Design of self-dispersible microsponge containing cyclosporine through wet milling and drop freeze-drying processes to improve dissolution behavior

摘要

Cyclosporine (Cyc) is an immunosuppressant used to treat psoriasis and atopic dermatitis and mainly commercialized as a soft capsule due to its poorly water-soluble characteristics. The authors attempted to develop the solid pharmaceutical formulations for oral use (granules, tablet) with improved solubility of Cyc. In this research, a manufacturing method of spherical granules containing nano-sized Cyc particles was newly developed by using the combination between wet milling and drop freeze-drying (DFD) technique. Cyc nanosuspension prepared through wet-milling process was poured dropwise into liquid nitrogen, and the resultant spherical ice grains were freeze-dried to prepare granules with around 300?μm in size. The granules prepared through these sequential processes were identified as porous spherical granules having submicron Cyc particles embedded in water-soluble fiber network structure of additives. When they were placed in aqueous phase, water would immediately penetrate into the matrix of granules through the pores. Subsequently, Cyc particles were spontaneously dispersed into the media as soon as matrix base was dissolved, resulting in the reconstitution of nano-suspension. As a result, the resultant DFD granule, named microsponge, had fast dissolution behavior of more than 80% within 10?min in aqueous phase. The dissolution rate of Cyc from the microsponge strongly depended on the size of embedded Cyc particles, demonstrating that the wet nano-milling must be indispensable process to prepare the microsponge.