Downstream drug product processing of itraconazole nanosuspension: Factors influencing tablet material properties and dissolution of compacted nanosuspension-layered sugar beads.

There has been limited research done on the downstream processing of nanosuspensions into solid oral dosage forms. This paper demonstrates the bead layering process with a layering level at 150% and 240%, as well as the selection and justification of the outer phase excipients for tabletability and disintegrating properties. In a previous study, an itraconazole nanosuspension stabilised by SDS and HPMC E5 was layered onto sugar beads with coating polymer HPMC VLV. In the current study, compression studies with these layered beads utilising the small bead size at 150% or 240% layering levels with outer phase cushioning excipients MCC, copovidone or isomalt were performed. Other excipients such as co-compressed crospovidone-PEG 4000; DCP functioning as a disintegrant; and HPC as a binder was also added. Target output variables were achieved with a balance between an adequate tensile strength and fast dissolution rate with a release of 99.0% (±1.0% SD) within 10min, which is in accordance with the FDA guidance for dissolution testing. The results show that the compaction of nanosuspension-layered beads is a suitable process for processing an itraconazole nanosuspension into a solid dosage form such as a compacted tablet without compromising on drug release.

Downstream drug product processing of itraconazole nanosuspension: Factors influencing drug particle size and dissolution from nanosuspension-layered beads.

There is more research required to broaden the knowledge on the downstream processing of nanosuspensions into solid oral dosage forms, especially for coated nanosuspensions onto beads as carriers. This study focuses on bead layering as one approach to solidify nanosuspensions. The aim was to systematically investigate the influence of type of coating polymer (HPMC VLV vs. copovidone), bead material and bead size (sugar vs. MCC, and small vs. large) and coating thickness (50%-150% layering level) on the properties of a dried itraconazole nanosuspension. A stable itraconazole nanosuspension with a mean particle size below 200nm was prepared and a ratio of itraconazole and coating polymer of around 1:1 was identified. XRD and DSC scans revealed that itraconazole remained mostly crystalline after the bead layering process. The fastest dissolution rate was achieved using the small bead size, sugar beads, HPMC VLV as film-forming polymer and lowest layering level, with the best formulation releasing 94.1% (±3.45% SD) within the first 5min. A deterioration of the release profile with increasing layering level was only observed for MCC beads and was more pronounced when copovidone was used as a coating polymer. It was observed that bead layering is a suitable method to process an itraconazole nanosuspension into a solid form without compromising release.

Development and characterization of novel highly-loaded itraconazole poly(butyl cyanoacrylate) polymeric nanoparticles.

Treatment of cryptococcal meningitis with antifungals such as itraconazol is difficult due their low concentration in the brain. Therefore, drug carriers with high payload are highly desired. But, generation of itraconazole loaded poly(butyl cyanoacrylate) nanoparticles with higher drug load, for instance more than 20% drug, is challenging. In present study we were able to generate novel highly loaded itraconazole poly(butyl cyanoacrylate) nanocapsules containing up to 99% (w/w) itraconazole and 1% polymer (w/w). Moreover, a controllable manufacturing procedure using a one-step emulsion solvent evaporation technique was established in order to discriminate between itraconazole loaded nanocapsules and nanospheres. Furthermore, it could be demonstrated that our novel nanocapsules can be decorated with targeting molecules such as apolipoprotein E. More precisely, apolipoprotein E was covalently bound to a maleimide linker, which was integrated within the surface of polymeric nanoparticle. This covalent binding of apolipoproteinE to the surface of a drug delivery system enables targeting of low density lipoprotein receptor (LDLR) expressed on endothelial brain capillary cell membranes, making our novel highly loaded itraconazole poly(butyl cyanoacrylate) nanocapsules a promising drug delivery system for treatment of cryptococcal meningitis.