Three recently published AAPS Journal articles examine dry powder inhalers for pulmonary drug delivery. The first, Inhalable Nanoparticles/Microparticles of an AMPK and Nrf2 Activator for Targeted Pulmonary Drug Delivery as Dry Powder Inhalers, by Acosta, Abrahamson, Encinas-Basurto, et al., demonstrates a method for aerosol delivery of metformin nanoparticles/microparticles to treat many pulmonary diseases. The second, Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?, by Hochhaus, Chen, Kurumaddali, et al., supports the use of PK studies to provide relevant information on the pulmonary performance characteristics using three fluticasone propionate dry powder inhaler formulations. The third, Elucidating the Effect of Fine Lactose Ratio on the Rheological Properties and Aerodynamic Behavior of Dry Powder for Inhalation, by Sun, Qin, Li, et al., emphasizes that fine lactose does indeed help with pulmonary delivery through dry powder inhalers, although it is ratio dependent.
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Inhalable Nanoparticles/Microparticles of an AMPK and Nrf2 Activator for Targeted Pulmonary Drug Delivery as Dry Powder Inhalers
By Maria F. Acosta, Michael D. Abrahamson, David Encinas-Basurto, Jeffrey R. Fineman, Stephen M. Black, and Heidi M. Mansour
OPEN ACCESS
Metformin is an activator of the AMPK and Nrf2 pathways which are important in the pathology of several complex pulmonary diseases with unmet medical needs. Organic solution advanced spray drying in the absence of water in closed-mode was used to design and develop respirable dry powders. Following comprehensive characterization, the influence of physicochemical properties was correlated with performance as aerosols using inertial impaction and three different human dry powder inhaler (DPI) devices varying in device properties. In vitro cell assays were conducted to test safety in 2D human pulmonary cell lines and in 3D small airway epithelia comprising primary cells at the air-liquid interface (ALI). In addition, in vitro transepithelial electrical resistance (TEER) was carried out. Metformin remained crystalline following advanced spray drying under these conditions. All SD powders consisted of nanoparticles/microparticles in the solid state. In vitro aerosol dispersion performance showed high aerosolization for all SD metformin powders with all DPI devices tested. High emitted dose for all powders with all three DPI devices was measured. Differences in other aerosol performance parameters and the interplay between the properties of different formulations produced at specific pump rates and the three different DPI devices were correlated with spray drying pump rate and device properties. Safety over a wide metformin dose range was also demonstrated in vitro. Aerosol delivery of metformin nanoparticles/microparticles has the potential to be a new “first-in-class” therapeutic for the treatment of a number of pulmonary diseases including pulmonary vascular diseases such as pulmonary hypertension.
Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?
By Günther Hochhaus, Mong-Jen Chen, Abhinav Kurumaddali, et al.
In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.8, and C-3.7), differing only in type and composition of lactose fines, exhibited median mass aerodynamic diameter (MMAD) of 4.5 μm (A-4.5), 3.8 μm (B-3.8), and 3.7 μm (C-3.7) and varied in dissolution rates (A-4.5 slower than B-3.8 and C-3.7). In vitro total lung dose (TLDin vitro) was determined as the average dose passing through three anatomical mouth-throat (MT) models and yielded dose normalization factors (DNF) for each DPI formulation X (DNFx = TLDin vitro,x/TLDin vitro,A-4.5). The DNF was 1.00 for A-4.5, 1.32 for B-3.8, and 1.21 for C-3.7. Systemic PK after inhalation of 500 μg FP was assessed in a randomized, double-blind, four-way crossover study in 24 healthy volunteers. Peak concentrations (Cmax) of A-4.5 relative to those of B-3.8 or C-3.7 lacked bioequivalence without or with dose normalization. The area under the curve (AUC0–Inf) was bio-IN-equivalent before dose normalization and bioequivalent after dose normalization. Thus, PK could detect differences in pulmonary available dose (AUC0–Inf) and residence time (dose-normalized Cmax). The differences in dose-normalized Cmax could not be explained by differences in in vitro dissolution. This might suggest that Cmax differences may indicate differences in regional lung deposition. Overall this study supports the use of PK studies to provide relevant information on the pulmonary performance characteristics (i.e., available dose, residence time, and regional lung deposition).
Elucidating the Effect of Fine Lactose Ratio on the Rheological Properties and Aerodynamic Behavior of Dry Powder for Inhalation
By Ying Sun, Lu Qin, Jiayi Li, Jian Su, Ruxiao Song, Xin Zhang, Jian Guan, and Shirui Mao
Dry powder inhaler (DPI) is recognized as the first choice for lung diseases’ treatment. However, it lacks a universal way for DPI formulation development. Fine lactose is commonly added in DPIs to improve delivery performance; however, the fine ratio-dependent mechanism is unclear. Therefore, the objective of this study is to explore the influence of fine lactose ratio on DPI powder properties and aerodynamic behavior, and the fine lactose ratio-dependent mechanism involved during powder fluidization and lung deposition. Here salbutamol sulfate was used as a model drug, Lactohale® 206 as coarse carrier, and Lactohale® 300 as fine component; the mixtures were prepared at 1% drug content, with fine content up to 20%. It was shown that with the fine addition, flowability of the mixtures was improved, interaction among particles was increased, and the presence of fines could help to improve DPI’s aerosolization performance. When the fines added were less than 3%, the “active site” hypothesis played a leading role. When the added fines were over 3% but less than 10%, fluidization enhancement mechanism was more important. After the added fines reaching 10%, aggregate mechanism started to dominate. However, FPF cannot be further increased once the fines reached 20%. Moreover, the correlations between FPF and dynamic powder parameters were verified in ternary mixtures, and cohesion had a greater impact on FPF than that of flowability. In conclusion, adding lactose fines is an effective way to improve lung deposition of DPI, with the concrete mechanism lactose fine ratio dependent.