Drug delivery and the drug modalities in the discovery and development pipelines of the Pharmaceutical and Biotechnology Industries have changed significantly over the last 25 years. Drug delivery was traditionally used primarily to enhance oral exposure or prolong exposure of small molecules and the early peptide drugs. The world is rapidly changing; the drug modalities are diversifying, and drug delivery scientists must play a more prominent role and are core to the genesis of innovative medicines of the future. This note shows where delivery science can play a critical role in treating diseases of the future. It outlines some of the skills, capabilities and behaviours that will be critical for the success of the next generation of medicines and illustrates where drug delivery science will be required at the inception of projects in discovery as well as in development where until recently this has predominantly been the case. Finally, it asks whether we are ready for this evolution.
Changing face of drug discovery and first-generation drug delivery
Drug delivery systems are a means of delivering drugs to patients. Drug delivery needs in the pharmaceutical industry have changed significantly over the last quarter of a century. The majority of drugs 25 years ago were small molecules. Small molecules have a robust discovery process, allow oral delivery with broad tissue distribution and intracellular access, have low cost of goods and can usually be formulated into relatively simple dosage forms. Generally, they are formulated for immediate release or with formulations to either enhance or prolong exposure and/or aid compliance in oral or parenteral dosage forms. These can be considered as the first generation of delivery systems.
Pharmaceutical development is challenging, efficiency is low, and attrition is high . Thirty years ago, one of the main reasons for this attrition in the top ten pharmaceutical companies was adverse pharmacokinetic and bioavailability factors which accounted for ∼ 40% of attrition . Recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption, a Biopharmaceutical Classification System (BCS) was developed  and later adopted by the FDA and other agencies. This has been routinely utilized to assess oral absorption and guide formulation development. A retrospective analysis of marketed and pipeline drugs in 2010 revealed that 40% of marketed and 90% of those in the pipeline were classed as poorly soluble . To help classify development risk and to steer delivery scientists towards the optimal delivery technologies, a number of classification schemes have been proposed for formulation development [5, 6]. From these, the Lipidic Formulation Classification System  and the Amorphous Classification System  have evolved to help drug formulation scientists to classify molecules and steer them towards the optimal delivery technology for a robust product. Poorly soluble drugs were often affectionately referred to as “brick dust” by formulation scientists and presented opportunities for creative scientists whose role was to enhance or enable their development into successful medicines.
Other opportunities for delivery science were to enhance delivery via modified or controlled release for those drugs where prolonged exposure was required. Peptides as an emerging drug modality presented such an opportunity. Controlled release technology was required for viable delivery of many peptide-based drugs, providing a means to prolong plasma concentrations of labile and short half-life peptides removing the need for daily injections (e.g. Zoladex®, Lupron Depot ®).
In 2012, AstraZeneca early drug portfolios (like many other big pharma’s) contained predominantly small molecules intended for oral delivery, and the medicinal chemists worked hard to ensure they obeyed Lipinski’s “rule of 5”. The rule describes the physicochemical properties of molecules suitable for successful permeability and absorption; molecules should have no more than 5 hydrogen bond donors, no more than 10 hydrogen bond acceptors, molecular weight less than 500 and Log P less than 5 . This meant that the ambitious delivery scientist had to be content with addressing any poorly soluble drugs’ formulation needs or extending exposure. The drug delivery challenges lacked diversity and were few and far between; medicinal chemistry was learning how to address solubility issues, and antibodies were growing, but many of these were relatively simple solution formulations. Pharmaceutical development was carried out by scientists in development departments mainly post-selection of the candidate drug. These first-generation drug delivery technologies generally affect the rate and extent of absorption providing either enhanced or prolonged plasma exposure and allow the drug to distribute throughout the body (see Fig. 1).
Second, third and fourth generations of drug delivery
The delivery world is changing, both in terms of drug delivery needs and opportunities. Small molecules still dominate the approved and late stage development pipeline (~ 60%) followed by antibodies with ~ 10% and proteins just behind (~ 9%) . This is despite 8 of the top 10 drugs in 2019 (by global sales) being antibodies or proteins.
