The Rise of Complex Oral Delivery Systems

Expert View

THE RISE OF COMPLEX ORAL DELIVERY SYSTEMS

In this article, María Fernández-Martos Balson, Biomedical Engineer, and Bastiaan De Leeuw, Head of Business Development, Drug Delivery, both of Cambridge Design Partnership, explore the oral delivery of biologics and the challenges that must be overcome in order to enhance bioavailability. The authors also take a look at some recently developed drug-device combinations.

After a series of failed experiments in if they could take a pill instead? From a November 1923, pathologist Geoffrey business perspective, drugs may be well Harrison concluded that the “oral suited to this approach if the projected administration [of insulin] in alcohol would market expansion for an oral formulation be so uncertain and so expensive as to be outweighs the development costs and risks, of little or no therapeutic value in diabetes as well as the projected increased cost mellitus in man”. He published his results due to any additional API that may be – and encouraged other researchers to join required to compensate for unavoidable him in publishing their own data – with a reduced oral bioavailability.4 To date, mind to “prevent the raising of false hopes predominantly diabetes-associated drugs in […] those suffering from diabetes”.1 have been considered, as the mechanism This was a mere two years after the is well understood and the opportunity to discovery of insulin. avoid the need for multiple daily injections Since then, peptide- and protein- is attractive. based therapies have risen in prominence, Yet, despite the obvious appeal and representing approximately 12% of the after nearly a hundred years, needles are pharmaceutical market as of 2018, and still required. The oral delivery of biologics with the potential to grow substantially remains a “holy grail” – a tantalising vision over the next 5-10 years.2,3 Hundreds of and a worthy goal. In this article we will biologics are now approved to treat a variety explore the challenges faced by a protein of ailments, from cancer to rheumatoid on its journey from the gastrointestinal (GI) arthritis. And, since Harrison, many lumen to the bloodstream and explain how María Fernández-Martos Balson attempts have been made to administer ingestible devices can be used to increase Biomedical Engineer such drugs in non-invasive manners, from oral bioavailability. The reward is self- T: +44 1223 264428 inhalation to transdermal patches. The evident. The challenge, not trivial. E: maria.balson@ oral route is of particular interest for its cambridge-design.com convenience and tolerability for patients, THE API’S PERILOUS JOURNEY and many recent efforts have been focused on this area. For a therapy to be effective, the API Of course, not all therapeutic peptides must reach the target delivery site (in this would benefit from oral administration, case, systemic circulation) in sufficient even when achievable from a technical concentrations. A key measure of success, perspective. Robustness of delivery, then, is bioavailability: the fraction of patient compliance, dosing regimen and the administered dose that reaches the bioavailability must all be weighed up, bloodstream, typically expressed as a Bastiaan De Leeuw along with the economic considerations. percentage. When delivered orally, proteins Head of Business Development, From a patient perspective, it is a have extremely low bioavailability, usually Drug Delivery no-brainer: who would choose an injection less than 1%.5 This is because their half-life T: +44 1223 264428 in the GI lumen is short and their ability to E: bastiaan.deleeuw@ permeate through the GI walls is limited. cambridge-design.com The human digestive system has evolved “The oral delivery of over millions of years to break down nutrients, Cambridge Design Partnership biologics remains a to eliminate waste and to protect itself. It is Church Road not a friendly environment, especially for Toft “holy grail” – a tantalising Cambridgeshire proteins (i.e. food). To reach the bloodstream, United Kingdom vision and a worthy goal.” a drug must first survive the acidic environment of the stomach, elude www.cambridge-design.com

Figure 1: A cross section of the small intestine wall, highlighting the location of the submucosal vascular bed and the capillary network within the villi. enzymatic degradation and get as far as the obstacles. That is, the delivery system must two broad categories: pharmaceutical GI wall. Once there, the drug faces a coating achieve the following high-level functions: strategies (relying on reformulation and of mucus and several layers of densely use of excipients) and mechanical strategies packed cells. • Protection: protect the API from (relying on physical parts and mechanisms). The mucus alone presents a formidable chemical and enzymatic degradation in The pharmaceutical approach typically barrier. Constantly shed and secreted, it the GI lumen involves the use of enzyme inhibitors to flows from wall to lumen, and from stomach • Localisation: enable the API to reach the decrease the rate of protein breakdown in to colon; drugs must diffuse upstream to GI wall the lumen (protection) and the use reach the epithelium. It is viscous, prone to • Absorption: ensure transport of the API of permeation enhancers to improve forming intermolecular bonds, and consists through the GI wall. diffusion of the drug through the of a fine mesh of mucin filaments – in epithelium (absorption), while relying summary, it is very effective at preventing Attempts to fulfil these functions – and on regular diffusion/advection and the the passage of large, interactive molecules.6 thus improve bioavailability – fall into increased drug half-life in the lumen for For any API that makes it past the mucus the final hurdle is in the wall itself. To reach the capillaries in the villi or the vascular bed within the submucosal layer (Figure 1), the API must cross the epithelium. Epithelial cells are tightly packed and connected to one another by the aptly named tight junctions (multiprotein complexes that seal the gaps between adjacent cells). There are two main paths across this barrier (Figure 2), neither of which is easy for therapeutic peptides, as they are typically too hydrophilic to permeate through the cellular membrane and across the cells themselves (transcellular transport), and too large to pass between tight junctions (paracellular transport).7 Overall permeability is therefore very low.

