A formulation comparison between micro- and nanosuspensions: the importance of particle size for absorption of a model compound, following repeated oral administration to rats during early development.
OBJECTIVE
The aim of this study was to maximize the exposure of a model compound (MC) for forthcoming high-dose toxicological studies with the physical form of the original compound unaffected.


METHODS
The two evaluated formulation approaches for the present poorly water-soluble compound were micro- and nanosuspensions.


RESULTS
The particle size was about 280 nm for the nanosuspensions and about 4 μm for the microsuspensions. The crystallinity and the crystalline form of the ground samples were conserved. The physical and the chemical stabilities of the two kinds of suspensions were unaffected during the investigated time period. The in vivo results of the study showed that the pharmacokinetic parameters investigated were comparable at the low-dose level (6 μmol/kg) for both formulations after single administration. However, at the two higher doses (60 and 300 μmol/kg), a significant difference in exposure was observed between the two suspensions with an improved exposure for smaller particles. After Day 7 of repeated administration, a significant difference in exposure was observed at all dose levels. The overall exposures were higher on Day 7, compared to the exposures on Day 1 (most significant for nanoparticles), due to an accumulation of compound in the body.


CONCLUSIONS
The nanoparticles have a larger surface, resulting in faster in vivo dissolution rate, faster absorption, and increased bioavailability, compared to microparticles. The differences in systemic exposure of model compound, following oral administration of nano- or microparticles of the drug substance, are probably caused by differences in the in vivo dissolution rate and possibly further enhanced by saturation of the systemic elimination.
Sigfridsson
Kalle
K
Pharmaceutical Development, AstraZeneca R&D Mölndal, Mölndal, Sweden. carl-gustav.sigfridsson@astrazeneca.com
Nordmark
Anna
A
Theilig
Stefanie
S
Lindahl
Anders
A
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003460:Crystallization; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004355:Drug Stability; D064420:Drug-Related Side Effects and Adverse Reactions; D008297:Male; D008863:Microspheres; D053758:Nanoparticles; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013535:Suspensions; D013997:Time Factors
D004364:Pharmaceutical Preparations; D013535:Suspensions