Just as drug delivery scientists have had many successes in addressing the pharmacokinetic/bioavailability reasons for attrition in the 1990s , there is now an opportunity for us to address today’s main reason for attrition for small molecules, lack of therapeutic index . For this targeted delivery presents an ideal solution and inevitably often requires moving to the nanoscale to allow penetration across biological barriers and greater targeting/tissue penetration. Targeted delivery systems can be considered as the second-generation drug delivery systems, depicted in Fig. 1, where the ambition is to afford tissue accumulation or targeting usually via nanoparticles, antibody drug conjugates (ADCs) or ligand targeted approaches. There has been much debate and criticism of the nanomedicine field [13, 14], but the field of nanomedicine also holds much promise [15, 16]. Sometimes, only a small shift in drug distribution and balance between on- and off-target modulation is required to enable an important medicine . This can be achieved via biophysical targeting, as in the case of Doxil®, an important standard of care in oncology, and ,the more recently approved Ovidyne®, the combination nanomedicine, Vyxeos® and the emerging nanomedicines of molecularly targeted drugs [18, 19]. Alternatively active targeting approaches can be employed as exemplified by antibody drug conjugate (ADCs), which seem to be “coming of age” with 4 approvals in the last year and over 80 being investigated in clinical trials . Appropriate targeted delivery will also be imperative for safe and controlled stimulation of the innate immune system in the burgeoning field of immuno-oncology. The cargo and target dictate the extent and precision of delivery required and how close we need to get to Ehrlich’s idealistic magic bullet. To successfully develop targeted delivery, disease led rather than formulation led design is vital, and a thorough understanding between the disease pathophysiology, the target and drug properties (e.g. pharmacokinetic -pharmacodynamic relationship) and the delivery system is needed, as discussed for oncology applications in Hare et al. 2016  and illustrated in Fig. 2.
Significantly, more diversified molecules are being explored in early drug discovery. It is considered that up to ~ 85% of the human proteome is currently “undruggable”, that is our current drugs, mainly small molecules and antibodies and peptides for extracellular use cannot modulate these proteins pharmacologically . For example, kRAS is one of the most commonly mutated proteins in cancer; it is a well-validated target, yet despite three decades of effort, there is no modulator of this target in late development. However, it is encouraging to see a number of early clinical studies with a range of modalities and drug delivery science playing an important role in their progression .
Advances in molecular biology, including protein expression and purification, genomics, proteomics and assorted analytical characterization tools including protein nuclear magnetic resonance spectroscopy and crystal structure determination, have improved disease understanding and target engagement. These, in turn, have resulted in a large range of new drug targets and therapeutic approaches to modulate those targets in a far broader biological space. Small molecules are certainly diverting from Lipinski’s “rule of five” or “drugs as we know them” as more complex and innovative chemistries are being rapidly employed to modulate more complex biologies, such as protein-protein and protein-nucleic acid interactions. These also include protein degraders, such as proteolysis-targeting chimeric molecules (PROTACs), which are heterobifunctional small molecules which serve to degrade the target protein rather than just agonize or antagonize the receptor as with traditional small molecules. Solid first-generation delivery science and technologies together with good collaboration with medicinal chemists and pharmacokineticists will be required to advance these new small molecule-based drugs.
For diseases with a well-understood genetic cause, discovering the “drug” increasingly is resulting in some sort of nucleic acid-based approach. Here, instead of interacting at the protein level, drugs are either knocking down the protein (e.g. siRNAs, ASOs, miRNAs), producing the protein (e.g. mRNA) or more recently editing the gene and function of the protein (e.g. CRISPR -Cas 9) opening up further “druggable” target space and treating many important diseases. Really understanding the target and how much needs to knocked down or produced to afford disease benefit is critical to improve success in delivery system evaluation. Mathematical modelling can play an important role in drug discovery and delivery here.
In addition, gene and cell therapies as well as providing new molecular strategies to treat disease can act as in vivo therapeutic factories using the body as a bioreactor. Antibodies and proteins make up ~ 20% of marketed drugs , yet their development and manufacture is long, complex and costly. Monoclonal antibodies are produced in mammalian cell lines, purified from complex media, prone to a variety of post-translational modifications affecting their biological activity and need to be thoroughly characterized and controlled to ensure their quality. Producing them from mRNA means we can avoid long, complex, inefficient and costly production inherent to protein-based drugs . In addition, the requirement for large volume containers, complex infrastructures and cold supply chains is not compatible with the desire for efficient and sustainable modern supply chains. However, perhaps more importantly from a patient’s perspective, in vivo expressed biologics can be designed to improve function over their recombinant counterparts  and express intracellular proteins to open up drug target space. In the case of infectious diseases and indeed global pandemics, RNA therapeutics can provide more rapid clinical translation of effective vaccines including offering the benefits of passive vaccination strategies. mRNA and replicating RNAs (self-amplifying RNAs) are seen as truly disruptive technologies; mRNA has been referred to as “the software of life”. However, successful delivery is key to their exploitation as drug modalities of the future. Successful intracellular drug delivery systems which can exploit intracellular trafficking pathways to deliver their cargo are critical to allow these important modalities to be utilized as drugs; these make up the third-generation delivery systems.
