Nano- and microcrystals of griseofulvin subcutaneously administered to rats resulted in improved bioavailability and sustained release

Abstract

Griseofulvin is a commonly used antifungal agent which is administered per oral (p.o.). The oral administration route, however, shows rather low bioavailability. The aim of this study was to improve the bioavailability and to evaluate and interpret the pharmacokinetic profiles after subcutaneous (s.c.) administration of crystalline griseofulvin nano- and microsuspensions. Both formulations were injected at 5 and 500 µmol/kg to rats. For the lower concentration, the profiles were similar after s.c. injection but extended as compared to p.o. administration. For the higher concentration, injection of microsuspension resulted in a maintained plateau whereas the nanosuspension resulted in an obvious peak exposure followed by extended elimination. Both suspensions showed improved exposure with dose. The differences in peak exposures between nano- and microparticles, at the high dose, were mainly ascribed to differences in dissolution rate, experimentally determined in vitro, using spectroscopic methods. The extended appearance in the circulation may depend on the physicochemical properties of the compound and the physiological conditions at the injection site. The bioavailability was improved for both formulations compared with an orally administered nanosuspension, suggesting the s.c. route to be a preferred administration option for compounds with low oral bioavailability regarding both overall exposure and extended efficacy.

Keywords:

• Dissolution rate
• intramuscular
• nanosuspension
• pharmacokinetics
• poorly soluble
• suspension
• implant
• sustained release

Acknowledgments

The authors gratefully acknowledge the contribution of several scientists at the bioanalytical department at AstraZeneca, Gothenburg, Sweden, and Torbjörn Arvidsson for preparing Figure 4.

Disclosure statement

No potential conflict of interest was reported by the authors.