Development and evaluation of PIK75 nanosuspension, a phosphatidylinositol-3-kinase inhibitor.
OBJECTIVE
PIK75 is a specific inhibitor of the p110 α isoform of phosphatidylinositol-3-kinase, an enzyme which is upregulated in several human cancers. However its poor water solubility and stability has limited its pre-clinical development.


METHODS
In our current work we developed and evaluated PIK75 nanosuspension prepared using high pressure homogenization technique. The nanosuspension was characterized for various properties such as size, surface charge and saturation solubility. The saturation solubility processing techniques were critically evaluated to optimize sample processing conditions. In vitro studies were conducted to determine the stability of the formulation and in vivo studies were carried out to understand the pharmacokinetic and tissue distribution properties of the nanosuspension.


RESULTS
The nanosuspension exhibited an 11-fold improvement in saturation solubility with drug recovery greater than 90% for 6h in the nanosuspension system and in human plasma. In vivo studies indicated that both PIK75 suspension and nanosuspension showed a similar plasma pharmacokinetic profile however tissue distribution studies indicated lower PIK75 levels in the kidney post nanosuspension administration.


CONCLUSIONS
The results of this study showed that PIK75 could be formulated as a nanosuspension to improve saturation solubility, enhance stability in plasma and minimize exposure to drug metabolizing tissues.
School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, New Zealand.
Meghna
M
Talekar
Jackie
J
Kendall
William
W
Denny
Stephen
S
Jamieson
Sanjay
S
Garg
D000818:Animals; D002152:Calorimetry, Differential Scanning; D006835:Hydrazones / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D049329:Nanostructures / Q000737:chemistry*; D010316:Particle Size; D000081082:Phosphoinositide-3 Kinase Inhibitors; D033362:Powder Diffraction; D013449:Sulfonamides / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D013535:Suspensions; D014018:Tissue Distribution; D014961:X-Ray Diffraction
D006835:Hydrazones; C549211:PIK 75; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; D013535:Suspensions