The antimycotic compound ITZ is extremely poorly water-soluble, which is mainly driven by its high lipophilicity. The oral solution as developed by the originator contains hydroxypropyl-β-cyclodextrin (40%), propylene glycol and hydrochloric acid (pH 2) as solubilising excipients. In spite of the cocktail of solubilisation strategies employed (cyclodextrin complexation, cosolvency and pH-adjustment), the ITZ concentration in this product is only 10 mg/ml. In general, developing a high-payload solubilised formulation is difficult, given ITZ's extremely low solubility in traditional excipients.
Harnessing the potential of our our deep eutectic solvent platform, we have designed a formulation that has equivalent biopharmaceutical performance but 14-fold higher ITZ loading than the marketed oral solution.
Itraconazole
The antimycotic compound itraconazole is extremely poorly water-soluble, which is mainly driven by its high lipophilicity. The oral solution as developed by the originator (Sporanox®, Janssen Pharmaceutica) contains hydroxypropyl-β-cyclodextrin (40%), propylene glycol and hydrochloric acid (pH 2) as solubilising excipients. Despite the cocktail of solubilisation strategies employed (cyclodextrin complexation, cosolvency and pH-adjustment), the total itraconazole concentration in this product is only 10 mg/ml.
| Molecular weight | 705.6 g/mol |
| Melting point | 169 ºC |
| LogP | 6.2 |
| pKa | 2.0 (b), 3.7(b) |
Designing a high-payload liquid formulation using our eutectic formulation technology
Using our eutectic formulation technology platform, we have designed a liquid formulation that contains 140 mg/ml itraconazole. This formulation was based on two small organic molecules that served to form the eutectic solvent with itraconazole, and one polymer that acted as a precipitation inhibitor.
The loading level in our formulation is 14-fold higher than that in the Sporanox® oral solution and two orders of magnitude higher than the solvent capacity in most traditional solubilising excipients (see table above). Oral gavage administration of our formulation to rats resulted in higher bioavailability to the Sporanox® oral solution.
Conclusion
Harnessing the potential of our eutectic formulation technology platform, we have designed a formulation that has 14-fold higher loading and greater than 2-fold better biopharmaceutical performance than the marketed oral solution Sporanox®. These findings illustrate the potential of our technology for the development of enhanced oral formulations for very water insoluble compounds.