Deep eutectic solvents are mixtures that are liquid at room temperature even though the individual components melt above room temperature. This melting point depression effect is usually driven by hydrogen bonding interactions between the components. A naturally occurring deep eutectic solvent is honey. Honey contains about 85% of solid components that melt above 100 °C in pure form (glucose, fructose, sucrose and maltose), but when these sugars are combined in the right ratio, in presence of around 15% of water, the resulting mixture is liquid at room temperature. We are harnessing this very principle for the delivery for poorly water-soluble drugs.
One of the key benefits of our deep eutectic solvent-based platform resides in its ability to create high-payload formulations for the entire spectrum of poorly soluble small molecules, from those that are solvation-limited (“grease-ball” APIs) to those that are solid-state-limited (“brick-dust” APIs). This is especially attractive for the latter class, as these compounds are difficult to formulate via solubilisation (too low loading capacity in vehicle), particle size reduction (inadequate absorption-increasing potential) or amorphisation (too low solubility in volatile organic solvents to enable spray drying and too high melting point to access melt extrusion).
To design our deep eutectic systems, we select excipients from a library that comprises hundreds of substances with widely documented safety, such as sugars, sugar alcohols, amino acids and carboxylic acids. As we typically use three, four or five excipients to construct our deep eutectic solvents, rather than relying on the use of one single cosolvent or surfactant, we reduce potential excipient-related side effects as these are typically related to exceeding a critical threshold level of a single component.
Upon contact with the aqueous fluids of the gastrointestinal tract, the hydrogen bonds that hold the components in our deep eutectic solvents together are disrupted, leading to hydration of the excipients and release of the API at concentrations far above those that would be achievable by dissolution of its crystalline form. This state of API supersaturation provides for a higher driving force for absorption. To prevent the API from precipitating into a less soluble form after release, we add pharmaceutical-grade polymers or surfactants to our formulations.
Bulk production of our formulations is conducted in a single-pot, solvent-free process at mildly elevated temperature. This process requires minimal development effort and is readily scaled up. The liquid formulation obtained via this procedure can directly be filled in capsules, vials or any other container type. This simple manufacturing process constitutes a great advantage over other solubility-enhancing approaches such as nanosuspensions or amorphous solid dispersions, which not only require intricate unit operations to produce the primary formulation (wet milling, melt extrusion or spray drying), but also need a series of downstream processing steps (drying, blending, granulation or compression) to produce the final dosage form.
- Powerful solubility enhancement
- Broad applicability
- High API loadings
- Well-tolerated excipients
- Ease of manufacture