Oral ingestion is the most common and convenient route to administer drugs to patients, and most small-molecule drugs created today are oral formulations. The properties of the drug molecules are critical to the success and effectiveness of the formulation. There are two properties of active pharmaceutical ingredients (APIs) that have typically been challenging for drug formulations: solubility and permeability. Poor solubility has been a key issue that has caused a low bioavailability for a lot of oral small-molecule drugs.
However, the solubility problem has now been solved thanks to new advanced formulation methods. Pharmaceutical manufacturers are using a combination of advanced drug formulations in their products – such as amorphous solid dispersions (ASDs), nanosizing and lipid-based carriers – to improve the solubility of poorly bioavailable drugs, while simultaneously using technology advances to speed up their discovery and production processes. These integrated models are now reducing drug development timelines for traditionally poorly bioavailable drugs, but some challenges remain.
Bioavailability challenges for oral drugs in early development phases
The oral bioavailability of a drug is the amount of drug dosage that reaches the therapeutic site and depends on many properties of the APIs – including their solubility, permeability, dissolution rate, intestinal stability and metabolism. The main causes of low oral bioavailability are poor solubility and low permeability. It’s estimated that more than 40% of new chemical entities (NCEs) developed in the pharmaceutical industry are insoluble in water, leading to slow drug absorption, variable bioavailability and gastrointestinal toxicity in conventional formulations. This means a lot of drugs can take longer to develop at higher costs due to their poor bioavailability.
The bioavailability challenges of many drug formulations are now solved long before they reach clinical trials and are an early-stage discovery and development problem. A lot of the solubility and formulation challenges are solved at the pre-clinical stage, and there are now fewer challenges with small-molecule API synthesis. A molecule won’t make it through to the later development stages unless it can be run at the higher exposure levels required in the animal studies – which is anywhere from 10 to 100 times higher dose and exposure that a human would ever receive. The industry has developed alternative formulation approaches to solve the bioavailability issue for many smallmolecule APIs that have a poor solubility.
Solving the solubility problem for small molecules
Addressing the solubility problem has involved pharmaceutical companies developing different formulation approaches. While some involve chemical changes, the most successful have involved making physical changes to the formulations – such as making the formulation amorphous and nanosizing the formulation – as well as loading the APIs into more soluble carriers, such as lipids. The decision of which one will be chosen for a specific API is determined at the discovery phase.
While not all drugs being developed today will need these advanced formulations, those classified in the biopharmaceutical classification system (BCS) class II (low solubility and high permeability) and class IV (low solubility and low permeability) are typically targeted for these advanced formulation techniques.
Amorphous solid dispersions
Among the formulation approaches that solve the solubility and bioavailability problem of insoluble APIs, ASDs have become the most common option within the industry. According to academic literature, around 30% of commercial products that require solubility enhancement used this approach between 2000 and 2020.
ASDs are amorphous formulations where the drug has been dispersed inside a polymer matrix – such as cellulose derivatives, polyvinylpyrrolidones and vinyl acetate balanced co-polymers, and methacrylic acid and methacrylate esters – as they all have chemical functional groups that promote dissolution in water. Because the drug is loaded inside the polymer and the amorphous form has a high surface area, the solubility and bioavailability of the drug is significantly increased. For example, an ASD increases the human bioavailability of vemurafenib five-fold compared with its crystalline form.
ASDs are synthesised by several methods, such as hot melt extraction, spray-drying and co-precipitation methods, which create a homogeneous dispersion of the API throughout the polymer matrix. Deciding whether a crystalline drug is suitable for being converted into an amorphous form is done at the discovery stage. Microscale screening and high throughput screening (HTS) combine the API with different polymer materials under different heating and cooling conditions to find the most stable ASD and optimal drug-polymer ratio. The different ASDs with different drug loading levels (μg to mg) are tested in very small amounts to ensure that they remain stable and don’t recrystallise.
Nanosizing – a key approach
Another key approach is nanosizing APIs in formulations, because the solubility of a drug is directly related to its particle size. As the API particles become smaller, the surface area to volume ratio increases. A larger surface area interacts more with a solvent and improves the wettability of the drug. This leads to an increased drug solubility.
In nanosizing methods, the API particle size is reduced to 100-200nm using top-down milling and homogenisation methods and bottom-up precipitations and supercritical fluid methods. The nanoparticles are then stabilised using either polymers or surfactants and processed into dosage forms.
The nanosized APIs have a higher dissolution rate and a reduced variability, leading to a higher oral bioavailability. Nanosizing does offer a way to get a higher drug loading than other methods, but it’s not an approach that is suitable for all APIs, so can only be chosen in certain circumstances. Nanosizing is also being enhanced by advanced data analysis approaches, such as machine learning, which are better at predicting the particle size and polymer dispersity index of these nanoforms when created by top-down methods.
Lipid carriers
Outside of physical modifications to the drug, carrying them in lipids is another key approach. Hydrophobic drugs are dissolved in lipids or encapsulated in a phospholipid bilayer, so the drug is delivered to the body without needing to change its physical form. Lipids have a high biocompatibility, solubilisation, degradability and low immunogenicity, so can deliver drugs to the body.
Some lipid carriers improve the uptake of poorly bioavailable drugs as they can penetrate through the membranes of the gastrointestinal tract, and selectively into the lymphatic system, allowing the drugs to get into the body and enhance cellular uptake. However, many of them tend to have a lower loading capacity than other approaches.
There are currently many different lipid carriers in use today, including liposomes, solid lipid nanoparticles, transferosomes, nanostructured lipid carriers, lipid nanocapsules and self-microemulsifying drug delivery system (SMEDDS) – so there are lots of choices depending on the drug and the target.
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 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.
