Spray-dried oil-in-water emulsion to improve the intestinal absorption and oral bioavailability of ZLR-8, a nitric oxide-releasing derivative of diclofenac

Objectives Spray‐dried emulsion (SDE) was prepared and characterized to improve the intestinal absorption and oral bioavailability of ZLR‐8, a nitric oxide‐releasing derivative of diclofenac, currently under preclinical development. Methods The intestinal absorption of ZLR‐8 was characterized by single pass intestinal perfusion technique to obtain its absorption and permeability parameters. SDE of ZLR‐8 was prepared and characterized by particle size measurements and in‐vitro release study. Accurate and precise RP‐HPLC methods for the detection of ZLR‐8 and its metabolite diclofenac were constructed to perform the bioavailability study. Key findings It was demonstrated that ZLR‐8 was absorbed in the whole intestine, of which the duodenum segment exhibited the largest absorption ability. ZLR‐8 can be classified into BCS Class 2. SDE significantly enhanced the intestinal absorption rate of ZLR‐8 in duodenum and jejunum but had indistinctive effect on permeability. All concentrations of ZLR‐8 in rat plasma was lower than the limit of detection. A bicompartment model gave the best fit to the plasma diclofenac concentration–time curves. Calculated on AUC_0–12h, the mean relative bioavailability of SDE was 105.4‐fold that of ZLR‐8 suspension. Conclusions SDE significantly improved the intestinal absorption of ZLR‐8 and resulted in a dramatic improvement in its bioavailability.