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

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Abstract

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 AUC0–12h, 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.

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