ENHANCING BIOAVALABILITY

In order to reach the bloodstream intact and in sufficient quantities, an API must Figure 2: Two paths across the epithelium to reach systemic circulation: successfully navigate the aforementioned through the cells themselves, or between them.

state, dissolving only upon reaching the were safely excreted and that there was “The challenge, of higher pH of the small intestine (which minimal damage to the epithelium at the then triggers the device’s active state). injection site, although long-term safety course, is to obtain a This targeted deployment serves a double remains to be demonstrated.13 useful improvement in purpose: protecting the API from chemical Rani Therapeutics (San Jose, CA, US) bioavailability (increasing degradation in the stomach, and bringing is developing a similar device. Upon the drug closer to the epithelium (simply reaching the small intestine, the RaniPill™ 5 it to 30-50%) while because the small intestine is much is activated. A partition between two mitigating the safety risks.” narrower than the stomach). compartments (containing dry citric acid and sodium bicarbonate respectively) IN THE PIPELINE dissolves, allowing the reagents to mix localisation. Other formulation techniques and produce CO2. The gas fills a balloon, include direct chemical modification Over the past 10 years, development efforts which in turn pushes a solid drug needle of the peptide or protein to increase in this space have been shifting towards into the mucosa. The needle dissolves and permeability (e.g. PEGylation) and the use drug-device combinations. This section the rest of the device is passed.14,15 Rani’s of carrier systems such as nanoemulsions describes some of the more mature designs technology has attracted interest from a and nanoparticles.8,5 (note that this is not a comprehensive list number of pharmaceutical companies, Chemical strategies such as these have and does not reflect the full breadth of including Novartis (Switzerland) and Shire demonstrated marginal improvements technologies currently in development). (now Takeda) (Japan), and they recently in the oral bioavailability of therapeutic In an ongoing collaboration, a team announced a successful Phase I study with macromolecules, with some formulations of engineers from Massachusetts Institute octreotide in humans with a bioavailability achieving 1–2% bioavailability in clinical of Technology (MIT) (US) and Novo claim of >70%,16 although their data have studies.9 This only provides an incremental Nordisk (Denmark) has developed several not yet been formally published in a peer- change, rather than truly enabling a shift devices that show promise in preclinical reviewed journal. in the attractiveness of oral administration. studies. The self-orienting millimetre-scale Progenity (San Diego, CA, US) and Moreover, the technologies deployed applicator (SOMA) delivers a solid Baywind Bioventures (San Diego, CA, can carry undesirable side effects, for drug needle into the gastric mucosa. US), two relatively new companies, are example some permeation enhancers may The device’s shape, inspired by the leopard developing devices that aim to deliver cause inflammation or allow pathogens tortoise, ensures that the device always high-velocity jets of drug solution directly to breach the epithelial layer, potentially lands and remains on the bottom of the through the epithelium. Both are in early leading to infections. The challenge, of stomach in the upright position. development phases currently. course, is to obtain a useful improvement Within minutes, a sugar trigger dissolves, in bioavailability (increasing it to releasing a spring that inserts the needle THE REAL CHALLENGE: SCALING UP 30–50%)5 while mitigating the safety into the mucosa. The needle, made of risks. Many specific drug formulations up to 80% compressed insulin, dissolves Promising preclinical results, such as those (and some platform technologies) that over the course of one hour, releasing of the LUMI system, demonstrate concept aim to strike this balance are currently the API.11 feasibility. The next challenge is ensuring in development.10 The luminal unfolding microneedle device safety and robust delivery at scale. In contrast to the purely pharmaceutical injector (LUMI), another MIT/Novo Typical candidate peptides for oral approach, device-enabled oral delivery Nordisk device, targets the small intestine delivery require frequent dosing (weekly aims to fulfil the three key functions by instead. It consists of three legs, joined to daily) and have large target patient mechanical means. In principle, the concept at the centre, and tipped with solid drug- populations. Assuming, for example, that is simple: the patient swallows a small loaded microneedles. Once it reaches the a once-weekly device was adopted by 5% device, as they would a pill. The device higher pH of the intestine, the device – of diabetics in the US, 80–90 million units becomes activated once it reaches the initially constrained within a capsule – is would be required per year.17 To be a viable desired location (typically the stomach or deployed by a spring. The tripod unfolds therapy, the device would have to deliver small intestine) and then, by some means, in the small intestine lumen, pressing the the drug safely and reliably every time. the device creates a high and localised needles into the wall, where they dissolve.12 It would have to be manufacturable and concentration of API adjacent to the Proof of principle studies in pigs achieved fillable, and fulfil its functions in tolerance epithelium – or else it penetrates the mucosa a bioavailability of 10% and demonstrated cases. This is the puzzle that must be solved in order to bypass the epithelium entirely that non-biodegradable device components if oral delivery of biologics is to succeed and thus achieve greater bioavailability. where other non-invasive approaches have Physical concepts for enhanced wall failed. Some of the key pieces are: penetration include the use of microneedles, ultrasound and electroporation, while a “Promising preclinical Miniaturisation common motif to address both protection results, such as those of the There is a trade-off between device size and and localisation is the use of enteric LUMI system, demonstrate potential payload. Drug loading should be materials.9 Enteric coatings or components maximised, but size is ultimately constrained allow a device to pass through the acidic concept feasibility.” by patient tolerability and the risk of environment of the stomach in a dormant intestinal obstruction. For frequently dosed

