Solid formulations by a nanocrystal approach: critical process parameters regarding scale-ability of nanocrystals for tableting applications.

Nanocrystallization is among the foremost drug delivery platform approaches for the commercial development of poorly soluble drugs. There exists an urge to enable a universal shift of the production of the solid nanocrystal formulations from laboratory scale to industrially feasible scale. The success of any formulation development depends on its transferability to large scale manufacture. The objectives of the study were to increase the nanocrystallization batch size and to screen and optimize parameters for industrially feasible itraconazole (ITC) and indomethacin (IND) nanocrystal composition for tablet formulation. Thus, ITC and IND were transformed into nanocrystal suspensions, using an increased batch size of a wet milling process, freeze-dried, and further developed into both direct compression (DC) and granulated (G) tableting masses. According to the investigated powder and tablet properties (true density, flowability, dose uniformity, maximum upper punch force, crushing strength, dissolution and disintegration) and stability testings, it was clear that the amount of the nanocrystals in the solid tablet formulation is critical in order to fully utilize the benefits of the nanocrystals, i.e., fast dissolution, and to produce high-quality tablets. The DC designs of both the model drugs with compositions including 40% of freeze-dried nanocrystalline drug powder outperformed the corresponding granulated tablets in all parameters after the stability surveillance.

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.

Brinzolamide nanocrystal formulations for ophthalmic delivery: reduction of elevated intraocular pressure in vivo.

Nanocrystal-based drug delivery systems provide important tools for ocular formulation development, especially when considering poorly soluble drugs. The objective of the study was to formulate ophthalmic, intraocular pressure (IOP) reducing, nanocrystal suspensions from a poorly soluble drug, brinzolamide (BRA), using a rapid wet milling technique, and to investigate their IOP reducing effect in vivo. Different stabilizers for the nanocrystals were screened (hydroxypropyl methylcellulose (HPMC), poloxamer F127 and F68, polysorbate 80) and HPMC was found to be the only successful stabilizer. In order to investigate both the effect of an added absorption enhancer (polysorbate 80) and the impact of the free drug in the nanocrystal suspension, formulations in phosphate buffered saline (PBS) at pH 7.4 and pH 4.5 were prepared. Particle size, polydispersity (PI), solid state (DSC), morphology (SEM) as well as dissolution behavior and the uniformity of the formulations were characterized. There was rapid dissolution of BRA (in PBS pH 7.4) from all the nanocrystal formulations; after 1 min 100% of the drug was fully dissolved. The effect was significantly pronounced at pH 4.5, where the dissolved fraction of drug was the highest. The cytotoxicity of nanocrystal formulations to human corneal epithelial cell (HCE-T) viability was tested. The effects of the nanocrystal formulations and the commercial product on the cell viability were comparable. The intraocular pressure (IOP) lowering effect was investigated in vivo using a modern rat ocular hypertensive model and elevated IOP reduction was seen in vivo with all the formulations. Notably, the reduction achieved in experimentally elevated IOP was comparable to that obtained with a marketed product. In conclusion, various BRA nanocrystal formulations, which all showed advantageous dissolution and absorption behavior, were successfully formulated.