In the case of cell therapies and regenerative medicines, better outcomes are possible providing cures in some patients and addressing underlying disease to regenerate tissues and restore or establish their normal function. These areas of science are progressing rapidly with CAR-T therapy providing dramatic results in haematological cancers. Various biological and synthetic drug delivery strategies are being explored to expand this success to a broader range of malignancies. Stem cell therapies, which have been termed “injury specific drug stores” initiate tissue healing and repair and harness the body’s own repair machinery. Since its first use in leukaemia over 50 years ago, stem cell therapies have provided success in a number of different diseases including avoiding often risky surgery in hip and knee replacements, avoiding amputation of ischemic limbs in diabetes and repairing heart tissue following myocardial infarction and a range of neurological disorders. Ensuring safe delivery and appropriate tissue tropism will require biomaterial, drug delivery and tissue engineers to work together [26, 27]. These cell therapies make up the fourth generation of delivery technologies (Fig. 1).
This diversity in therapeutic strategies has resulted in a far more diverse set of drug modalities in discovery . For example, at AstraZeneca, we now have more than the 11 different modalities in our early portfolio. This diversity and the requirement to deliver large, charged, fragile and often immunostimulatory drugs to specific organelles in specific cells in complex tissues provides many challenges and opportunities for the drug delivery scientist. In addition, the ambition to treat diseases earlier to drive better patient outcomes opens up the possibility of more local or regiospecific delivery and thus greater variety in routes of administration further adding to delivery needs.
Drug delivery is no longer simply improving or prolonging exposure as it was historically for the majority of small molecules and early peptides or only required for a small percentage of any drug portfolio. It is now an absolute necessity and core to enabling the success of the drugs of the future and exploiting these new modalities as medicines. Second-, third- and fourth-generation drug delivery approaches need to be progressed and rapidly to enable drug delivery to realize the potential of these new therapeutic approaches.
Skills, capabilities, location, culture and mindset?
Typically, traditionally, drug delivery scientists have resided in development departments and in the older “over the wall mentality” were often expected to “fix” a drug’s non-ideal properties via formulation approaches. However, today with many of these nucleic acid-based therapeutics, we are required at the inception of drug discovery programs to provide early input to feasibility studies designed to show whether a drug target can be prosecuted by a particular approach and modality often along with an integrated delivery system.
I firmly believe that as drug delivery scientists, we can do far more to move towards precision medicine and enable new targets, and there will be more nanomedicines improving the health of patients. The recent approval of a glut of ADCs in the last year taking the total to nine, despite a slow and difficult history, should provide both motivation and inspiration for drug delivery scientists to drive to more precision medicine and design better targeted systems and alternatives to the various “armed” antibody approaches.
Novel materials for effective delivery of a range of therapeutic compounds will be critical to enable successful clinical translation. Ideal carriers should be efficient in their aim, be it targeting and/or intracellular delivery or enabling cell therapies. They need to be non-toxic, non-immunogenic, ideally biodegradable, stable and easy to robustly manufacture, scale up and purify. Such biomaterials can be based on synthetic materials such as lipids, polymers or peptides or biomacromolecules. Certainly, we must learn from nature, as we have seen all too vividly, that recently viruses are both highly efficient at both intracellular delivery and tissue/cell tropism. Both viruses and ADCs are in the nanosize range, and to enable us to deliver many of the diverse modalities successfully, we will need to improve our ability to design smaller nanosize-based delivery technologies, whether they are for tumour targeting where reducing the size improves tissue penetration and retention  or for intracellular delivery where size is important for membrane wrapping and accessing different endocytic pathways .
