A dry powder aerosol comprising a small molecule prosthetic ion-channel for treatment of people with cystic fibrosis

NACFC Conference

Background: Although CFTR modulators have been highly effective for about 90% of people with cystic fibrosis (CF), there remains 10% of the population who have Class I or other mutations for which current modulators are ineffective. Amphotericin B (AmB) is a small-molecule natural product that forms monovalent ion channels, suggesting its potential to operate as a molecular prosthetic for treating CF. Previous studies have demonstrated that AmB with cholesterol (Chol) are able to restore bicarbonate secretion and increase airway surface liquid pH in cultured airway epithelia independent of the CFTR mutation [1,2]. Here, we report on the development of an inhaled dry powder ion-channel therapeutic comprising AmB and Chol for treatment of people with CF in the remaining 10% of the population.

Methods: Lipid-coated crystals of AmB (formulation ABCI-003) were prepared by spray drying an aqueous feedstock comprising wet-milled AmB crystals and submicron emulsion droplets stabilized by a mixture of phospholipids (hydrogenated soy phosphatidylcholine (HSPC), distearoylphosphatidylglycerol (DSPG)) and Chol. The theoretical drug loading was 14.0% w/w and the Chol/AmB ratio was 0.40 mol/mol. 

AmB and Chol content and purity were determined by RP-HPLC. Particle morphology was assessed by scanning electron microscopy. The primary particle size distribution of the spray-dried powder was determined by laser diffraction (Sympatec). Bulk and tapped densities were also assessed. The physical form of the materials was determined by X-ray powder diffraction and differential scanning calorimetry. Aerosol performance for powders administered with a variant of the RS01 DPI were determined with a Next Generation Impactor at a pressure drop of 4 kPa and an inhaled volume of 4 L.

Results: The spray-dried particles comprised submicron crystals of AmB coated with a porous layer of lipids. The fine particles had an X50 of 2.01±0.02 mm, an X90 of 3.77±0.07 mm, a bulk density of 0.06 g/mL, and a tapped density of 0.08 g/mL. The gel to liquid crystal phase transition temperature (Tm) of the phospholipid acyl chains was 91°C. The crystallinity and purity of the drug substance was maintained through the manufacturing process. 

The emitted dose of AmB from the portable dry powder inhaler was 88%, with an FPF< 5mm of 81%, and a mass median aerodynamic diameter (MMAD) of 2.1 mm. Deposition on the USP throat to stage 2, stages 3 to 5, and stages 6 to filter were 6.1%, 71.8%, and 10.6% of the nominal dose, respectively. This pattern of deposition on the impactor stages should lead to targeted delivery to the bronchial airways.

Conclusions: The spray-dried particles have particle characteristics optimal for high efficiency delivery to the bronchial airways of people with cystic fibrosis.

See More News and Updates