Citation: Fernández-Martos Balson M, De Leeuw B, “The Rise of Complex Oral Delivery Systems”. ONdrugDelivery Magazine, Issue 109 (July 2020), pp 35–39
María Fernández-Martos Balson and Bastiaan De Leeuw 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 November 1923, pathologist Geoffrey Harrison concluded that the “oral administration [of insulin] in alcohol would be so uncertain and so expensive as to be of little or no therapeutic value in diabetes mellitus in man”. He published his results – and encouraged other researchers to join him in publishing their own data – with a mind to “prevent the raising of false hopes in […] those suffering from diabetes”.1 This was a mere two years after the discovery of insulin.
“The oral delivery of biologics remains a
“holy grail” – a tantalising vision and a worthy goal.”
Since then, peptide- and protein-based therapies have risen in prominence, representing approximately 12% of the pharmaceutical market as of 2018, and with the potential to grow substantially over the next 5-10 years.2,3 Hundreds of biologics are now approved to treat a variety of ailments, from cancer to rheumatoid arthritis. And, since Harrison, many attempts have been made to administer such drugs in non-invasive manners, from inhalation to transdermal patches. The oral route is of particular interest for its convenience and tolerability for patients, and many recent efforts have been focused on this area.
Of course, not all therapeutic peptides would benefit from oral administration, even when achievable from a technical perspective. Robustness of delivery, patient compliance, dosing regimen and bioavailability must all be weighed up, along with the economic considerations.
From a patient perspective, it is a no-brainer: who would choose an injection if they could take a pill instead? From a business perspective, drugs may be well suited to this approach if the projected market expansion for an oral formulation outweighs the development costs and risks, as well as the projected increased cost due to any additional API that may be required to compensate for unavoidable reduced oral bioavailability.4 To date, predominantly diabetes-associated drugs have been considered, as the mechanism is well understood and the opportunity to avoid the need for multiple daily injections is attractive.
Yet, despite the obvious appeal and after nearly a hundred years, needles are still required. The oral delivery of biologics remains a “holy grail” – a tantalising vision and a worthy goal. In this article we will explore the challenges faced by a protein on its journey from the gastrointestinal (GI) lumen to the bloodstream and explain how ingestible devices can be used to increase oral bioavailability. The reward is self-evident. The challenge, not trivial.
THE API’S PERILOUS JOURNEY
For a therapy to be effective, the API must reach the target delivery site (in this case, systemic circulation) in sufficient concentrations. A key measure of success, then, is bioavailability: the fraction of the administered dose that reaches the bloodstream, typically expressed as a percentage. When delivered orally, proteins have extremely low bioavailability, usually less than 1%.5 This is because their half-life in the GI lumen is short and their ability to permeate through the GI walls is limited.
The human digestive system has evolved over millions of years to break down nutrients, to eliminate waste and to protect itself. It is not a friendly environment, especially for proteins (i.e. food). To reach the bloodstream, a drug must first survive the acidic environment of the stomach, elude enzymatic degradation and get as far as the GI wall. Once there, the drug faces a coating of mucus and several layers of densely packed cells.
The mucus alone presents a formidable barrier. Constantly shed and secreted, it flows from wall to lumen, and from stomach to colon; drugs must diffuse upstream to reach the epithelium. It is viscous, prone to forming intermolecular bonds, and consists of a fine mesh of mucin filaments – in summary, it is very effective at preventing the passage of large, interactive molecules.6
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.
In order to reach the bloodstream intact and in sufficient quantities, an API must successfully navigate the aforementioned obstacles. That is, the delivery system must achieve the following high-level functions:
- Protection: protect the API from chemical and enzymatic degradation in the GI lumen
- Localisation: enable the API to reach the GI wall
- Absorption: ensure transport of the API through the GI wall.
Attempts to fulfil these functions – and thus improve bioavailability – fall into two broad categories: pharmaceutical strategies (relying on reformulation and use of excipients) and mechanical strategies (relying on physical parts and mechanisms).
The pharmaceutical approach typically involves the use of enzyme inhibitors to decrease the rate of protein breakdown in the lumen (protection) and the use of permeation enhancers to improve diffusion of the drug through the epithelium (absorption), while relying on regular diffusion/advection and the increased drug half-life in the lumen forlocalisation. Other formulation techniques include direct chemical modification of the peptide or protein to increase permeability (e.g. PEGylation) and the use of carrier systems such as nanoemulsions and nanoparticles.8,5
Chemical strategies such as these have demonstrated marginal improvements in the oral bioavailability of therapeutic macromolecules, with some formulations achieving 1–2% bioavailability in clinical studies.9 This only provides an incremental change, rather than truly enabling a shift in the attractiveness of oral administration. Moreover, the technologies deployed can carry undesirable side effects, for example some permeation enhancers may cause inflammation or allow pathogens to breach the epithelial layer, potentially leading to infections. The challenge, of course, is to obtain a useful improvement in bioavailability (increasing it to 30–50%)5 while mitigating the safety risks. Many specific drug formulations (and some platform technologies) that aim to strike this balance are currently in development.10
“The challenge, of course, is to obtain a useful improvement in bioavailability (increasing it to 30-50%)5 while mitigating the safety risks.”
