NANOPARTICLE ENGINEERING – Lighting the Way to a Patient-Centric Future
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.
- https://publications.aap.org/ pediatrics/article-abstract/115/6/e718/67454/How-Do-You-Improve-Compliance?redirectedFrom=fulltext.
- https://www.ncbi.nlm.nih.gov/ books/NBK557852/.
- https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC4629443/.
- https://pubmed.ncbi.nlm.nih.gov/ 17601629/.
- https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC3494002/.
- https://onlinelibrary.wiley.com/ doi/epdf/10.1002/med.20140.
- https://jpet.aspetjournals.org/ content/370/3/602.
- https://pubmed.ncbi.nlm.nih.gov/ 25193514/.
- 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.
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