Dr. Gonçalo Rebelo de Andrade, Chief of Business Operations at Nanoform, describes how the latest nanoparticle engineering technology promises to improve efficiency in the pharmaceutical industry.
 

Bringing a new drug to market is a monumental task, involving the combined efforts of scientists across the drug discovery and development pipeline. The entire process can often take 12-15 years, and the development of a single drug often comes with a price tag of over $1 billion.^[1] Considering the life-changing benefits that new medicines can bring to patients globally, this is not such a high price – a bigger problem arises from the low success rates associated with drug development. For example, while $182 billion was poured into R&D in 2019 alone, only 48 drugs were approved for use.^[2-3] This is far from an anomaly – from 2010 through to 2018, the FDA has averaged approval of just 37 novel drugs per year, despite ever-increasing funding. Moreover, the chance of success for a compound entering Phase 1 trials is slightly under 10 per cent. This is significant: no other major business type operates under such a high failure rate.^[4]

 

With the incredible expense and low success rates associated with drug development, there is a shared feeling in the pharmaceutical industry that technological innovations are greatly needed to improve efficiency. Nanoforming, the process of engineering drug compounds into nanoparticles, has emerged as one such innovative technology.

 

 

Major causes of attrition in pharma are issues arising from low bioavailability and solubility of drugs.^[5] If a drug cannot reach its target area, no matter how promising its pharmacodynamic properties in vitro, it will fail in clinical trials.

 

The solubility of a compound defines its ability to dissolve in a solvent to produce a homogeneous solution.^[6]A drug’s bioavailability, meanwhile, refers to the extent and rate at which the drug enters systemic circulation in an unchanged form, thereby reaching its target area. A large proportion of drugs is administered orally and absorbed into the body through the gastrointestinal (GI) tract and poor water solubility will result in poor drug absorption through the intestinal wall, negatively impacting bioavailability.^[7]

 

With more than 40 per cent of new chemical entities (NCEs) developed in the pharmaceutical industry almost entirely insoluble in water, this is a major problem for formulation chemists.^[6] A further issue is the increasing complexity of drug compounds, resulting in higher molecular weights and increased hydrophobicity. These characteristics decrease drug solubility, complicating drug development. As the trend towards more complex drug compounds further establishes itself in pharma, it is expected that the emphasis on finding new ways to improve drug solubility and bioavailability will continue to grow.^[5]

 

 

There are a number of technologies on the market today that strive to address the issue of poor bioavailability and solubility of drug candidates. One of the most frequently used techniques is that of spray-drying formulations of amorphous solid dispersions. While effective, the technique can produce amorphous material and make it challenging to form tablets or capsules. Nanomilling, meanwhile, is an example of a top-down approach by which particle size is reduced through milling in a wet medium. It can successfully produce nanoparticles as small as 150nm. However, by introducing mechanical stress the technique can also create amorphous domains, causing aggregation and potentially changing the polymorphic form of the drug.

 

Furthermore, while techniques such as co-crystals – in which drugs with poor water solubility are engineered to form co-crystals with water soluble molecules – are highly effective, they may not be suitable for all drug molecules. ^[8]

 

 

Nanoforming, the process of engineering drug compounds into nanoparticles, has emerged as a compelling solution to the problems associated with poor drug solubility and bioavailability. By shrinking API particle sizes down to the nano scale, nanoforming maximizes their contact with solvent molecules, thereby improving solubility. 

 

The latest nanoforming technology, referred to as the ‘controlled expansion of supercritical solutions’ (CESS), achieves uniform nanoparticle sizes by employing a bottom-up recrystallization technique to produce crystalline materials from solution in a controlled process. The resulting particles are tunable in size, shape and polymorphic form. The nanoformingprocess dissolves and extracts API particles from supercritical carbon dioxide (scCO₂) without changingthe API’s inherent chemical properties. Furthermore, supercritical methods offer better scalability than other nanoforming techniques and are therefore more industrially relevant.

