Background: Olmesartan medoxomil (OLM) is a promising prodrug hydrolyzed to olmesartan
(OL) during absorption from the gastrointestinal tract. OL is a selective angiotensin II receptor antagonist,
with high drug resistance and low drug interaction. However, OLM has low solubility and low
bioavailability. Therefore, it is extremely urgent to reduce the drug particle size to improve its biological
Objective: The aim of the study was to improve the oral bioavailability of poorly water-soluble olmesartan
medoxomil (OLM) by using different particle size-reduction strategies.
Method: Raw drug material was micronized or nanosized by either jet or wet milling processes, respectively.
The particle sizes of the prepared nanocrystals (100-300 nm) and microcrystals (0.5-16 μm) were
characterized by DLS, SEM, and TEM techniques. Solid state characterization by XPRD and DSC was
used to confirm the crystalline state of OLM after the milling processes.
Results: We demonstrated that OLM nanocrystals enhanced solubility and dissolution in the non-sink
condition in which high sensitivity was found in purified water. After 1 h, 65.4% of OLM was dissolved
from nanocrystals, while microcrystals and OLMETEC® only showed 37.8% and 31.9% of drug dissolution,
respectively. In the pharmacokinetic study using Beagle dogs, an increase in Cmax (～2 fold) and
AUC (～1.6 fold) was observed after oral administration of OLM nanocrystals when compared to microcrystals
and reference tablets, OLMETEC®. In contrast, OLM microcrystals failed to improve the
oral bioavailability of the drugs.
Conclusion: Particles size reduction to nano-scale by means of nanocrystals technology significantly
increased in vitro dissolution rate and in vivo oral bioavailability of OLM.