devices, the device envelope should ideally fit within a size 0 capsule (L = 21.7 mm, “Basic feasibility of device-enabled delivery has been ø = 7.34 mm), a requirement that places a significant burden on the manufacturing demonstrated in preclinical studies, with data supporting process. Component features require the potential to obtain much improved bioavailability.” micrometre accuracy, and manufacturers may need to develop specialist processes and equipment to handle and assemble LOOKING AHEAD 2. https://www.medgadget.com/2019/12/ millimetre-sized components, to fill the protein-therapeutics-market-2020- primary container (if delivering a liquid) Compared with 1923, we are surely closer to global-analysis-opportunities-and- or to manufacture components out of solid being able to solve the oral delivery puzzle. forecast-to-2025.html, accessed on drug (e.g. microneedles). Basic feasibility of device-enabled delivery July 9, 2020. has been demonstrated in preclinical studies, 3. Aitken M, Kleinrock M, Anatomy and Physiology with data supporting the potential to obtain Simorellis A, Nass D, “The Global Not only do device tolerances matter, the much improved bioavailability. Whether Use of Medicine in 2019 and device must also work reliably in spite of this promise will become a commercial Outlook to 2023”. IQVIA Institute inter- and intra-patient variability. Human reality remains to be seen, but the goal is Report, 2019. anatomy is not subject to drawing tolerances; certainly worth the journey. 4. Shields P, “Oral Peptide Therapeutics patient’s GI tracts vary significantly in To get there, companies should focus - A Holy Grail or Quixotic Quest?”. shape, size and motility patterns. There are on turning the technical advances that have Drug Discovery World, 2017. also differences between the fed and fasted been made so far into robust and scalable 5. Shaji J, Patole V, “Protein and states, and differences due to disease states technologies, through a deep understanding Peptide Drug Delivery: Oral and co-morbidities. Ensuing variations of physiology, manufacturing and material Approaches”. Indian J Pharm Sci, in the chemical and enzymatic makeup selection. 2008, Vol 70(3), pp 269–277. of the gastric and intestinal fluids, the 6. Boegh M, Nielsen HM, “Mucus presence or absence of chyme, peristalsis, ABOUT THE COMPANY as a Barrier to Drug Delivery – gastric emptying times, etc, must all be Understanding and Mimicking the taken into account. Cambridge Design Partnership is an Barrier Properties”. Basic Clinl To succeed here, device engineers must employee-owned technology and product Pharmacol Toxic, 2015, Vol 116(3), gain a deep understanding of anatomical design partner, located in Cambridge (UK) pp 179–186. and physiological variability in the GI tract, and Raleigh, North Carolina (US). CDP 7. Renukuntla J, Vadlapudi AD, and of how its extremes affect each of the provide an integrated and holistic product Patel A, Boddu SH, Mitra AK, device functions, from localisation, though development capability through a highly “Approaches for Enhancing Oral delivery, to eventual dissolution or passing. qualified team, well equipped development Bioavailability of Peptides and labs and ISO 13485/9001 approved methods. Proteins”. Int J Pharm, 2013, Material Selection This encompasses research and strategy, Vol 447 (1–2), pp 75-93. Choosing the right materials can prove design, technology and digital innovation, 8. Bruno BJ, Miller GD, Lim CS, challenging too, as there are often conflicting product development and regulatory and “Basics and recent advances in requirements. There may be a need for manufacturing support. CDP experts are peptide and protein drug delivery”. components that store energy (e.g. springs), able to take combination products through Ther Deliv, 2013, Vol 4(11), dissolve at certain times (e.g. triggers) a full design cycle and submission, enabling pp 1443–1467. and/or act as impermeable membranes customers to launch products that are user- 9. Caffarel-Salvador E, Abramson (e.g. to prevent dry reagents from mixing centric and commercially effective. A, Langer R, Traverso G, “Oral prematurely). These requirements must all With broad experience developing devices delivery of biologics using drug- be balanced alongside manufacturability, across all forms of drug delivery, our team