TY - JOUR
T1 - Fixed-dose dry powder for inhalation of nintedanib, pirfenidone and mycophenolic acid by thin-film freezing (TFF) technology
AU - Praphawatvet, Tuangrat
AU - Sahakijpijarn, Sawittree
AU - Moon, Chaeho
AU - Peters, Jay I.
AU - Williams, Robert O.
N1 - Funding Information:
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Robert O. Williams III reports a relationship with TFF Pharmaceuticals Inc. that includes: consulting or advisory, equity or stocks, and funding grants. Tuangrat Praphawatvet, Chaeho Moon, and Robert O. Williams III has patent licensed to TFF Pharmaceuticals, Inc. from the University of Texas at Austin. Jay I. Peters reports a relationship with TFF Pharmaceuticals Inc. that includes consulting and advising (uncompensated). Chaeho Moon reports a relationship with TFF Pharmaceuticals Inc. that includes consulting or advising. Authors acknowledge TFF Pharmaceuticals, Inc. for their financial support to the University of Texas at Austin through a sponsored research agreement.Robert O. Williams III: Conceptualization, Resources, Supervision, Writing - review & editing, Project administration, Funding acquisition.
Publisher Copyright:
© 2023 Elsevier B.V.
PY - 2023/8
Y1 - 2023/8
N2 - Nintedanib and pirfenidone have been approved to treat idiopathic pulmonary fibrosis (IPF) by delaying progression of the disease. Recently, mycophenolic acid has also been used as an additive treatment for IPF. This study aims to produce and evaluate fixed-dose combinations (i.e., two-drug and three-drug combinations) of nintedanib, pirfenidone, and mycophenolic acid dry powders for inhalation produced by thin-film freezing (TFF). The TFF process, which is a bottom-up particle engineering technology using a rapid freezing process, allows the formation of a homogeneous powder matrix of the fixed-dose combinations of the two or three drugs. X-ray powder diffraction (XRPD) and modulated differential scanning calorimetry (mDSC) confirmed the presence of amorphous nintedanib and crystalline pirfenidone (NIN-PIR), and amorphous nintedanib and amorphous mycophenolic acid (NIN-MPA) in the two-drug combinations. Two-drug formulations of nintedanib and mycophenolic acid prepared by the TFF process exhibited homogenous porous matrix powders with a high surface area and brittle fracture behavior. The in vitro aerodynamic testing of the two-drug combinations demonstrated that nintedanib and mycophenolic acid have similar particle size distributions and high aerodynamic performance of up to 78–82% fine particle fraction (FPF) of the recovered dose. However, pirfenidone was crystalline in the nintedanib/pirfenidone combinations, resulting in poor aerodynamic performance with FPF (of recovered dose) of 6%–28%. In the three-drug formulations, the TFF process produced a coformer of pirfenidone and mycophenolic acid that prevented pirfenidone crystallization and consequently enhanced aerosolization. Therefore, nintedanib, pirfenidone, and mycophenolic acid exhibited as homogenous brittle matrix powders, resulting in a similar aerodynamic performance with FPF (of recovered dose) of 56%–60%. In conclusion, the fixed-dose combinations produced by the TFF process exhibited drug-excipient miscibility and homogenous brittle matrix powders to enhance aerodynamic performance for inhalation.
AB - Nintedanib and pirfenidone have been approved to treat idiopathic pulmonary fibrosis (IPF) by delaying progression of the disease. Recently, mycophenolic acid has also been used as an additive treatment for IPF. This study aims to produce and evaluate fixed-dose combinations (i.e., two-drug and three-drug combinations) of nintedanib, pirfenidone, and mycophenolic acid dry powders for inhalation produced by thin-film freezing (TFF). The TFF process, which is a bottom-up particle engineering technology using a rapid freezing process, allows the formation of a homogeneous powder matrix of the fixed-dose combinations of the two or three drugs. X-ray powder diffraction (XRPD) and modulated differential scanning calorimetry (mDSC) confirmed the presence of amorphous nintedanib and crystalline pirfenidone (NIN-PIR), and amorphous nintedanib and amorphous mycophenolic acid (NIN-MPA) in the two-drug combinations. Two-drug formulations of nintedanib and mycophenolic acid prepared by the TFF process exhibited homogenous porous matrix powders with a high surface area and brittle fracture behavior. The in vitro aerodynamic testing of the two-drug combinations demonstrated that nintedanib and mycophenolic acid have similar particle size distributions and high aerodynamic performance of up to 78–82% fine particle fraction (FPF) of the recovered dose. However, pirfenidone was crystalline in the nintedanib/pirfenidone combinations, resulting in poor aerodynamic performance with FPF (of recovered dose) of 6%–28%. In the three-drug formulations, the TFF process produced a coformer of pirfenidone and mycophenolic acid that prevented pirfenidone crystallization and consequently enhanced aerosolization. Therefore, nintedanib, pirfenidone, and mycophenolic acid exhibited as homogenous brittle matrix powders, resulting in a similar aerodynamic performance with FPF (of recovered dose) of 56%–60%. In conclusion, the fixed-dose combinations produced by the TFF process exhibited drug-excipient miscibility and homogenous brittle matrix powders to enhance aerodynamic performance for inhalation.
KW - Fixed-dose combinations
KW - Mycophenolic acid
KW - Nintedanib
KW - Pirfenidone
KW - Pulmonary delivery
KW - Thin-film freezing
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U2 - 10.1016/j.jddst.2023.104559
DO - 10.1016/j.jddst.2023.104559
M3 - Article
AN - SCOPUS:85163563411
SN - 1773-2247
VL - 85
JO - Journal of Drug Delivery Science and Technology
JF - Journal of Drug Delivery Science and Technology
M1 - 104559
ER -