Development and Characterization of a Dry Powder Formulation for Anti-Tuberculosis Drug Spectinamide 1599

Abstract

Purpose: Human tuberculosis (TB) is a global health problem that causes nearly 2 million deaths per year. Anti-TB therapy exists, but it needs to be administered as a cocktail of antibiotics for six months. This lengthy therapy results in low patient compliance and is the main reason attributable to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis.

Methods: One alternative approach is to combine anti-TB multidrug therapy with inhalational TB therapy. The aim of this work was to develop and characterize dry powder formulations of spectinamide 1599 and ensure in vitro and in vivo delivered dose reproducibility using custom dosators.

Results: Amorphous dry powders of spectinamide 1599 were successfully spray dried with mass median aerodynamic diameter (MMAD) = 2.32 ± 0.05 μm. The addition of L-leucine resulted in minor changes to the MMAD (1.69 ± 0.35 μm) but significantly improved the inhalable portion of spectinamide 1599 while maintaining amorphous qualities. Additionally, we were able to demonstrate reproducibility of dry powder administration in vitro and in vivo in mice.

Conclusions: The corresponding systemic drug exposure data indicates dose-dependent exposure in vivo in mice after dry powder intrapulmonary aerosol delivery in the dose range 15.4 - 32.8 mg/kg.

Keywords: aerosol; inhalation; spectinamide; tuberculosis.

Figure 1.

Representative SEM images for spectinamide 1599:Leu spray dried powder with API:excipient ratios of A) 100:0, B) 90:10, C) 80:20, D) 75:25, E) 50:50, F) 75:25, G) 10:90, and H) 0:100. Note the scale bars are equivalent in all panels except A.

Figure 2.

DSC thermograms, from bottom to top, for as received spectinamide 1599 and L-leucine (black squares and red circles, respectively), spray dried spectinamide 1599 and L-leucine alone (green triangles and purple stars, respectively), and spray dried spectinamide 1599:Leu = 80:20 (blue inverted triangles). SD = spray dried.

Figure 3.

XRD patterns for, from bottom to top, spectinamide 1599 API as received (black squares), L-leucine powder as received (red circles), spray dried spectinamide 1599 without excipient (green triangles), spray dried spectinamide 1599:Leu = 0:100 (purple stars) and spray dried spectinamide 1599:Leu = 80:20 (blue inverted triangles). SD = spray dried.

Figure 4.

Thermogram curves of weight with respect to temperature for spectinamide 1599 API as received (black squares), Leu as received (red circles), spray-dried spectinamide 1599 without excipient (green triangles), spray dried Leu (magenta stars), and spray dried spectinamide 1599:Leu = 80:20 (blue inverted triangles). SD = spray dried.

Figure 5.

Mass distribution following actuation of 10 mg spray dried spectinamide 1599 without excipient (first, green bars), spray dried spectinamide 1599:Leu = 80:20 (represented as only spectinamide 1599 mass collected; third, gray bars), spray dried spectinamide without excipient after six months (second, blue bars), and spray dried spectinamide 1599:Leu = 80:20 after six months storage (black, fourth bars) via RS-01 (n = 3, mean+/− SD). The NGI was operated at an air flow of 60 L/min for four seconds.

Figure 6.

A) Impact on delivered mass of spectinamide 1599 as a function of L-leucine content using previously designed dosators capable of holding larger amounts of powder (23). B) Mass of powder delivered as a function of tamps in to spectinamide 1599:Leu = 80:20 powder bed using custom dosators designed in this work (n=3, mean +/− SD).