Meeting New Needs: The Key Trends Shaping Oral Dosage Formulation
Increasingly complex and diverse molecules in the development pipeline and greater demand for patient-centricity are leading to a need for developers to employ advanced formulation approaches and strategies.
Oral dosage forms comprise the largest proportion of drug products that are commercially available. The market is expected to continue to grow, reaching USD 1.03 trillion by the end of 2032, according to market research (1). To learn more about the key trends shaping the oral dosage formulation market, The Pharma Navigator spoke with Tamas Solymosi, PhD, Lead Scientist, Nanoform Finland.
OSDs: Here to Stay
TPN: Could you give an overview of the oral dosage formulation market, highlighting any key trends that have been/are set to be impactful?
Solymosi: Oral small-molecule dosage formulations still account for over 80% of drugs on the market, primarily due to their stability and ease of administration. Orally delivered formulations are here to stay: each year more than 50% of NME [new molecular entity] approvals are oral solid doses, and oral therapies continue to dominate development pipelines. As technologies advance, conventional oral dosage forms are expected to evolve toward more patient-centric (fewer and smaller tablets) and personalized on-demand therapies, especially for pediatric and geriatric patients.
Shifting Strategies to Earlier in Development
TPN: The development pipeline is being saturated with increasingly complex and poorly soluble molecules, how are formulation approaches shifting to cope with these challenges?
Solymosi: The default step after identifying a lead candidate is to perform salt screening and/or micronization to address slow dissolution and low solubility. For poorly soluble drugs — which make up the majority of drugs in development — these typically yield suboptimal formulations with low bioavailability, large food effect, and extreme variability in exposure PK parameters. Advanced formulation strategies such as, amorphous solid dispersions (ASDs), nanoparticles, lipid formulations, are shifting to earlier stages of the drug development process. Traditional, market-proven processes like spray drying, melt extrusion, and nanomilling are likely to remain; however, there is no universal formulation process, and a wide range of technologies are needed to meet the specific needs of increasingly complex and diverse molecules.
Among emerging technologies, drug–drug co-amorphous systems can offer the simultaneous advantages of improved solubility and long-term physical stability.
Nanoforming is also worth mentioning: It is a green process involving the nanoprecipitation of APIs from supercritical CO2. Pure API nanoparticles as small as 10 nm can be produced, and these nanoformed APIs can be incorporated into a wide variety of final dosage forms and administration routes. This enables high drug load and more patient-centric oral drug formulations compared to ASDs [amorphous solid dispersions], while achieving comparable bioavailability.
For compounds that are both extremely poorly soluble and permeable, for example, certain PROTACs [proteolysis targeting chimeras], RIPTACs [regulated induced proximity targeting chimeras] and other large molecules outside the rule-of-five, subcutaneous or intramuscular injectable suspensions may be favored over poorly absorbed oral medications. Here, nanoparticles can offer advantages over conventional injectables.
Unlocking API Potential with Patient-Centric Formulation
TPN: Patient-centricity has been a priority for several years now, are there any recent innovations that are helping oral dosage formulators in this area?
Solymosi: Large pill size, pill burden, and suboptimal in vivo performance are typical issues associated with high dose, poorly soluble drugs.
Some excellent APIs are marketed in suboptimal final dosage forms leading to therapy discontinuation and ultimately worse outcomes. Improved formulations of these APIs could unlock their full potential. For example, ASDs are great in solving dissolution/solubility issues, but the improved performance typically comes at the cost of low drug loading in pills. For high dose compounds (>100 mg), pill size and pill burden of ASD formulations can be excessive.
High drug-load nanoformed API formulations, matching the performance of ASDs, can alleviate pill burden and decrease pill size for a more patient-centric formulation, ultimately yielding better adherence to therapy.
Another noteworthy technology is 3D printing, which can customize the strength, size, and shape of a pill or even allow the in-situ preparation of fixed dose combinations. These factors are imperative when treating patients who have difficulties swallowing conventional pills.
Potentially Significant Future Regulatory Updates
TPN: In light of potential regulatory updates, involving certain ingredients, could you offer some insights into how oral dosage formulation might be impacted?
Solymosi: There have been few complete excipient bans by the FDA or EMA, though several important ones are pending. Some bans have little to no impact or may cause a few sleepless nights for formulators, while others may turn out to be very significant. For example, discontinuing certain dyes used in tablet or capsule coatings is primarily an aesthetic issue, and many alternatives exist.
There are two significant bans that may take effect in the future:
The expected ban of titanium dioxide (TiO2) in pharma applications by the EMA (has already been banned as a food additive by the EMA). TiO2 is used in tens of thousands of products, and serves multiple functionalities (e.g., white/opaque coloring, UV protection, and as a filler). So far, no single excipient can fully replace it.
The potential ban of methylene chloride, also known as dichloromethane (DCM). The majority of marketed solid dispersions are produced by spray drying and DCM is a typical solvent used in that process. It is a powerful solvent that can dissolve many APIs, even the ones that are poorly soluble in alternative spray drying solvents such as lower alcohols or acetone. The US EPA [Environmental Protection Agency] prohibited the manufacture, processing, and distribution of DCM for many industrial and commercial uses in 2024. While DCM can still be used where essential (e.g., manufacture of pharmaceuticals), it poses a risk to human health. Therefore, it may be phased out in the future, limiting the parameter space of the spray drying process. This also highlights the need for alternative and green enabling technologies such as nanoforming.
Reference
Fact.MR. Oral Solid Dosage Pharmaceutical Market. Market Research Report, July 2022.
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