 

 

Using this method, nanoparticles as small as 10nm can be produced in some instances. This is a highly significant breakthrough. While previous technologies were limited to producing nanoparticles of 100nm and above, granting a 20-30 fold increase in specific surface area, decreasing particle size to the50nm mark can boost specific surface area by 1000-fold. As a result of this major advance in nanoforming technology, the technique can now dramatically improve the solubility and bioavailability of drug compounds.

 

This has exciting implications for the pharmaceutical industry, offering the possibility that drugs previously discarded due to issues with bioavailability and solubility can now be revisited. The technology also provides a solution to the increasing complexity (and insolubility) of drug candidates. Furthermore, by improving absorption the technique can reduce drug dosage, driving down manufacturing costs. As a result of the notable power of the technology for enhancing bioavailability and solubility, it is estimated that the latest nanoforming process can double the number of drugs reaching clinical trials.

 

 

Shrinking down the size of drug compounds also creates new opportunities for drug delivery into difficult-to-reach areas. For example, nanoforming enables drug particles to be transported into the deep lung, opening up new possibilities for the treatment of respiratory diseases. Nanoparticles can be exhaled from the lung due to their low inertia, therefore nanoparticle medicines are often coupled to a larger delivery framework. Particles of 1-5 microns are ideally suited to pulmonary delivery, possessing the correct aerodynamic parameters for transport into the periphery of the lung. Systemic circulation of the drug through the lung is also possible with decreased drug particle size, and an attractive option due to the rapid onset of action observed through this route.^[9,10]

 

In addition to facilitating drug delivery into and through the deep lung, nanoforming also creates exciting possibilities for ocular delivery. The human eye presents a huge challenge for drug delivery as a consequence of the numerous physical barriers that must be penetrated, including the ocular surface epithelium and tear film. Nanoforming offers high drug loading and increased adhesiveness, enhancing transport and retention of the formulation in the ocular sac.^[11]

 

Drug delivery through the blood-brain barrier is afurther example of the power of nanoforming technology. Notoriously difficult to penetrate, the blood-brain barrier protects the central nervous system (CNS) from invading pathogens and neurotoxic molecules. In order to create successful therapies for treatment of CNS disorders, however, it is an obstacle that must be overcome. Studies have shown that exceptionally small molecules can diffuse through the blood-brain barrier,^[12] highlighting the potential of technologies such as CESS to facilitate breakthroughs in this area.

 

Finally, decreasing particle size can also enhance drug delivery through the skin. Another challenging route, the skin is in effect specially designed to present a barrier between internal and external entities. Drug treatments must penetrate through several layers, in particular the stratum corneum, to reach systemic circulation. Research has shown, however, that nanoparticles can be transported through channels created by hair follicles, opening up new avenues for the development of topical treatments.^[13]

 

 

Studies also show that by improving the absorption of drug compounds into the body, the latest nanoforming processes enable a smaller quantity of API to achieve the same therapeutic effect. The implications of lowering the required dose are manifold, impacting patients, manufacturers and even the environment.

 

While 350nm API particles have already been shown to display a 4 per cent dose reduction, 50-100nm API particles are expected to show at least a 90 per cent reduction in dose. If achieved, this could help to reduce side effects for patients, as much smaller quantities of API will be ingested. Lowering the quantity of drug dose in a capsule will also decrease the cost of manufacturing, improving cost-effectiveness and helping the industry to move towards a more carbon-neutral footprint. Moreover, by making use of CO₂, CESS technology represents a green particle engineering process for the production of nanonized APIs. The process is also free from excipients and organic solvents, further reducing environmental impact.

 

 

Nanoforming has emerged as a compelling solution to the high rate of attrition and increasing complexity of drug candidates in pharmaceutical development today. The benefits it brings to the industry are manifold, from addressing a leading cause of drug failure by improving bioavailability and solubility to improving cost-effectiveness and creating new avenues for drug delivery. With the pharmaceutical industry struggling under the weight of inefficiency, the exciting implications of the technology are expected to make an important difference, providing failed drugs with a second route to market and doubling the number of drug candidates entering clinical trials. Moving forward, there can be no doubt that this technology will make a lasting mark.