Development and Pharmacokinetics of a Novel Acetylsalicylic Acid Dry Powder for Pulmonary Administration

Abstract

Aspirin is an historic blockbuster product, and it has been proposed in a wide range of formulas. Due to exacerbation risks, the pulmonary route has been seldom considered as an alternative to conventional treatments. Only recently, owing to overt advantages, inhalable acetylsalicylic acid dry powders (ASA DPI) began to be considered as an option. In this work, we developed a novel highly performing inhalable ASA DPI using a nano spray-drying technique and leucine as an excipient and evaluated its pharmacokinetics compared with oral administration. The formulation obtained showed remarkable respirability and quality features. Serum and lung ASA DPI profiles showed faster presentation in blood and higher retention compared with oral administration. The dry powder was superior to the DPI suspension. The relative bioavailability in serum and lungs claimed superiority of ASA DPI over oral administration, notwithstanding a fourfold lower pulmonary dose. The obtained ASA DPI formulation shows promising features for the treatment of inflammatory and infectious lung pathologies.

Keywords: acetylsalycilic acid; aspirin; dry powders; inhalation; pharmacokinetics; pulmonary delivery.

Figure 1

Surface plots of the four responses in Table 2: (a) Yield, (b) ASA content, (c) FPF, and (d) ED. Graphs were built against significant factors according to the results of ANOVA validation of the models obtained (see Table S1). Color map: red-shaded = high, green-shaded = medium, and blue-shaded = low response values.

Figure 2

Morphological observation of samples produced at 95% of ASA loading. Pictures are representative of run# (a) 11, (b) 13, (c) 14, (d) 18, (e) 19, and (f) 20 of the experimental design in Table 2. Dimensional bars correspond to 2 µm.

Figure 3

Theoretical flowability expressed as (a) H together with ρ_t and size distribution expressed as (b) FMD ± S.D. across the different runs of the experimental design. Horizontal lines delimit flowability regions: flowing (H < 1.25), partially flowing (1.25 < H < 1.6), and non-flowing (H > 1.6) powders.

Figure 4

Desirability plot indicating the area of satisfaction (red-shaded) of the defined target properties of the obtained ASA inhalable powders: process yield ≥ 50%, ED ≥ 90%, FPF ≥ 50%, and ASA content ≥ 40%. Satisfaction of FPF and ED criteria was prioritized over the other responses. Maximum desirability was obtained at T_inlet = 85 °C.

Figure 5

Feret’s size distribution (left) and morphology (right) of the chosen formulation corresponding to the run# 7 of the experimental design (Table 2). (Right) Dimensional bars correspond to 2 µm (above) and 1 µm (below).

Figure 6

Serum (A) and lungs (B) SA time profiles after insufflation of ASA DPI (▲) and nebulization of ASA DPI suspension (♦) and after oral administration of ASA saturated solution (●). Data (n = 5) are expressed as mean ± SD.