New nano-matrix oral formulation of nanoprecipitated cyclosporine A prepared with multi-inlet vortex mixer

We present a combined nanoparticle (NP) formation process and spray drying to create a nano-matrix formulation of cyclosporine A (CsA) and mannitol (nCsA/MAN) to increase the bioavailability of CsA. CsA NPs were prepared by flash nano precipitation (FNP) using a multi-inlet vortex mixer, and spray-dried with or without mannitol to prepare nCsA/MAN or nanoprecipitated CsA powder (nCsA), respectively. Pre-forming the NPs by FNP uncouples the sizes of the CsA inclusions from the ultimate micron-sized powders produced by spray drying. Both CsA formulations were physicochemically characterized, and a pharmacokinetic study in rats was conducted after oral administration of CsA samples (10 mg-CsA/kg). In the nCsA/MAN, CsA NPs dispersed in the mannitol matrix. In water, both the nCsA and nCsA/MAN reconstituted into NP form with average sizes of 317 and 298 nm, respectively. In dissolution testing, nCsA and nCsA/MAN exhibited marked improvement in the dissolution with 31- and 41-fold higher drug release at 60 min, compared with amorphous CsA, suggesting the significant impact of CsA NP size on dissolution. The higher dissolution rate with the mannitol matrix indicates the role of mannitol on wetting and dispersing the NP aggregates. Both nCsA formulations provided enhancement in CsA exposure in rats with a ca. 3-fold increase of the oral bioavailability compared with amorphous CsA. The nCsA/MAN showed faster absorption in vivo than nCsA, possibly due to the improved dissolution rate. From these findings, the nano-matrix formulation appears to be an efficacious oral dosage form to enhance the biopharmaceutical properties of CsA.

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