Synthetic oligosaccharides are used in clinical practice as anticoagulants. Due to their poor oral bioavailability, oligosaccharides — along with most pharmaceutical macromolecules — are formulated as solutions or suspensions and delivered by invasive intravenous (IV) or subcutaneous injection. When oral bioavailability is increased, macromolecule can potentially be converted from injectable to oral drug delivery. This case study demonstrates how OptiGel ™ Bio technology significantly increases oral bioavailability of a synthetic oligosaccharide, thus enabling oral conversion.
Delivered orally, oligosaccharides are faced with several intrinsic and external environmental challenges to achieving the desired therapeutic effects. Though water soluble, they are unstable in the acidic condition of the stomach and the molecular steric hindrance prevents permeation through the GI tract.
OptiGel Bio technology helps overcome two major barriers to the oral delivery of macromolecules — stability and bioavailability. By formulating an oligosaccharide using OptiGel Bio technology, a formulation with enhanced oral bioavailability was developed, eliminating the need for costly and invasive IV delivery.
After screening five different water-in-oil (W/O) emulsions of the oligosaccharide, the optimized formulation (designated F3 in Figure 1) was identified for further development. To assess duodenal permeation and absorption, the formulations were administered using an intra-duodenal catheter to Wistar Han rats. API plasma concentrations were collected and compared to results from IV injection.
Figure 1 Bioavailability of W/O Emulsions in Rat Model
F3 was then formulated as softgel capsules (with or without enteric coating) to investigate whether the coating can protect the oligosaccharide in the acidic stomach environment. The softgel capsules were administered into the stomach of beagle dogs, and their bioavailability is shown in Figure 2. The results demonstrate that enteric coated softgel capsules showed an almost three times higher bioavailability compared with the non-coated formulation. In addition, incorporation of silicon dioxide (SD) in the W/O emulsion fill reduced variability by three times which can translate into less dosing variability in patients.
Figure 2 Bioavailability of Softgel Capsules in Dog Model
Using OptiGel Bio technology, Catalent optimized the W/O emulsion composition for the oligosaccharide and utilized enteric coated softgel capsules to protect the formulation in acidic gastric conditions, significantly increasing oral bioavailability by as much as 300%. By combining enteric protection and permeability enhancements, OptiGel Bio technology can provide better macromolecular treatments with lower cost, easier dosing and an optimal therapeutic profile.