Last year was no deviation from the norm; the great expense and low success rates associated with drug development have long been noted. For example, the period from 2010 through 2018 averaged approval of merely 37 novel drugs per year, despite a 39% increase in investments. It is therefore imperative that the industry adopts technological innovations that can greatly improve the efficiency of drug development.

A leading cause of pharmaceutical attrition is poor drug solubility and bioavailability, with around 40% of promising active pharmaceutical ingredients (APIs) currently suffering from low solubility. Out of the large fraction of drugs administered orally, most only become bioavailable following oral ingestion and penetration through biological membranes within the gastrointestinal (GI) tract. For Biopharmaceutics Classification System (BCS) II substances in particular — defined by low solubility and high permeability — bioavailability can be improved by increasing the solubility and dissolution rate of the drug in the gastrointestinal fluids.

As dissolution rates can be significantly improved by reducing the size of the drug particle, advanced nanoparticle engineering technologies are providing a revolutionary answer to this long-standing problem.

Drug Nanoparticle Engineering

The production of nanoparticle­s or “nanoforming” can be achieved through either a “top-down” or a “bottom-up” approach. Current top down approaches, such as nanomilling, use a significant amount of energy to achieve 200 nm size materials and require excipients — sub­stances formulated alongside the active ingredient — and often polymers to stabilize materials. Bottom-up techniques such as solid dispersion often leverage solvent-acting agents and produce physically unstable amorphous particles that lack a crystalline structure.

The utilization of excipients results in a more complex solubility-enhancing route, which creates scalability challenges. The latest nanoforming technology, a proprietary process developed by Nanoform, utilizes a bottom-up recrystallisation technique to produce crystalline or stable amorphous materials from solution in a controlled and scalable process. The Controlled Expansion of Supercritical Solutions (CESS) process dissolves and extracts API particles from supercritical carbon dioxide (scCO2) without additional excipients. A key advantage of nanoforming drug compounds with­out excipients is that it reduces the need for extended compatibility studies and therefore significantly accelerates initiation of clinical trials. The patented technology is the first to produce drug particles as small as 10 nm, while also enabling the tuning of other surface properties through tight control of thermodynamic processes.

Benefits of Nanoforming Drug Particles

Nanoforming offers many benefits for the pharmaceutical industry, with projections indicating that the technology might be able to double the number of drugs reaching clinical trial. By enhancing the bioavailability of drug compounds, the latest nanoparticle engineering technology can reduce the quantity of API required to achieve the same therapeutic effect. This has wide-ranging implications, from reducing side effects for patients to facilitating the development of more environmentally friendly drug manufacture.

Studies have found that Dv50 ~350 nm API particles provide a 54% increase in the area under the curve (AUC) compared with Dv50 ~2 micron particles for Piroxicam which could translate to a 54% dose reduction. It is therefore expected that 50-100 nm API particles will display a 90% reduction in dose, which will significantly lower the quantity of API that is ingested by patients. It is also expected that this dose reduction capability will be highly relevant for BCS II and possibly also for BCS IV compounds, the two classes into which 70-90% of all drugs in development fall. This can help to reduce side effects for patients, and also reduce the cost of manufacturing.

Pharmaceutical companies have an increasing responsibility to adapt their processes as the industry moves towards a more carbon neutral footprint. Nanoforming can help the industry considerably in this endeavor by reducing the quantities of API that are manufactured. Moreover, the utilization of supercritical CO2 permits a greener particle engineering process for the production of nanoformed APIs. With a production process that is free of excipients and organic solvents, the latest nanoforming technology is well positioned to decrease the environmental impact of drug development.

Not only does a significant reduction in dose through enhanced bioavailability imply patient and environmental benefits, it is also a novel way of improving manufacturing efficiency, of reducing volumes of drug substance and drug product manufacture, as well as manufacturing footprints and capital expenditure required for manufacturing. This is a step change that could enable major pharma companies to increase efficien­cies in their supply chains by using such techniques.

Facilitating Novel Drug Delivery Routes

Shrinking drug particle size has exciting implications for drug delivery, opening up previously inaccessible routes. Ultimately, this results in the development of more effective treatments for patients. Enhanced pulmonary delivery is a prime example. While nanoparticles can be exhaled from the lung due to their low inertia, nanoparticle medicines can be coupled to a larger delivery framework of 1-5 µm or can be delivered in suspension as a pressurized metered-dose inhaler (pMDI) or through nebulized delivery. This enables drugs to be delivered into the periphery of the lung and can also facilitate systemic circulation of the drug following absorption from the lung into the blood. This is followed by a rapid onset of action, making it an appealing option for pharmaceutical developers. By facilitating transport of nanomedicines into the deep lung, a wide array of new opportunities can be realized for treatment of respiratory disorders. In addition, it is expected that if the particles were tuned to 10-50 nm size, they could become entrapped by the cells in the lung and not cleared effectively. This would therefore permit increased local delivery and potentially provide advantages for lung cancer treatments. Nanoparticle engineering creates new possibilities for ocular delivery.

A notoriously challenging target, drugs penetrating through the human eye must overcome numerous physical barriers such as the ocular surface epithelium and tear film. Nanotechnology can help to overcome the challenge posed by the natural barriers present in the human eye, offering benefits over nanocarrier technology — including high drug loading and increased adhesiveness to improve both transportation and retention of the drug formulation in the ocular sac.

Nanoforming and the Challenges of Tomorrow

One of the greatest challenges society faces is the dramatic increase in age-related diseases as a result of shifting global demographics. Indeed, the number of people in the world aged 60 years or over is expected to grow by 56% between 2015 and 2030. This will place an unprecedented demand on healthcare systems and requires the development of novel and more efficient therapies to treat age-related diseases.

Nanoforming technology will be critical for the delivery of these new treatments, as the innovation provides a number of benefits for elderly patients. For instance, enhanc­ing bioavailability and lowering drug ­dosage can reduce the risk of adverse drug reactions (ADR). This is particularly important for elderly populations, as twice as many pa­tients over the age of 65 are hospitalized due to ADR-related events when compared to younger people. Moreover, the smaller quantity of API also en­ables a significant reduction in the overall size of the tablet, which can help elderly patients suffering from xero­stomia — difficulty swallowing caused by reduced or absent saliva flow — continue their drug regime.

Age-related diseases of the brain, including Alzheimer’s disease, are also expected to increase with aging populations. Treating Alzheimer’s disease still presents a great challenge to drug developers as drug delivery to the central nervous system (CNS) is limited by the blood-brain barrier (BBB). Nevertheless, research has shown an inverse correlation between nanoparticle size and successful penetration of the BBB. This indicates that advanced nanoforming technologies may permit the development of effective therapeutic options for Alzheimer’s in the future.

Looking to the Future

Nanoparticle engineering increases the likelihood of successful drug development and provides multiple benefits to the pharmaceutical industry. With the invention of advanced nanoforming technologies capable of producing stable nanoparticles smaller than 50 nm by size, new opportunities for novel therapeutics and drug delivery applications have been introduced. Nanoparticle engineering is therefore an incredible example of the power of nanotechnology for advancing the field of medicine.