Impact of sodium caprate dosed as a mini-tablet or suspension on insulin delivery and mucosa histomorphology

Oral administration of solid dosage forms for delivery of therapeutic peptides is highly desired. Preclinical investigations on co-administration with permeation enhancers (PEs) to enable sufficient oral bioavailabilities are, however, predominantly done using liquid formulations despite the commercial end-goal being a solid dosage form. Given the amounts needed of PE, this will typically result in a compacted tablet with high amounts of the PE of choice. The aim of this study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of insulin after co-formulation with a fixed dose of sodium caprate (C10) in solid dosage forms versus liquid dosage forms. PK/PD parameters in rats were evaluated after dosing mini-tablets and liquid formulations with different amounts of insulin and 26 mg/kg C10 after intestinal administration. Absorption of insulin was dose-dependent in the presence of the PE for both types of dosage forms, which was also reflected in the blood glucose levels. A significant absorption enhancing effect of C10 was found when dosing a 75 IU/kg insulin mini-tablet, resulting in a 26-fold increase in bioavailability. The effect of C10 on the rat intestinal tissue was investigated by histomorphological assessment evaluating erosion and villi height. Effects caused by the C10 mini-tablets and the liquid formulations were similar and shown to be transient. Overall, the findings in this study suggest that mini-tablets can be used to assess peptide bioavailability and the effect of PEs in rats as a preclinical model, and PK data may be nominally different from those obtained with liquid formulations.