Oral drug delivery is the most favored route of drug administration. However, poor oral bioavailability is a leading reason for weak clinical efficacy. Clearly, no matter how much of a drug you take, if it doesn’t reach the target organ in sufficient doses, it isn’t going to do much good! With estimations that up to 70% of drug molecules are insufficiently soluble for good bioavailability, this poses a serious challenge for drug developers seeking to demonstrate the efficacy of their products.

Formulation scientists have adopted various strategies to enhance drug bioavailability. Their approaches have the potential not just to improve the success rates of new and innovative treatments, but also to provide improved formulations of old medications. In fact, the large number of poorly soluble drugs on the market has provided profitable strategies for more than one pharma company to file NDAs for improved formulations of older drugs with enhanced bioavailability profiles.

Enhanced bioavailability also means that lower doses of these improved formulations might be sufficient, potentially reducing the overall drug load and minimizing side effects. Furthermore, as APIs become more potent (due to higher bioavailability), the lower loads of drug required could result in smaller drug manufacturing volumes, reduced environmental impact and a smaller manufacturing footprint.

Modern approaches to enhancing drug bioavailability have generally focussed on the molecular optimization of the drug molecule. Broadly speaking, four technologies are used to overcome these challenges: hot melt extrusion, spray drying, lipid-based formulations and particle sizing.

Hot melt extrusion and spray drying both enhance the absorption of poorly soluble drugs through the formulation of ‘a(chǎn)morphous solid dispersions’. Spray Drying and hot melt extrusion are the main manufacturing processes to obtain these amorphous materials, which represent the fastest growing approach to overcoming poor bioavailability. In practice, spray drying is more suitable for heat-sensitive products such as biologics, and it is often the preferred route for inhalable drugs, while hot melt extrusion can be more efficient in developing some poorly water-soluble drugs in hydrophilic carriers.

Lipid-based carrier systems have long been a focus of interest. The incorporation of poorly water-soluble active drug molecules into inert oils, emulsions, self-emulsifying formulations or liposomes, for example, can provide a vehicle to enhance absorption and bioavailability. These delivery systems have been used for decades but, more recently, they have been used for the delivery of relatively large DNA and RNA-based drugs, including plasmids, antisense oligonucleotides and ribozymes.

Particle sizing for enhanced bioavailability typically involves increasing the surface area of a drug molecule by reducing its particle size. Although particle size may have little effect on drugs that are readily water soluble, reducing the size of poorly water-soluble drug molecules can lead to higher dissolution rates due to the larger surface area to volume ratio and, therefore, a better chance for faster absorption. However, particle size reduction may not be useful for very fine powders with poor wettability and handling difficulties.

The choice of technology will depend on the drug molecule in question, and the way in which it will be administered in practice. However, while contract services for lipid-based carrier systems and particle sizing are widely available, hot melt extrusion and spray drying are still niche offerings. As a snapshot view of the global situation, of 1,589 listed CMOs, the Contract Pharma directory lists only 38 offering spray drying, and 24 offering hot melt extrusion (these CMOs are mostly based in North America). If that is an accurate reflection of the current global capability, then about 98% of CMOs are still not offering these technologies, and there is a relative dearth in the CMO-rich countries of China and India. Since they are among the fastest growing approaches to overcoming poor drug bioavailability, rapidly growing demand could make them a good long-term investment.

Nanotechnology is also on the threshold of providing a new approach to enhanced bioavailability. Nanodrugs can stay in the blood stream for a prolonged period and enable the release of drugs as per the specified dose. Being nanosized, these structures can more easily target and penetrate the target organ. Nanotechnology has already been shown to rescue ‘failed’ drug candidates that were deemed to be ‘bioavailability failures’.

Nanoform, winners of last year’s CPhI Excellence in Pharma Award for Formulation, are a great example of a company addressing the pharma industry’s bioavailability issues with an innovative nanotech approach. The company’s nanotechnology – a bottom-up method of recrystallization that works by controlling the solubility of an API in supercritical carbon dioxide – controls the shape and increases the active surface area of API particles. This enables significant improvements in dissolution rates and bioavailability. According to Edward Haeggstr?m, Nanoform’s Chief Executive Officer, when he spoke to me at CPhI last year (2019), the approach addresses numerous challenges facing the pharma industry right now, including the rescue of ‘failed’ drugs if low bioavailability was the barrier to efficacy. This could potentially increase the number of drugs entering the market and lower overall development costs (which currently include to costs of 9/10 ‘failed’ drugs).

In summary, enhancing the bioavailability of a drug may improve its efficacy, reduce its side effects (due to lower doses required), minimize its manufacturing footprint, and it might even breathe new life into ‘failed’ drugs that just couldn’t exert their efficacy due to problems with bioavailability. This is a core area of research, and deservedly so. As the pharma industry continues to witness rapid growth in outsourcing services, the CMO market remains highly competitive and offerings such as expertise in – and the technology for – enhancing bioavailability may be one of several key areas that differentiate the long-term winners of the future.

Author biography

Sarah Harding, PhD

Sarah Harding worked as a medical writer and consultant in the pharmaceutical industry for 15 years, for the last 10 years of which she owned and ran her own medical communications agency that provided a range of services to blue-chip Pharma companies. She subsequently began a new career in publishing as Editor of Speciality Chemicals Magazine, and then Editorial Director at Chemicals Knowledge. She now focusses on providing independent writing and consultancy services to the pharmaceutical and speciality chemicals industry.

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