NANOPARTICLE ENGINEERING - Lighting the Way to a Patient-Centric Future

INTRODUCTION

When developing a new drug, a strong focus is placed on ensuring the compound is effective, safe, and feasible to manu­facture at scale. These are all important concerns. However, it is crucial to bear in mind that a drug’s impact goes far beyond its chemistry. While a drug may be able to achieve its objective per­fectly, if it is unpalatable, difficult to swallow, or results in a mul­titude of side effects, patient compliance will suffer. Put simply, if an efficacious drug is not taken, it will not be effective.

As a result, medication adherence is widely recognized as an increasingly relevant issue in healthcare. Poor adherence to therapy naturally results in worse patient outcomes and can also place an economic strain on the healthcare system. This issue is especially notable for geriatric and pediatric patients.

Enhancing the properties of drugs to make them more con­venient for patients, with potentially fewer side effects or a smaller pill size, could significantly impact a patient’s quality of life. One way to accomplish this is by utilizing the latest technologies to en­hance the properties of both new and existing drugs. In particular, nanoparticle engineering technologies could help improve com­pliance and patient outcomes, for both small-molecule and bio­logical drugs. The following will discuss how nanotechnology can help facilitate a shift toward more patient-centric medicine.

CHALLENGES FACED BY PATIENTS

Elderly patients often have complex drug regimens, with a variety of side effects that must be managed. Mobility is also a significant challenge amongst the geriatric community. Medicines that cannot be self-administered and require hospital visits cause great inconvenience and reluctance among patients.

With the number of older persons aged 60 or over is ex­pected to double by 2050, the impact of non-compliance among the elderly is only expected to grow.¹ Advances in biological de­livery devices and biological nanoparticles that allow a higher drug concentration could be of use here. Meanwhile, children may not understand the need to take an unpleasant-tasting med­icine, and their reluctance can result in non-compliance. It has been estimated that a third of pediatric patients fail to complete even relatively short-term drug regimens.² Treatment sessions for chronic conditions that require children to frequently visit a hos­pital can also result in significant disruptions to everyday life and absences from school. As a result, there are very clear quality-of-life benefits to be gained when the pharmaceutical community places the patient first and foremost during drug development.

OBSTACLES IN THE WAY OF PATIENT-CENTRIC MEDICINES

In order for more patient-centric drugs to reach the market, a number of challenges must be overcome during development. For instance, systemic circulation of drugs can result in more side effects compared to a product delivered locally to the therapeutic target, for example, treating an ophthalmic disorder through top­ical eye drops. However, biological membranes in the eye can prevent local delivery of drugs. Equally, treating a lung disorder through an inhaled therapy would in some cases be ideal. How­ever, for drugs to penetrate the lung, they must possess the correct aerodynamic parameters, which requires them to be 1 to 5 mi­crons in size, ideally. Technologies that can facilitate this and other local drug delivery could allow more patient-centric, localized therapies to reach the market.

Additionally, a trend toward more complex and, consequently, poorly soluble new drug candi­dates means many life-changing drugs never reach the patients who need them. Low aqueous solubility leads to poor ab­sorption in the body and subsequently poor bioavailability, defined as the extent and rate of drug entering systemic circula­tion.³ This can mean a drug will not reach The latest nanoparticle engineering technologies promise to address these challenges and more, improving care for patients around the world. its target area in sufficient quantities to achieve a therapeutic effect. Poor solubility is a leading cause of failure in drug devel­opment, with up to 90% of new drug can­didates falling within the Biopharmaceutical Classification System (BCS) low solubility categories.⁴

NANOPARTICLE-BASED APPROACHES FOR PHARMACEUTICAL DEVELOPMENT

Nanoparticle engineering ap­proaches work by shrinking down the size of drug particles to improve their pharma­cokinetic properties or to help them access challenging drug delivery routes.

