
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And with the PK study, we pick up the best formulation for the tox study or phase one study later on.
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So it's by definition the amorphous solid dispersion, it's a solid dispersion and in which the active ingredients of drug dispersing within the polymer matrix is substantially amorphous form at the molecular level.
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So it's an amorphous stage of the drug molecules is very critical to achieve the higher bioavailabilities.
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So compared to the crystalline form of the drug, there is no energy required to break those the lattice, the Crystalline lattice.
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So which result the higher apparent the solubility and also higher dissolution rate polymer is play key roles in the ASD formulation.
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So interactions of the interaction between the API and also the polymer will be the, basically it will prevent the re crystallisation process.
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Plus polymer typically has the higher glass transition temperature will raise the inherent glass transition temperature of the systems, which reduces the amorphous the form of the molecule.
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The notabilities in the ASD formula in the ASD, so it prevents re crystallisation process improve the stability of the ASD also is the maintain the situations situation for a longer time.
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So also it's many times especially ASD meaning by the spray dry they have the smaller particle size.
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In other words they have large surface area and also for the help for the faster dissolution as well.
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So for the ASD formulation, so some of the key consideration, one important of course is the drug property itself and the second is the technology applicability.
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So a lot of time we use the spray drying and hot melt extrusion because the two of the technology are most sophisticated manufacturing process and also it's a widely and commercial available so far.
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Polymer selection is critical, so it plays a key role in determining the success of the ASD.
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So there's a variety depend based on their chemical, the structures, that can be classified in the many groups.
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So basically in the polymer, they have different physical chemical properties and different such as like gas transition temperatures and the degradation temperatures solubilization capacity wise.
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So because this polymers will help us to make the ASD with very different distinct the solubility capability for the ASD formulation, surfactant also important surfactant sometimes we use as a commonly used in the ASD formulation as a [unclear]
8:54
So surfactant always has by nature improve the variabilities possibilities and also the improve the drug release as well in evaluations like I said before ASD formulation, amorphous state, the API the drug is critical.
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So after we have the ASD, so we will check its amorphous and by the XRPD or DSC by nature ASD is not stable that some of dynamic is not stable.
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So we evaluate the period of time to make sure that the ASD formulation is stabilised, stay in the amorphous form and not going to quickly re crystallise.
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And so within the stability period.
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So we do and also in vitro and that's the purpose we're doing the ASD formulation.
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We want to make sure have the higher solubility.
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So it's we do the in vitro screening, kinetic solubility testing evaluation and the plus with the in vivo evaluation together search engine 2.0 that is earlier said it's solely developed by the BioDuro Sundia.
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It's been running over 28 years already.
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It is a rapid way to help you for the ASD formulation development.
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The nice thing about this programme it's so we first we use a silicon modelling.
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Basically use the modelling and we have a couple of theories behind the to help the for the polymer screening.
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So at this stage basically no API is required.
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So we can significantly cut down the number of the polymer use for the experiment later on.
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The second stage is all based on the silicon modelling.
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We are running the miniaturized screening and at least here 10 to 20 different combinations.
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Actually we running numbers that are much higher.
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So some of the time we're running different compilation, the 50 or even 80 different experiments just to find out based on the like studies, the API, the polymer, the different ratios combination with the and the surfactant at the different ratio drug loading, et cetera.
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So based on the for the out of the result, we pick up the ASD composition with higher the kinetic solubilities are used for the animal PK study.
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So animal PK study we can basically do everything in house.
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And for BioDuro Sundia for each run, we have less than 5 day for each run.
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So if we're adding together, let's say two rounds of the PK study in vivo in vitro together, it's about the months and the months half time.
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So the solution engine 2.0 that's the programme, one we use a minimum, very minimum API for the screening study and the time in vitro only takes two or three weeks.
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We run up to 10, 20 and up to the 80s different combination of the experiment and then do the in house PK study to find out what's the best formulation to move forward.
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And of course at BioDuro Sundia, we have all the capacities from lab scale, middle scale, pivotal scale all way to the commercial scale to support the ASD manufacturing.
