Formulation of Ketoconazole Nanocrystal-Based Cryopellets
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Titre | Formulation of Ketoconazole Nanocrystal-Based Cryopellets |
Type de publication | Journal Article |
Year of Publication | 2020 |
Auteurs | Touzet A, Pfefferle F, Lamprecht A, Pellequer Y |
Journal | AAPS PHARMSCITECH |
Volume | 21 |
Date Published | JAN 3 |
Type of Article | Article |
ISSN | 1530-9932 |
Mots-clés | cryopelletisation, Freeze drying, Ketoconazole, Nanosuspension, Wet media milling |
Résumé | Commercial development of nanosuspensions for oral drug delivery generally involves a drying step which aims to generate a stable product that rapidly releases the nanocrystals once rehydrated and can be easily processed into a final dosage form (e.g., filled into hard capsule). Cryopelletisation is a freeze drying technique allowing the production of lyophilised micrometric spheres with good flowability. In the current work, the possibility to formulate redispersible ketoconazole nanocrystal-based cryopellets able to withstand intensive handling was investigated. Cryopellets were generated by first freezing regular droplets of nanosuspension using liquid nitrogen followed by water removal by sublimation in a standard freeze dryer. Low-friable cryopellets (< 1%) were produced by embedding the nanocrystals in a stabilizing hydroxypropyl cellulose SSL grade matrix, thus proving that these structures can withstand intensive handling. A threshold quantity of hydroxypropyl cellulose SSL grade (5/20 hydroxypropyl cellulose SSL grade-to-drug mass ratio) was required in combination with D-alpha-tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS) to successfully recover the nanocrystals over storage. A further addition of micronised crospovidone has shown a positive effect on the dissolution performance of cryopellets. Altogether, this study demonstrated that the design of cryopellets combining the strengths of freeze-dried powders (porous internal structure, low residual humidity) and pellets (free-flowing units, mechanical resistance during handling) can potentially improve the nanocrystal's redispersibility compared with other drying techniques while facilitating the downstream processing. |
DOI | 10.1208/s12249-019-1570-1 |