Chemicals & raw materials
Tools for speeding up formulation development Alongside the advanced formulations that are improving the bioavailability of insoluble drugs, a range of technologies are also being used to improve the drug discovery and drug development timelines: ■ Micro-scale screening – a discovery phase necessity: micro-scale screening in the process of testing different formulations using microgram levels of APIs to bring drug development times down to a few weeks. It’s a key part of high throughput screening (HTS) where many potential formulations need to be evaluated quickly to find the best options for the next discovery stage and larger-scale testing. Testing many small sample formulations – all with different API loading and formulation properties – helps to reduce both formulation/API synthesis timelines and lower the cost of drug discovery for pharmaceutical companies – as it’s not uncommon for 100mg of a new drug to cost up to $5,000.
■ Advanced data analytics for accelerating drug discovery: finding new APIs and the ideal formulations is often time-intensive, especially with the need for regulatory compliance. A lot of data is generated during micro-scale screening on different formulation compositions, and advanced data analysis methods – including artificial intelligence and machine learning (AI/ ML) – are helping to analyse data much more efficiently, leading to shorter development times.
The drug discovery process has many phases, and advanced analytics are now being used every step of the way. From identifying potential APIs of interest for different disease mechanisms and biological targets at the early conception phase to screening large libraries of molecules for identifying the lead compounds for a new drug, to analysing data taken from various testing stages along the development path (from pre-clinical to clinical), advanced data analysis methods now play a key role in reducing the development times of many new drugs.
Permeability: the new drug discovery challenge
Despite the advances made in bringing API and formulation development closer through new formulations that enhance solubility, there are still some challenges for the industry to solve. Even though the solubility challenges have been solved, problems persist regarding the permeability of the new generation of larger small-molecule modalities (i.e. PROTACs, etc), peptide and oligonucleotide-based drugs. Most peptides only have around 1% bioavailability, with some leading peptides
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only having a 3% bioavailability. However, these peptides are very potent so not as much needs to be absorbed by the body. Permeability is the drug’s ability to cross a biological membrane and be absorbed through the intestine and into the bloodstream. The size of these molecules combined with their hydrophilicity makes it difficult for them to cross these membranes compared with small-molecule APIs. Peptides, particularly, have a lot of hydrogen bonding sites, a high hydrophilicity and a low lipophilicity, leading to a low absorption from the gastrointestinal tract. If these drugs are to be used in more oral formulations going forward (as they are used more as injectables) the permeability will have to be solved via chemical modifications combined with formulation design – just like the solubility problem – otherwise they will continue to have poor bioavailability.
New polymer materials for ASDs Even though ASDs are the most prominent solubility and bioavailability solution today, there is still more work to be done. Drug loading remains a challenge for many ASDs, with most formulations only being able to achieve 30% drug loading for low-potency drugs. This means that a patient that requires a 500–1,000mg dose may have to ingest multiple large tablets or capsules to achieve a systemic response. This often leads to tablet sizes and doses unfeasible for many drugs, other than for critical illnesses where other options are limited. The hope is to get beyond 40% to reduce the number of tablets required per dose.
Related to drug loading is stability, because the more drug that is loaded into the amorphous formulation, the less stable it will be. To reduce the chance of ASDs from crystallising, the hope going forward is that they will have improved chemical and physical stability in above room temperature conditions and higher humidity levels. Finding new polymer materials that are more effective could help to unlock higher drug loading capabilities for ASDs; however, there is a reluctance to take risks in the industry that has led to only well-known and well-tested polymers being used. It might be the case that more research, and more risks, on other host materials is going to be the way forward for improving ASDs beyond their current capabilities today.
Overall, the solubility challenge for poorly bioavailable compounds has been solved through new formulation challenges, and pharmaceutical companies are reducing development times by integrating advanced technological approaches into the drug development cycle. But like anything, there is still more work to be done to increase the effectiveness of formulations containing poorly bioavailable APIs. ●
www.worldpharmaceuticals.net
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