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So because of time, I’m watching my time carefully.
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There’s many theories behind the silicon modelling.
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I list a couple of them.
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Here is the one is the Hansen Solubility parameters.
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Basically for each compound that depend on the structures, they have their own Hansen's solubility parameters.
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So we calculate the Hansen solubility parameters of the API and the polymer you use and you calculate the difference.
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And many companies they have their own criteria in our company BioDuro Sundia, the difference typically we like to control within 7 MPA.
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So if everything higher the difference, the higher than the seven the MPA.
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So it's that means the polymer may not be suitable for your ASD formulation.
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Another one commonly used is Flory-Huggins theory.
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I won't go to a lot of detail here and if you have a question, welcome to stop by our booth outside.
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So basically we use this one equation.
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This is initial one, the equation it's based on the Flory-Huggins theory.
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And then we all check the interaction, the parameter of the Ki values, the Ki value.
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I would like to keep Ki negative.
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So it's in this chart you can see the API with solid plus.
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So the Ki value is -0.36.
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That means the API have very strong the interaction with good miscibility with the solid plus and the HPMCAS.
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In the other hand you can see the Ki value is a positive value that means the miscibility pool between the API and the HPMCAS.
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So it's a nice thing about the Flory Huggins theory.
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It's another effort to identify the polymer we use for the study and also to help us to find out what's the theoretically what's the best concentration, the drug loading to how much API used, how much the polymer is used before we even conduct the experiment in the lab, in vitro, in vivo screening.
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And so it's the first step that is always the API characterization.
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So we check the mailing point and by the DSC and the thermal check the thermal stabilities or the crystallinities by PXRD.
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Doing the solubility in the aqueous and also different solvents in this stage is only the very less than 10 Mg the Pi will be consumed.
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And the second stage, it will be a polymer screening.
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And like I said, we based on the silicon modelling result and we're doing the MicroEvap solubility, the MicroEvap experiment in house for the hot melt extrusion.
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Sometimes we can use the DSC to find out the API miscibility with polymers.
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So for the spray drying, doing the solvent screenings effects screening is for the HPE or the spray drying and we do the optimization in the lab to find out what's the best ratio of the drug and the polymer and the surfactant.
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At this stage it's a lot of time you run 100 mg and if we run a higher number of experiments, let's say the 50,80 different experiments, the API use.
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And again, so it's ASD evaluation like I won't repeat it's important, it's amorphous form state and the Connecticut solubility that's important.
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And then the view in vivo typically doing we are doing the rodent and sometimes we do the dog as well.
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So solution engine 2.0 really brings the significant values and to our client programmes especially for the BCS II and the BCS IV compound.
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It accelerates the discovery to the development programme through this powerful platform.
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And basically we salvage poor soluble compounds that otherwise may be discarded.
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And due to the poor solubilities, a couple case studies and as I said, one of the preclinical study, you can see, I won't go to all the details because the timings, but you can see the chart we have here and on the left grabbing the left, you can see the in this one is HPMCAS-L provides the highest solubility improvement and the chart on the right and we use the surfactant, the E-TPGS Poloxamer 407 and further boost of the solubilities.
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So another case study is the clinical studies.
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And we done this solution engine early on at the discovery stage.
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And then we carry on the formulation to the carry out ASD formulation all way to the clinical formulation.
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So it's basically the support.
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And then it's for the phase one clinical manufacturer, this one already successful in for the IND application in the US we have at BioDuro Sundia, we have the ASD capacity from the R&D GMP manufacturing.
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So it's capturing the summary.
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And so a couple thing remember for this programme, the very minimal amount API, fast delivery time in vivo in vitro together, the combination of the study to help to select the best formulation and to move forward.
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Last page is BioDuro Sundia and we are the US based company.
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The provide fully integrated service from the discovery all the way to the API to the all the way to drug product manufacturing.
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So we do have the booth outside and the welcome to stop by anytime.
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Thank you.
