Abstract by Konstantinos Raptis

In the last decade, more than 50 % of U.S. Food and Drug Administration (FDA) drug approvals are complex large molecular entities, with 8 % of them to being peptide therapeutics. Thus, there is an increasing number of newly approved drugs that fall beyond the Lipinski Rule of Five, limiting their oral absorption due to their large size, hydrophilicity and poor stability in the gastrointestinal fluids. However, they are highly valuable since numerous previously “undruggable” targets -such as those involving receptors at cell surfaces or intracellular protein–protein interactions -cannot be effectively addressed with small molecule drugs due to their inherently limited binding surface area. Peptides occupy an intermediate position between small molecules and proteins, combining advantages of both: they offer the high target specificity and reduced off-target binding, typical advantages of proteins, while maintaining the relatively low synthetic cost and low complexity associated with small molecules.

Oral drug administration is the preferred route of administration, offering the highest level of patient compliance. However, peptide therapeutics deviate significantly from the ~500 Da molecular weight limit described by the Lipinski Rule of Five to predict sufficient oral absorption. Consequently, peptide drugs are primarily administered as injectables, highlighting the unmet need for advanced drug delivery systems to enable their oral bioavailability. In addition to the higher patient compliance, oral delivery of peptide therapeutics also holds promise for eliminating the cold-chain requirements, thereby reducing associated costs of production, transportation, and storage, supporting the green transition of the pharmaceutical industry, and ultimately allowing peptide drugs to reach a broader patient population.

The current PhD work conceptualizes and develops an ionogel-based drug delivery system, inspired by the previously reported high relative oral bioavailability of insulin achieved with CAGE, an ionic liquid composed of choline and geranic acid, following oral administration in rats. Ionic liquids are widely used and recognized as biocompatible. The most common approach in oral peptide delivery is the use of permeation enhancers. Permeation enhancers are a wide class of molecules that can directly or indirectly enhance the transcellular or paracellular transport of drugs with most characteristic examples being the medium-chain fatty acids and their derivatives. One of the most tested permeation enhancers is sodium decanoate that has demonstrated a good efficacy and safety in clinical trials. Thus, we hypothesized that a sodium decanoate-based ionic liquid would demonstrate superior oral peptide bioavailability, and we aimed to synthesize, characterize, and fine-tune the design towards optimal material properties aiming for synergistic improvement of oral peptide delivery.

We unveiled the importance of the counterion ratio for both the material properties and physical stability, and for its efficacy to permeabilize in vitro biomimetic membranes. We demonstrated that the 1:2 ratio between choline and decanoate give rise to a smectic ionic liquid crystalline mesophase with ideal material properties for a drug delivery system. The smectic ionic liquid crystal of choline decanoate 1:2 is a viscoelastic hydrophobic gel, and its material properties are translated to sustained insulin release in vitro and result in a prolonged absorption profile in vivo. Choline decanoate 1:2 molar ratio achieved a relative insulin bioavailability superior to that of the previously developed CAGE, confirming the efficacy of the developed drug delivery system. Thus, the ionogel technology combines the material properties of the smectic liquid crystalline mesophase with the permeation enhancing effect of the ionic liquid and the controlled release of decanoate molecules, resulting in a prolonged and superior absorption profile as well as a higher maximum plasma concentration. These findings validated the improved permeation enhancement achieved with this drug delivery system and the potential for further development. Further, although the viscoelastic properties of the ionogel counteract the fast transit times and dilution seen with liquid formulations, we aimed to enhance the formulation performance by loading the ionogel on a self-unfolding foil. An in vivo proof-of-concept study showed that the unidirectional release of the ionogel in close proximity to mucosa significantly enhanced insulin absorption providing evidence that such combinations of devices with advanced drug delivery systems can provide an additional upside in peptide absorption.

In conclusion, this work conceptualizes, develops, and characterizes a novel advanced drug delivery system that employs a smectic ionic liquid crystalline mesophase to create a gel-like formulation with finely tuned material properties designed to enhance oral peptide absorption. The mechanistic insight that we here provide on the function and effect of the ionogel technology lays the foundation for further optimization regarding the physicochemical properties of the formulation. The novel permeation enhancer-based ionogel technology holds promise for future in vivo testing and development of a dosage form.