The future of oral drug delivery : from nanotechnologies to electromechanical devices

Implications of the route of drug administration in patient care

The challenges of developing a pharmaceutical product go well beyond the discovery and successful testing of APIs (Active Pharmaceutical Ingredients, the molecules that produce the intended effects). The formulation of these molecules into a final product must take into consideration several factors including their stability in the desired dosage form (e.g., tablet, liquid solution, aerosol), the patient’s acceptability, and the conditions to ensure the absorption and distribution of the active molecule in the organism.

The administration of drugs via the oral route (i.e., intake of capsules, tablets, syrups, etc.) is perceived by patients as the most convenient way of taking medications and is the most common route of administration for most drugs, particularly for long-term treatments.  Among its unique advantages are sustained and controllable delivery, ease of administration, and feasibility for solid formulation.

Nevertheless, the absorption of drugs via the oral route depends on a complex interaction between the pharmaceutical product and the environmental conditions in the GI tract. In the case of macromolecules (i.e., molecular weight higher than 1kDa), oral administration is a major challenge given: their large size, which prevents them from passing through the intercellular junctions between intestinal epithelial cells; their low lipophilicity, which hinders passive uptake from the cellular membrane and their susceptibility to be degraded by both the enzymatic action and the acidic conditions of the GI tract.

Additionally, the absorption of drugs is most efficient when they are administered by injection. In the case of intravenous administration, drugs access the systemic circulation directly; and in the case of subcutaneous administration the barrier of the skin is bypassed. Except for some relatively small macromolecules that can be administered orally, injection is almost exclusively the only possible route of administration for drugs with a molecular weight exceeding 1kDa. However, injection administration is more resource-intensive, as it requires sterilization and aseptic conditions, and self-administration is sometimes not possible. Additionally, it is potentially painful and overall unsuitable for patients with needle phobia.

Recent developments in oral drug delivery for peptides

As biological macromolecular drugs gain more importance in the treatment of chronic diseases, there has been an increased interest in developing oral delivery systems that allow these drugs to overcome the absorption barriers that have restricted their administration to injection administration. However, progress in this area has been slow and limited to the oral delivery of some peptides with molecular weights below 5kDa. For comparison, the molecular weight of Insulin is 5.8 kDa, and although it is the most studied target for oral delivery, an oral dosage form for this protein is yet to be achieved. To date, only 4 peptides have been approved in oral dosage forms (desmopressin, cyclosporin, octreotide and semaglutide), the most recent developments being the approval of oral semaglutide in 2019 and oral octreotide in 2020.

Among the peptides approved in oral dosage forms, the most significant success case might be semaglutide, by far the largest of these molecules, with molecular weight of about 4.1 kDa. Semaglutide is a glucagon-like peptide-1 receptor agonists (GLP-1RAs) and is among the most effective anti-diabetic drugs.  Traditionally available only on injection form, in 2019 an oral tablet of semaglutide commercialized by Novo Nordisk under the name of Rybelsus® was approved by the FDA. This breakthrough was possible thanks to the co-formulation with sodium N-[8-(2-hydroxybenzoyl) amino caprylate (SNAC). This chemical substance, which belongs to a category of excipients known as permeation enhancers, is crucial to realize the oral administration of semaglutide, as it allows to temporarily alter the intestinal barrier to improve the absorption of the drug.

As exciting as the success of oral semaglutide is, research and development efforts with the use of permeation enhancers are focused on the administration of drugs ranging from 1 to 6kDa, and it seems unlikely that they would be considered for the delivery of larger molecules, such as monoclonal antibodies, whose molecule weight can be over 150 kDa.

From nano to macroscale, perspectives for the future

One of the most important technologies under exploration is the use of carriers. Carrier-based delivery includes a broad range of systems that have the capacity to encapsulate or couple with a therapeutic agent to improve its ability to be absorbed safely, controlling the release of the drug (payload) into systemic circulation.

Although drug protection from the GI environment can in any case be addressed using standard capsules, the use of carriers as nanoparticles, for instance, allows for controlling interactions on the molecular scale, and provides a much wider arrange of possibilities for optimizing absorption and uptake.

However, the clinical translation of nanoscale platforms for oral delivery has been hindered by several obstacles, and most research efforts remain in preclinical stage. Among these obstacles, one of the most prominent is the low predictive value of preclinical data gathered from studies using rodents.

The therapeutic efficacy and safety in these studies tend to deviate significantly from clinical expectations, given the numerous variables (such as the scale-up of the final formulation, dilution, spreading, and release of payload during transit) that are heavily dependent on the cross-sectional size of the gut lumen, and negatively affect the utility of rodents as a translational animal model. As reproducibility of both formulation and the rodent data seems to be a major hurdle, some authors have proposed to rather use pigs as animal models, as they align very closely to humans in terms of diet, GI residence, fluid volume and gastric pH than dogs or rodents.

Moving up from the nanoscale to the macroscale, ingestible devices have emerged in recent years as an appealing alternative for oral delivery of drugs. The principle of these technologies is to load the formulation into a mechanical capsule that protects it from the harsh conditions of the GI tract, and then physically disrupts the intestinal barrier to deliver the drug through the gut barrier.

Among the possible mechanisms of gut barrier disruption, injection using dissolvable intestinal microneedles is the most advanced in terms of clinical development.  Rani Therapeutics, an American biotech company, has developed a “robotic pill” using this principle, and in 2020 announced positive results from a Phase I clinical study for oral delivery of octreotide, a peptide used in the treatment of acromegaly and neuroendocrine tumors.

However, ingestible-device technology is still incipient. Studies to investigate the long-term safety implications of their use and validation across diverse populations will be needed before widespread clinical adoption is considered.

The remarkable dynamism of recent years in the development of oral delivery systems has been, in great part, spurred by the difficulties encountered in the delivery of macromolecule drugs, which are currently administered almost exclusively by injection. New technologies, such as nanocarriers and ingestible devices, offer exciting opportunities to facilitate patient access to macromolecule drugs, although their translation to clinical use is still hindered by insufficient data on safety, effectiveness, and reproducibility. The recent success achieved concerning the oral delivery of some peptides, such as semaglutide, enabled by the coformulation with a permeation enhancer substance, is a good example of how innovative technologies are transforming the administration of pharmaceutical products.

Considering, on one hand, the substantial benefits in terms of patient convenience and cost, and on the other hand, the increasing demand for home-care boosted by the Covid-19 crisis, the development of new oral drug delivery technologies is bound to be accelerated in the coming years, and our healthcare team at Alcimed is here to support you in this fascinating field of exploration!

About the authors
David, Senior Consultant and Céline, Project Manager in Alcimed’s Healhcare team in France