In contrast to the purely pharmaceutical approach, device-enabled oral delivery aims to fulfil the three key functions by mechanical means. In principle, the concept is simple: the patient swallows a small device, as they would a pill. The device becomes activated once it reaches the desired location (typically the stomach or small intestine) and then, by some means, the device creates a high and localised concentration of API adjacent to the epithelium – or else it penetrates the mucosa in order to bypass the epithelium entirely and thus achieve greater bioavailability.
Physical concepts for enhanced wall penetration include the use of microneedles, ultrasound and electroporation, while a common motif to address both protection and localisation is the use of enteric materials.9 Enteric coatings or components allow a device to pass through the acidic environment of the stomach in a dormant state, dissolving only upon reaching the higher pH of the small intestine (which then triggers the device’s active state). This targeted deployment serves a double purpose: protecting the API from chemical degradation in the stomach, and bringing the drug closer to the epithelium (simply because the small intestine is much narrower than the stomach).
IN THE PIPELINE
Over the past 10 years, development efforts in this space have been shifting towards drug-device combinations. This section describes some of the more mature designs (note that this is not a comprehensive list and does not reflect the full breadth of technologies currently in development).
In an ongoing collaboration, a team of engineers from Massachusetts Institute of Technology (MIT) (US) and Novo Nordisk (Denmark) has developed several devices that show promise in preclinical studies. The self-orienting millimetre-scale applicator (SOMA) delivers a solid drug needle into the gastric mucosa. The device’s shape, inspired by the leopard tortoise, ensures that the device always lands and remains on the bottom of the stomach in the upright position. Within minutes, a sugar trigger dissolves, releasing a spring that inserts the needle into the mucosa. The needle, made of up to 80% compressed insulin, dissolves over the course of one hour, releasing the API.11
“Promising preclinical results, such as those of the LUMI system, demonstrate concept feasibility.”
The luminal unfolding microneedle injector (LUMI), another MIT/Novo Nordisk device, targets the small intestine instead. It consists of three legs, joined at the centre, and tipped with solid drug-loaded microneedles. Once it reaches the higher pH of the intestine, the device – initially constrained within a capsule – is deployed by a spring. The tripod unfolds in the small intestine lumen, pressing the needles into the wall, where they dissolve.12 Proof of principle studies in pigs achieved a bioavailability of 10% and demonstrated that non-biodegradable device components were safely excreted and that there was minimal damage to the epithelium at the injection site, although long-term safety remains to be demonstrated.13
Rani Therapeutics (San Jose, CA, US) is developing a similar device. Upon reaching the small intestine, the RaniPill™ is activated. A partition between two compartments (containing dry citric acid and sodium bicarbonate respectively) dissolves, allowing the reagents to mix and produce CO2. The gas fills a balloon, which in turn pushes a solid drug needle into the mucosa. The needle dissolves and the rest of the device is passed.14,15 Rani’s technology has attracted interest from a number of pharmaceutical companies, including Novartis (Switzerland) and Shire (now Takeda) (Japan), and they recently announced a successful Phase I study with octreotide in humans with a bioavailability claim of >70%,16 although their data have not yet been formally published in a peer-reviewed journal.
Progenity (San Diego, CA, US) and Baywind Bioventures (San Diego, CA, US), two relatively new companies, are developing devices that aim to deliver high-velocity jets of drug solution directly through the epithelium. Both are in early development phases currently.
THE REAL CHALLENGE: SCALING UP
“Basic feasibility of device-enabled delivery has been demonstrated in preclinical studies, with data supporting the potential to obtain much improved bioavailability.”
Promising preclinical results, such as those of the LUMI system, demonstrate concept feasibility. The next challenge is ensuring device safety and robust delivery at scale.
Typical candidate peptides for oral delivery require frequent dosing (weekly to daily) and have large target patient populations. Assuming, for example, that a once-weekly device was adopted by 5% of diabetics in the US, 80–90 million units would be required per year.17 To be a viable therapy, the device would have to deliver the drug safely and reliably every time. It would have to be manufacturable and fillable, and fulfil its functions in tolerance cases. This is the puzzle that must be solved if oral delivery of biologics is to succeed where other non-invasive approaches have failed. Some of the key pieces are:
There is a trade-off between device size and potential payload. Drug loading should be maximised, but size is ultimately constrained by patient tolerability and the risk of intestinal obstruction. For frequently dosed devices, the device envelope should ideally fit within a size 0 capsule (L = 21.7 mm, ø = 7.34 mm), a requirement that places a significant burden on the manufacturing process. Component features require micrometre accuracy, and manufacturers may need to develop specialist processes and equipment to handle and assemble millimetre-sized components, to fill the primary container (if delivering a liquid) or to manufacture components out of solid drug (e.g. microneedles).
