Using thin film freezing to minimize excipients in inhalable tacrolimus dry powder formulations

June 27, 2020

Dilip Ramani(1), Yadvinder Singh(1), Robin T. White(1), Matthew Wegener(1), Francesco P. Orfino(1), Monica Dutta(2), Erik Kjeang(1)
International Journal of Pharmaceutics, 586, June 2020. DOI: 10.1016/j.ijpharm.2020.119490


Keywords

Tacrolimus, Dry powder for inhalation, Thin film freezing, Lung transplantation, Nanostructured aggregate, Brittle matrix, Immunosuppressant


Abstract

We investigated the feasibility of preparing high-potency tacrolimus dry powder for inhalation using thin film freezing (TFF). We found that using ultra-rapid freezing can increase drug loading up to 95% while maintaining good aerosol performance. Drug loading affected the specific surface area and moisture sorption of TFF formulations, but it did not affect the chemical stability, physical stability, and dissolution of tacrolimus. Tacrolimus remained amorphous after storage at 40 °C/75% RH, and 25 °C/60% RH for up to 6 months. Lactose functioned as a bulking agent, and it had little to no effect as a stabilizer for amorphous tacrolimus due to a lack of interaction between the drug and excipient. Additionally, the aerosol performance of TFF tacrolimus/lactose (95/5) did not significantly change after six months of storage at 25 °C/60% RH. For processing parameters, the solids content and the processing temperature did not affect the aerosol performance of tacrolimus. Furthermore, both low- and high-resistance RS01 showed optimal and consistent aerosol performance over the 1–4 kPa pressure drop range. In conclusion, TFF is a suitable technology for producing inhalable powder that contain high drug loading and have less flow rate dependence.


How Our Software Was Used

Dragonfly was used to binarize ToF-SIMS images.


Author Affiliation

(1) The University of Texas at Austin, College of Pharmacy, Division of Molecular Pharmaceutics and Drug Delivery, Austin, TX, USA.
(2) Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
(3) TFF Pharmaceuticals, Inc., Austin, TX, USA.
(4) The University of Texas at Austin, Texas Materials Institute, Austin, TX, USA.