Historically, drug delivery scientists, perhaps put off by the challenges of introducing new excipients, have focused on GRAS (generally regarded as safe) materials and those with clinical precedence which has led to a narrow range of materials in their toolbox. Currently, there is considerable effort to try to find new materials to improve the poor efficiency of intracellular delivery. It is estimated to be only 1–2% endocytosed material that is successfully delivered to the cytosol in many systems [30, 31], taking overall “bioavailability” to fractions of a percent. This is far from ideal, for some of the most expensive and challenging drugs to manufacture, seen to date. In particular, significant effort has focused on better lipidic systems following the success of Onpattro®, the first siRNA drug in a lipid nanoparticle (LNP) , which has enabled the approval of first siRNA drug based on a novel ionizing lipid. Currently, significant effort is focused on designing alternative delivery materials for safe and more efficient delivery of different nucleic acid drugs to both the liver, which can act as an efficient “protein factory”, and other diseased tissues, where avoidance of the liver is desirable. Despite the large efforts in LNPs, they are complex delivery systems . They are composed of materials hard to purify, and processing and purity affect functionality of their cargo. In addition, they often require a frozen supply chain. Currently, novel materials for intracellular delivery are discovered using either a sophisticated high-throughput screening approach, which has resulted in several materials progressing to the clinic and range of patents , or a more focused medicinal chemistry “fast follower” approach where a design make test cycle, typical of small molecule drug design and testing cascade, is applied to finding optimal and safe materials for intracellular delivery. This also creates a new subdiscipline of the “delivery chemist” along with associated drug delivery cell biology skills to understand their intracellular delivery potential, mechanism and intracellular trafficking pathways. To date, these disciplines have not commonly been roles within the pharmaceutical industry and have associated new skill sets. Discussion is also needed with regulatory colleagues and the respective regulatory authorities to ensure successful introduction of these new excipients/biomaterials into pharmaceutical products.
Working in the nano-size range with complex materials drives the need for more advanced analytical characterization techniques. Measuring size accurately and in physiological media is fundamental. Existing particle sizing techniques are inadequate, and the need to understand sizing data and provide orthogonal methodologies as expected by the regulatory authorities has driven investment in new techniques and skills . The definition of critical quality attributes is required by regulatory authorities to identify those factors affecting the in vivo performance of drug products are thoroughly understood and controlled. Measuring the release rate from a nanocarrier in physiologically representative material is important and technically challenging. Bioanalytical methods are required to support pharmaceutical development of any product. Challenges of separating encapsulated/conjugated and free drug which maybe more than 1000-fold lower than that in a nanocarrier in complex media provide challenges in development. Bioassays, required to show functionality of non-synthetic molecules like nucleic acids, are new to many development organizations. These new development science areas, together with lack of clinical and regulatory precedence and, sometimes, different expectations from regulatory agencies across the globe, drive a new skill set and investment in many different skill sets. Successful clinical translation of nanomedicines needs thought and careful design right from the concept stage .
Are we ready for the impetus and these new delivery challenges?
So are we ready? I think we are getting ready; we have made good progress and are improving. It is certainly an exciting time to be a drug delivery scientist. We need an ever-growing “smorgasbord” of multidisciplinary skills, as depicted in Fig. 3, as we build on traditional pharmaceutics skills used for the first-generation technologies to deliver the second, third and fourth generations of delivery technologies. Harnessing collective knowledge, capabilities, experience and sound fundamental science together with an agile and flexible mindset, strong drive and an ability to collaborate across disciplines is imperative. Learning new skills and robust questioning of data will also aid success. An education in Pharmaceutical Sciences with its breadth is invaluable, but depth and aptitude to understand the disease, drug and delivery system and how they interact together (as shown in Fig. 2) and an inquisitive mind are also imperative for any successful drug delivery scientist. New science is needed in other areas too, for example many preclinical disease models generally do not mimic the human disease accurately, and better models are required. Here, the progress with microphysiological systems should aid translation. If we are successful, we should make a huge impact on transforming these many new approaches into important innovative medicines of the future and impact the lives of many patients throughout the world. As expressed as part of a tribute to one of the true leaders in Pharmaceutical Sciences, Kinam Park, at the recent virtual annual Controlled Release society meeting “what a wonderful (delivery) world”.
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I would like to thank Dr John Fell for his support and discussions to help the genesis and development of this article, Dr Paul Gellert for reading and commenting on an early draft and to Emily Fell for her expert assistance with the figures.
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Ashford, M. Drug delivery—the increasing momentum. Drug Deliv. and Transl. Res. 10, 1888–1894 (2020). https://doi.org/10.1007/s13346-020-00858-6
- Drug Delivery
- Pharmaceutical Research and Development
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- Future medicines