device combinations”. Curr Opin sterilisability and patient safety. builds upon technological advances from Pharmacol, 2017, Vol 36, pp 8–13. For example, from a safety perspective, various industries and sectors to develop 10. Muheem A et al, “A review on the it is preferable for sharp components, such reliable devices that can be manufactured strategies for oral delivery of proteins as hollow needles, to be able to dissolve at scale. We are well positioned to and peptides and their clinical in the GI tract, in order to mitigate the address the technical challenges posed by perspectives”. Saudi Pharm J, 2016, risk of damage to the epithelium as the miniaturisation, material selection and Vol 24(4), pp 413–428. device is passed. However, soluble materials physiological variability, critical to deliver 11. Abramson A et al, “An ingestible can rarely hold an edge for very long in upon the promise of oral biologics delivery. self-orienting system for oral delivery the moist environment of the GI tract. of macromolecules”. Science, 2019, Engineers must weigh such considerations REFERENCES Vol 363 (6427), pp 611–615. and choose wisely to ensure reliable delivery 12. 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peptides by the oral route: Formulation and medicinal chemistry approaches”. Adv Drug Delivery Rev, 2020. 14. https://www.ranitherapeutics.com/technology/. Accessed July 9, 2020. 15. Imran M, “Device, system and methods for EDITORIAL CALENDAR the oral delivery of therapeutic compounds”. International Patent No WO2013003487, Publication Issue Materials Issued 2013. Month Deadline 16. “Rani Therapeutics Announces Positive Phase I Topic Study Results of Oral Octreotide using RaniPill™”. Press Release, Rani Therapeutics, January 30, 2020. Aug 2020 Industrialising Drug Delivery PASSED 17. Centers for Disease Control and Prevention. “National Diabetes Statistics Report, 2020”. Atlanta, GA: Centers for Disease Control and Aug 21, Sept 2020 Wearable Injectors Prevention, US Dept of Health and Human 2020 Services, 2020. NEW TOPIC – INAUGURAL ISSUE! Sept/Oct Sep 10, Drug Delivery & ABOUT THE 2020 2020 AUTHORS Enviromental Sustainability María Fernández-Martos Balson has a Masters Prefilled Syringes & Sep 24, Oct 2020 degree in Bioengineering and Mechanical Injection Devices 2020 Engineering from the University of Cambridge, where she focused on the computational modelling Oct 8, of dynamic cell tissues, with a view to understand Nov 2020 Pulmonary & Nasal Drug Delivery how tumour metastasis begins. Prior to joining 2020 CDP, Ms Fernández-Martos Balson worked in the innovation department of a leading drug delivery Nov 5, Dec 2020 Connecting Drug Delivery device manufacturer, where she contributed to 2020 a range of development projects, including the early-stage design of an intraocular injection Skin Drug Delivery: Dermal, Dec 3, device and the late-stage development of a gas- Jan 2021 powered autoinjector. Since joining CDP, she Transdermal & Microneedles 2020 has been involved in the design of subcutaneous, intratumoural and oral drug delivery devices. Jan/Feb Prefilled Syringes & Dec 17, 2021 Injection Devices 2020 Bastiaan De Leeuw has been active in the field of drug delivery for the last 20 years. Mr De Jan 7, Feb 2021 Novel Oral Delivery Systems Leeuw has led projects covering dry-powder 2021 formulation development, inhaler design and development, and autoinjector design and Feb 4, development, as well as the associated stages Mar 2021 Ophthalmic Drug Delivery of clinical and regulatory evaluations. In 2021 addition, he led the initial clinical evaluation of urologic diagnostic tests at NovioGendix Mar 4, Apr 2021 Pulmonary & Nasal Drug Delivery (the Netherlands) (now MDxHealth, Irvine, 2021 CA, US) and has worked at Focus Inhalation (Turku, Finland), Akela Pharma (Austin, TX, Delivering Injectables: Apr 1, US), Oval Medical (Cambridge, UK) and Bespak May 2021 Devices & Formulations 2021 (Norfolk, UK). Mr De Leeuw obtained his MSc Biopharmaceutical sciences at Leiden University May 6, (the Netherlands), focusing on polymeric drug Jun 2021 Connecting Drug Delivery delivery systems for formulation of proteins 2021 and peptides. His research there combined pharmaceutical technology and pharmacology in Jun 3, Jul 2021 Novel Oral Delivery Systems industry-sponsored projects. 2021