In principle, the smaller the particles, the greater the surface-area-to-volume ratio of the active pharmaceutical ingredi­ent (API). Put simply, as the API particles re­duce in size, their surface area increases, leading to greater interaction with the sol­vent and improved solubility. For example, crystals of aprepitant (an NK-1 tachykinin receptor antagonist used to treat chemotherapy-induced nausea) exhibit a 41.5-fold increase in surface area, when particle size changes from 5 μm to 120 nm.⁵

There are a number of nanoparticle engineering approaches that capitalize on this effect and can be used to create small molecule nanoparticles, including the fol­lowing:

• Nanomilling is a technique that works by milling in a liquid medium. It can successfully reduce drug particles to the range of 100s of nm in some cases. However, mechanical energy is used to break up the crystals into smaller sizes, which raises surface free energy. And may cause defects in the crystal lattice and amorphous regions. Such domains could also lead to differences in disso­lution and, therefore, potential variabil­ity in therapeutic response for patients.
• Spray drying is another popular method for particle size reduction, typically mi­cron-sized. This approach transforms a fluid material into a dried powder by spray-drying APIs with a polymer, which prevents the API particles from interact­ing with each other, to create an amor­phous solid. While effective for certain applications, the polymer can add sig­nificant weight to the preformulated material, making it more challenging to form products at the intended dose and in the desired format.
• Controlled Expansion of Supercritical Solutions (CESS) technology has emerged as an alternative, game-changing solution to the challenge of poor solubility and patient-centricity in BSC Class II and IV molecules. Particles are dissolved in supercritical carbon dioxide (scCO2) and crystallized under controlled temperature and pressure, without excipients. The process is scal­able, and allows uniform particles of tunable size, shape, and polymorphic form to be produced in the low nanoscale range. In addition, as this approach makes use of green scCO2 as its solvent, it is environmentally friendly and can help to reduce the manufacturing footprint.

CREATING NEW AVENUES FOR PATIENT-CENTRIC DRUG DELIVERY

Using the CESS^® process, it is possible to create small-molecule nanoparticles as small as 10 nm in some cases – potentially small enough to cross the blood-brain barrier, which is ordinarily impassable. Designed to shield the brain from toxic substances in the blood, epithelial-like tight junctions within the brain capillary endothelium block the passage of approx­imately 98% of small molecule drugs, and most biologics.⁶ As a result, nanoparticle engineering could open up new drug tar­gets, creating exciting possibilities for treat­ing debilitating central nervous system (CNS) disorders such as Alzheimer’s and Parkinson’s.

Meanwhile, many diseases of the lung, such as such as asthma, emphy­sema, chronic obstructive pulmonary dis­ease (COPD), cystic fibrosis, primary pulmonary hypertension, and cancer, are prime candidates for local delivery. This can help avoid first-pass metabolism in addition to avoiding systemic side effects by depositing directly at the site. In the case of the lung, particles smaller than 1 μm tend to be exhaled due to their low in­ertia, while particles larger than 5 μm can struggle to reach the deep lung. Nanopar­ticles can be clustered to create larger par­ticles in the ideal 1-5-μm aerodynamic range, allowing them to penetrate the pe­riphery of the lung and create new possi­bilities for improved inhaled therapies to treat respiratory disorders.⁷

The eye presents another challenge. Topical administration is an ideal route for ophthalmic delivery. In this case, systemic delivery would require a relatively high cir­culating drug concentration for a thera­peutically effective dose to reach the eye, so topical medicines can have significantly reduced side effects by comparison.⁸ How­ever, high tear-fluid turnover rate and na­solacrimal drainage rapidly remove fluid from the eye, meaning a drug’s bioavail­ability must be high for it to be effective.

Physiological barriers designed to prevent entry of toxic chemicals, such as the corneal epithelia, present another complication in the way of ophthalmic de­livery. By reducing the size of drug particles to increase their permeability across these barriers, as well as improving their bioavailability, nanoparticle engineering can potentially provide an ideal way for­ward for topical ophthalmic therapies struggling under the weight of these obsta­cles.

LOWER DOSE; HAPPIER PATIENTS

In addition to creating new avenues for drug delivery, reducing drug particle size to the extent that the CESS^® process can opens up a variety of opportunities to transform the patient experience. By re­ducing particle size to the nanoscale, and eliminating the need for bulky excipients to stabilize nanoparticles, the consequent up­surge in dissolution rate and bioavailability could mean that a lower dosage and reg­imen can achieve the same therapeutic ef­fect. This would mean the number of pills a patient has to take in a day, referred to as pill burden, could be reduced – a sig­nificant patient benefit.

