Investigating the effect of permeation enhancers on oral absorption of a BCS IV compound, ombitasvir, utilizing animal models.

Discovery of complex biological targets and novel treatment modalities have led to an increase in the number of compounds with poor permeability. Generally, formulation design and development are primarily focused on overcoming poor solubility. Improving oral bioavailability by utilizing permeation enhancers for poorly permeable new chemical entities (NCEs) has not been widely explored. Therefore, in this work the effect of permeation enhancers on a poorly soluble and poorly permeable compound, ombitasvir (OBT), was investigated. Structurally diverse permeation enhancers (PEs) with good safety profile-labrasol® ALF, lauroyl L- and palmitoyl L-carnitine, salcaprozoate sodium (SNAC), and sodium caprate-were tested. To study the impact of solid form and formulation, OBT was dosed as crystal form and as amorphous formulations. To avoid the influence of preclinical in vitro/ex vivo method artifacts on data interpretation, studies were conducted in whole animal models (rat and dog). OBT was dosed at 2 mg/kg and PEs were dosed at 20 mg/kg by peroral route. In rats, OBT was administered as an amorphous colloidal suspension. Only the carnitines showed meaningful enhancement (∼2X) in oral bioavailability. In dogs, OBT was dosed in enteric capsules as crystal form, a slow dissolving 15% drug load (DL) amorphous solid dispersion (ASD) that slowly reached amorphous solubility, and a rapidly dissolving 5% DL ASD that reached amorphous solubility and formed amorphous nanoprecipitates, with and without PEs. OBT was not detected in the blood upon dosing of neat crystalline solid. However, when co-dosed with PEs significantly high oral bioavailability (11-17%) was observed. 15% DL ASD alone showed a meaningful increase in oral bioavailability (∼4%) relative to the crystal form; and combination with PEs further increased the bioavailability by 2-5 fold. All the PEs showed enhancement in oral bioavailability when combined with the crystal form and 15% DL ASD. The enhancement in bioavailability due to SNAC was attributed to dissolution rate enhancement whereas, that due to lauroyl L-carnitine and labrasol was attributed to both dissolution and permeability enhancement. 5% DL ASD by itself increased the oral bioavailability to ∼8% which was attributed to its rapid dissolution. A massive increase in the oral bioavailability to 78% (∼10-fold enhancement) was observed with lauroyl L-carnitine. In contrast to the crystal form and 15% DL ASD groups, other PEs, were found to be ineffective when combined with the 5% DL ASD. Physicochemical characterization including solubility determination in presence of PEs, dissolution performance of the forms/formulations and particle size distribution of the amorphous precipitated phase (for 5% DL ASD) in presence of PEs was performed to understand in vivo results. It was concluded that the dissolution rate of the form/formulation, the amount of drug concomitantly available with PE at the site of absorption, the association of PE with the precipitated amorphous phase and the particle size of this phase impacts the overall performance of PE towards improving oral bioavailability. The results of this study present promising approaches to formulate BCS IV compounds.