Advanced spray dried proliposomes of Fasudil monohydrochloride microparticles and nanoparticles as dry powder inhalers using surfactant mimic-phospholipids for treatment of pulmonary arterial hypertension (PAH)

Abstract

Fasudil monohydrochloride salt (FMCS) and inhalable lung surfactant-based carriers composed of synthetic phospholipids DPPC (1,2-palmitoyl-sn-glycero-3-phosphocholine) and DPPG (1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-1-glycerol]) were designed and optimized as Co-spray dried powders using advanced organic solutions. The materials can potentially be used for treatment of various complex pulmonary diseases with this current work focusing on pulmonary arterial hypertension (PAH). Physicochemical characterization was carried out to analyze the morphology, surface structure, size, phase behavior, chemical composition, residual water content, and in vitro aerosol dispersion of the particles. The particle chemical composition was confirmed using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. Scanning electron microscopy (SEM) was performed to visualize the surface structure, morphology, and particle size. The residual water content was quantified by Karl Fisher coulometric titration (KFT). Phase behavior was measured using differential scanning calorimetry (DSC). The in vitro aerosol dispersion performance was conducted using Next Generation Impactor (NGI) and FDA approved human dry powder inhaler (DPI) devices (Aerolyzer®, Neohaler®, Handihaler®). Well defined, small, smooth nanoparticles/microparticles were engineered at different molar ratios of FMCS:DPPC/DPPG (25:75, 50:50, 75:25) and had low residual water content. Characteristic absorption bands regions in ATR-FTIR as well as defined endotherm DSC peaks confirmed that the molecular integrity of Fasudil monohydrochloride salt was not affected by the lung surfactant. In vitro aerosol performance demonstrated that the FMCS:DPPC/DPPG formulations may be suitable for targeted pulmonary drug delivery as inhalable powders. These engineered nanoparticles/microparticles composed of FMCS:DPPC/DPPG can be a suitable inhalable pharmacotherapeutic option for the treatment of pulmonary arterial hypertension as well as other complex lung diseases.