In addition to addressing pill burden, lowering the dose of API needed could also help to reduce the size of the pill. With difficulty swallowing, known as dysphagia, affecting an estimated 9 million people in the US alone and disproportionately af­fecting the elderly, children, and those with certain medical conditions that make swal­lowing more challenging, this benefit has the potential to positively impact many lives.⁹ Lowering the dose can also help re­duce adverse side effects, enhancing qual­ity of life – especially for patients taking multiple medications. Taken together, the impact of lowering the dose has the po­tential to increase medical compliance across the board.

BROADENING THE BIOLOGICS FIELD

The biologics market is growing rap­idly. Valued at approximately $302.63 bil­lion in 2020, it is expected to reach $509.23 billion by 2026.¹⁰ Derived from natural sources and encompassing thera­peutic proteins and other large biomole­cules, as well as nucleic acid (DNA and RNA)-based therapies, the growth in the biologics field can be partially attributed to their potency, high specificity and safety profiles. This makes them excellent candi­dates for patient-centric therapeutics.

However, developing biological drugs presents its own unique challenges. While many biological drugs are water soluble, their large size can make accessing a drug delivery route challenging due to their in­ability to cross barriers in the body. In ad­dition, biologics often struggle with stability due to a tendency for particles to aggre­gate. Any process applied to them must also avoid negatively impacting biological activity – for example, enzymes cannot be exposed to high temperatures or they could lose their activity.

The latest nanoparticle engineering technology could offer a means to help bi­ological drugs reach their full potential. By reducing the size of biological particles to as low as 50 nm without necessitating high temperatures, shear stresses, or damaging biological activity, it may be possible for them to access new drug delivery routes that were previously barred. For instance, a collaboration between Nanoform and Herantis is currently investigating whether a therapeutic compound for Parkinson’s disease, HER-096 (a synthetic chemical peptidomimetic version of the active par­ent CDNF protein), can be delivered to the brain through the oral route. If successful, this could be game-changing in the search for a cure to this debilitating disease.

LOOKING TO THE FUTURE

In light of the latest technologies, the future of patient-centric medicines looks bright. Patient-centricity is an increasing focus in the pharma industry, and this is only expected to continue moving forward. This is reflected by the updated ICH Q8, Q9, and Q10 guidelines, which focus in part on the needs of the patient and for quality by design (QbD) to ensure the quality of therapeutics. The shift toward patient-centricity is driven not only by an aging population, but also by advances in digital health technology that provide key insights into patients’ comfort. This makes it easier than ever to incorporate feedback that can improve treatment. Collaboration within the industry to bring together data, enabling technology, and pharmaceutical problem solvers are keys to enabling more patient-centric care. By partnering to lever­age advanced technologies such as nanoparticle engineering during drug de­velopment, patient compliance and com­fort can be dramatically increased.

From young to old, patients around the world stand to benefit from more pa­tient-friendly medicines with fewer side ef­fects, higher drug loads, and patient-friendly administration routes. Ul­timately, this can both ease the burden of poor medication adherence on the health­care system and improve quality of life.

REFERENCES 

1. https://www.who.int/news-room/fact-sheets/det­ail/ageing-and-health
2. https://publications.aap.org/ pediatrics/article-abstract/115/6/e718/67454/How-Do-You-Im­prove-Compliance?redirectedFrom=fulltext.
3. https://www.ncbi.nlm.nih.gov/ books/NBK557852/.
4. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC4629443/.
5. https://pubmed.ncbi.nlm.nih.gov/ 17601629/.
6. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC3494002/.
7. https://onlinelibrary.wiley.com/ doi/epdf/10.1002/med.20140.
8. https://jpet.aspetjournals.org/ content/370/3/602.
9. https://pubmed.ncbi.nlm.nih.gov/ 25193514/.
10. https://www.mordorintelligence.com/ industry-reports/biologics-market

Dr. Christopher Worrall earned his PhD in Synthetic Organic Chemistry from the University of Manchester, UK, and has multiple publications in the areas of atropisomerism and enantioselective synthesis. After his studies, he spent 2 years developing synthetic processes for GMP syntheses within SAFC before moving to Pharmorphix. Subsequently, he has spent 13 years specializing in the area of crystallization and physicochemical modification, starting as a scientist before being promoted to project leader and rising to become US business development manager. He has been involved in the development of 5 commercial pharmaceutical products and is an inventor on patents in the areas of liquid crystals, organic semi-conductors, and pharmaceutical solid form. A native of North West England, he has spent the past 9 years in San Diego, CA, where he is currently Vice President of US Business Development at Nanoform.