Nanocrystal-based per-oral itraconazole delivery: superior in vitro dissolution enhancement versus Sporanox® is not realized in in vivo drug absorption.

Nanoscience holds true promise in enabling efficient formulation development and in vivo delivery of poorly water soluble drugs. The objective of this study was to formulate solid oral nanocrystal delivery systems of itraconazole, and thus enhance the oral bioavailability of the very poorly soluble drug. Nanocrystal suspensions were prepared by a rapid wet milling technique, after which the suspensions were transformed into solid dosage forms by both freeze drying and granulating. Finally, the obtained nanocrystalline powders were capsule-packed as well as compacted to tablets. After in vitro analysis, the formulations (nanocrystal suspension (NPs), freeze dried NPs, granulated NPs) were tested in vivo in a rat model, and compared with commercial itraconazole formulation (Sporanox). Importantly, the results indicated rapid dissolution of the nanocrystalline itraconazole with enhanced bioavailability compared to physical mixture. Drug dissolution in vitro was immediate from NPs and freeze dried powder, and differed significantly from the marketed product (P=0.004 and 0.002, correspondingly) until 30min. Freeze drying was detected to be especially advantageous for the solid dosage forms. It is possible to maintain the original character of the nanocrystals, e.g. rapid dissolution, even after tableting of the nanocrystalline powders. Interestingly, the marketed product out-performed the nanocrystalline formulations in vivo, even though the nanocrystals provided reasonable bioavailability of itraconazole absorption as well. The efficient in vitro dissolution enhancement of the nanocrystalline formulations compared to Sporanox® was not realized in in vivo drug absorption.

Dissolution study of nanocrystal powders of a poorly soluble drug by UV imaging and channel flow methods.

Application of drug nanocrystals provides advantageous options for the pharmaceutical formulation development of poorly soluble drugs. The objective of this study was to investigate the dissolution behavior improving effects of differently sized nanocrystals of a poorly soluble model drug, indomethacin. Nanocrystal suspensions were prepared using a top-down wet milling technique with three stabilizers: poloxamer F68, poloxamer F127 and polysorbate 80. The dissolution of the differently sized indomethacin nanocrystals were investigated using a channel flow dissolution method and by UV imaging. Unmilled bulk indomethacin and physical mixtures were used as references. According to both the dissolution methods, the dissolution properties of indomethacin were improved by the particle size reduction. UV imaging was used for the first time as a dissolution testing method for fast dissolving nanoscale material. The technique provided new information about the concentration of the dissolved drug next to the sample surface; with the smallest nanocrystals (580 nm) the indomethacin concentration next to the particle surface exceeded five-fold the thermodynamic saturated indomethacin solution concentration. Thus the solubility improvement itself, not only the increased surface area for dissolution, may have an important role in the higher dissolution rates of nanocrystal formulations. Poloxamer F68 was the most optimal stabilizer in the preparation of the indomethacin nanocrystal suspensions and in the solubility and dissolution enhancement as well.