Particle size reduction for improvement of oral absorption of the poorly soluble drug UG558 in rats during early development.
BACKGROUND
The exposure of UG558 was not good enough using traditional microsuspensions.


OBJECTIVE
The aim of this study was to find out whether nanosuspensions were a better choice compared with a microsuspension, for an acidic substance with a water solubility in the order of 2 microM (pH 6.8, small intestinal pH) and no permeability limitations.


METHODS
UG558 was ground by a planetary ball mill. The particle size was measured by laser diffraction and the stability of the particle sizes was followed. The pharmacokinetic parameters of UG558 administered as nanosuspension have been compared with those from microsuspension using rat as in vivo specie. Both formulations were administered orally. The nanosuspension was also administered intravenously.


RESULTS
The particle size of the nanosuspensions was about 190 nm and about 12 microm for the microsuspensions. At the administered doses, solutions were no alternative (e.g. due to limited solubility). Already at the lowest dose, 5 micromol/kg (5 ml/kg), a significant difference was observed between the two suspensions. These results were further confirmed at a high dose (500 micromol/kg, 5 mL/kg). Thus, the study demonstrated a clear correlation between particle size and in vivo exposures, where the nanosuspensions provided the highest exposure. Furthermore, no adverse events were observed for the substance nor the nanosuspension formulations (i.e., the particles) in spite of the higher exposures obtained with the nanoparticles. To make it possible to calculate the bioavailability, 5 micromol/kg doses of the nanosuspensions (5 ml/kg) were also administered intravenously. No adverse events were observed.


CONCLUSIONS
The nanoparticles have a larger surface, resulting in faster in vivo dissolution rate, faster absorption, and increased bioavailability, compared to microparticles. The lower overall bioavailability observed at the high dose, compared with the low dose, was due to a combination of low dissolution rate, low solubility, and a narrow intestinal absorption window for UG558.
Sigfridsson
Kalle
K
Pharmaceutical and Analytical R&D, AstraZeneca R&D Mölndal, Mölndal, Sweden. carl-gustav.sigfridsson@astrazeneca.com
Lundqvist
Anders J
AJ
Strimfors
Marie
M
D000284:Administration, Oral; D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D007408:Intestinal Absorption; D053758:Nanoparticles; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013535:Suspensions
D002317:Cardiovascular Agents; D013535:Suspensions