(M1530-04-22) Co-formulating Inhalable Powders of Nintedanib, Pirfenidone and Mycophenolic Acid by Thin-Film Freezing Technology

Purpose: Nintedanib, pirfenidone and mycophenolic acid are drugs to treat idiopathic pulmonary fibrosis and other fibrosing lung diseases by delayed progression of the disease [1-3]. However, oral administration of each drug causes adverse drug reactions due to the high dose of administration. Since bioavailability of each drug can be affected by food, coadministration of the oral drugs may have difficulty in drug management [3-5]. Dry powder for inhalation can improve local treatment and decrease systemic side effects that are encountered in oral drug therapy. This study aims to develop and characterize co-formulating inhaled powder formulations including two- and three-drug combinations of nintedanib, pirfenidone and mycophenolic acid prepared by thin-film freezing (TFF) process.

Methods: Inhaled two-drug combinations (NM) containing nintedanib (NIN) and mycophenolic acid (MA) and inhaled three-drug combinations (T) containing nintedanib (NIN), pirfenidone (PIR) and mycophenolic acid (MA) were prepared by thin-film freezing (TFF) process. Excipients and solvent systems (30%v/v and 50%v/v of acetonitrile (ACN)/water) were designed to improve aerodynamic performance. Lactose (Lac), mannitol (Man) and leucine (Leu) were used as dispersing agents and stabilizers. Powder morphology of each formulation was evaluated by X-ray Powder Diffraction (XRPD) and Scanning Electron Microscopy (SEM). Specific surface area (SSA) was investigated by a Monosorb MS-21 surface area analyzer using a modified Brunauer-Emmett-Teller (BET) method. Moreover, intermolecular bonding and miscibility of formulations were investigated by Fourier-Transform Infrared Spectroscopy (FT-IR). Aerodynamic particle size distribution of each formulation was evaluated by a Next Generation Pharmaceutical Impactor (NGI).

Results: The crystallinity evaluation of each drug by XRPD confirmed that the two- and three-drug combinations contained amorphous nintedanib, pirfenidone and mycophenolic acid. However, the crystalline peaks of excipients including mannitol and leucine were detected on the XRPD pattern, while lactose was amorphous. The powder morphology using SEM showed homogenous and brittle matrix structures of the inhaled combinations (Figure 1). SSA of the three-drug combinations showed in the range of 124-125 m²/g. In terms of two-drug combinations, NM06 prepared using 50%v/v of acetonitrile/water showed higher aerodynamic performance compared with NM01 prepared by 30%v/v of acetonitrile/water (Figure 2). NM08 containing the active ingredients of nintedanib and mycophenolic acid with lactose and leucine as excipients demonstrated the highest aerodynamic performance. The fine particle fraction (FPF, of recovered dose) of nintedanib and mycophenolic acid was found to be 76.33±3.97% and 74.19±4.48% respectively. Moreover, both drugs showed a similar aerodynamic particle size distribution. In terms of three-drug combinations, lactose showed a greater ability to disperse drugs with similar aerodynamic particle size distribution compared to mannitol and leucine. T36 containing lactose showed the highest FPF of nintedanib, pirfenidone and mycophenolic acid at 57.81±6.48%, 56.24±5.43% and 60.13±2.08% respectively. FT-IR spectrum revealed that mycophenolic acid exhibited intermolecular hydrogen bonding with pirfenidone, which enhanced aerodynamic performance with a similar drug particle distribution (Figure 3).

Conclusion: Inhaled two- and three-drug combinations of nintedanib, pirfenidone and mycophenolic acid, which were produced by thin-film freezing process, exhibited physical characteristics resulting in acceptable aerosol performances (FPF over 50%). Therefore, the co-formulated drug combinations exhibiting homogeneous drug particle distribution should be further studied for pulmonary administration to enhance the treatment of idiopathic pulmonary fibrosis.

References: 1. Xaubet, A., et al., Guidelines for the Medical Treatment of Idiopathic Pulmonary Fibrosis. Archivos de Bronconeumología (English Edition), 2017. 53(5): p. 263-269.
2. Raghu, G., et al., An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. American Journal of Respiratory and Critical Care Medicine, 2015. 192(2): p. e3-e19.
3. Nambiar, A.M., A.R. Anzueto, and J.I. Peters, Effectiveness and safety of mycophenolate mofetil in idiopathic pulmonary fibrosis. PloS one, 2017. 12(4): p. e0176312-e0176312.
4. SUMMARY OF PRODUCT CHARACTERISTICS: Esbriet 267 mg hard capsules. 2015, Roche Registration: Germany.
5. SUMMARY OF PRODUCT CHARACTERISTICS: Ofev. 2019, Boehringer Ingelheim International GmbH: Germany.

Acknowledgements: Williams, Peters, Moon, and Praphawatvet are co-inventors on IP related to this abstract. The University of Texas System has licensed this IP to TFF Pharmaceuticals, Inc. Williams owns equity in TFF Pharmaceuticals, Inc. Moon, Williams and Peters (uncompensated) are consultants to TFF Pharmaceuticals, Inc. This work was supported by a Sponsored Research Agreement with TFF Pharmaceuticals, Inc.


Figure 1 SEM images of inhaled two- and three-drug combinations with a magnification of 10.0 K X


Figure 2 Aerodynamic performance of each formulation


Figure 3 FT-IR spectrum and aerodynamic particle size distribution of the three-drug combination (T36)