Anatomy and Physiology
Not only do device tolerances matter, the device must also work reliably in spite of inter- and intra-patient variability. Human anatomy is not subject to drawing tolerances; patient’s GI tracts vary significantly in shape, size and motility patterns. There are also differences between the fed and fasted states, and differences due to disease states and co-morbidities. Ensuing variations in the chemical and enzymatic makeup of the gastric and intestinal fluids, the presence or absence of chyme, peristalsis, gastric emptying times, etc, must all be taken into account.
To succeed here, device engineers must gain a deep understanding of anatomical and physiological variability in the GI tract, and of how its extremes affect each of the device functions, from localisation, though delivery, to eventual dissolution or passing.
Choosing the right materials can prove challenging too, as there are often conflicting requirements. There may be a need for components that store energy (e.g. springs), dissolve at certain times (e.g. triggers) and/or act as impermeable membranes (e.g. to prevent dry reagents from mixing prematurely). These requirements must all be balanced alongside manufacturability, sterilisability and patient safety.
For example, from a safety perspective, it is preferable for sharp components, such as hollow needles, to be able to dissolve in the GI tract, in order to mitigate the risk of damage to the epithelium as the device is passed. However, soluble materials can rarely hold an edge for very long in the moist environment of the GI tract. Engineers must weigh such considerations and choose wisely to ensure reliable delivery while mitigating the associated risks (and while operating in a regulatory environment that is not yet set up for this new class of devices).
Compared with 1923, we are surely closer to being able to solve the oral delivery puzzle. Basic feasibility of device-enabled delivery has been demonstrated in preclinical studies, with data supporting the potential to obtain much improved bioavailability. Whether this promise will become a commercial reality remains to be seen, but the goal is certainly worth the journey.
To get there, companies should focus on turning the technical advances that have been made so far into robust and scalable technologies, through a deep understanding of physiology, manufacturing and material selection.
- Harrison GA, “Insulin in alcoholic solution by the mouth”. Br Med J, 1923, Vol 22;2 (3286), pp 1204–1205.
- https://www.medgadget.com/2019/12/protein-therapeutics-market-2020-global-analysis-opportunities-and-forecast-to-2025.html, accessed on July 9, 2020.
- Aitken M, Kleinrock M, Simorellis A, Nass D, “The Global Use of Medicine in 2019 and Outlook to 2023”. IQVIA Institute Report, 2019.
- Shields P, “Oral Peptide Therapeutics – A Holy Grail or Quixotic Quest?”. Drug Discovery World, 2017.
- Shaji J, Patole V, “Protein and Peptide Drug Delivery: Oral Approaches”. Indian J Pharm Sci, 2008, Vol 70(3), pp 269–277.
- Boegh M, Nielsen HM, “Mucus as a Barrier to Drug Delivery – Understanding and Mimicking the Barrier Properties”. Basic Clinl Pharmacol Toxic, 2015, Vol 116(3), pp 179–186.
- Renukuntla J, Vadlapudi AD, Patel A, Boddu SH, Mitra AK, “Approaches for Enhancing Oral Bioavailability of Peptides and Proteins”. Int J Pharm, 2013, Vol 447 (1–2), pp 75-93.
- Bruno BJ, Miller GD, Lim CS, “Basics and recent advances in peptide and protein drug delivery”. Ther Deliv, 2013, Vol 4(11), pp 1443–1467.
- Caffarel-Salvador E, Abramson A, Langer R, Traverso G, “Oral delivery of biologics using drug-device combinations”. Curr Opin Pharmacol, 2017, Vol 36, pp 8–13.
- Muheem A et al, “A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives”. Saudi Pharm J, 2016, Vol 24(4), pp 413–428.
- Abramson A et al, “An ingestible self-orienting system for oral delivery of macromolecules”. Science, 2019, Vol 363 (6427), pp 611–615.
- Abramson A et al, “A luminal unfolding microneedle injector for oral delivery of macromolecules”. Nat Med, 2019, Vol 25 (10), pp 1512–1518.
- Brayden DJ et al, “Systemic delivery of peptides by the oral route: Formulation and medicinal chemistry approaches”. Adv Drug Delivery Rev, 2020.
- https://www.ranitherapeutics.com/ technology/. Accessed July 9, 2020.
- Imran M, “Device, system and methods for the oral delivery of therapeutic compounds”. International Patent No WO2013003487, Issued 2013.
- “Rani Therapeutics Announces Positive Phase I Study Results of Oral Octreotide using RaniPill™”. Press Release, Rani Therapeutics, January 30, 2020.
- Centers for Disease Control and Prevention. “National Diabetes Statistics Report, 2020”. Atlanta, GA: Centers for Disease Control and Prevention, US Dept of Health and Human Services, 2020.