Inhaled sildenafil as an alternative to oral sildenafil in the treatment of pulmonary arterial hypertension (PAH)

Abstract

The practice of treating PAH patients with oral or intravenous sildenafil suffers from the limitations of short dosing intervals, peripheral vasodilation, unwanted side effects, and restricted use in pediatric patients. In this study, we sought to test the hypothesis that inhalable poly(lactic-co-glycolic acid) (PLGA) particles of sildenafil prolong the release of the drug, produce pulmonary specific vasodilation, reduce the systemic exposure of the drug, and may be used as an alternative to oral sildenafil in the treatment of PAH. Thus, we prepared porous PLGA particles of sildenafil using a water-in-oil-in-water double emulsion solvent evaporation method with polyethyleneimine (PEI) as a porosigen and characterized the formulations for surface morphology, respirability, in-vitro drug release, and evaluated for in vivo absorption, alveolar macrophage uptake, and safety. PEI increased the particle porosity, drug entrapment, and produced drug release for 36 hours. Fluorescent particles showed reduced uptake by alveolar macrophages. The polymeric particles were safe to rat pulmonary arterial smooth muscle cell and to the lungs, as evidenced by the cytotoxicity assay and analyses of the injury markers in the bronchoalveolar lavage fluid, respectively. Intratracheally administered sildenafil particles elicited more pulmonary specific and sustained vasodilation in SUGEN-5416/hypoxia-induced PAH rats than oral, intravenous, or intratracheal plain sildenafil did, when administered at the same dose. Overall, true to the hypothesis, this study shows that inhaled PLGA particles of sildenafil can be administered, as a substitute for oral form of sildenafil, at a reduced dose and longer dosing interval.

Inhaled combination of sildenafil and rosiglitazone improves pulmonary hemodynamics, cardiac function, and arterial remodeling

“…Preparation and characterization of PLGA particles of sildenafil and rosiglitazone. Sildenafil-and rosiglitazone-loaded microparticles were prepared according to our previously established water-in-oilin-water (W 1/O/W2) double emulsion-solvent evaporation method (46,48). In short, 0.5 ml of an internal aqueous phase (W1) containing rosiglitazone maleate (20 mg/ml) or sildenafil citrate (20 mg/ml) in a mixture of methanol and double-deionized water (20:80) plus 0.5% polyethyleneimine (PEI) in water was first emulsified in a PLGA polymer solution in dichloromethane (organic phase) using a Branson Sonifier 450 (Branson Ultrasonics, Danbury, CT).…”

“…One group of healthy rats was used as the sham group. IT administration was performed using a Penn Century MicroSprayer (Penn Century, Wyndmoor, PA) upon illuminating the trachea using a rat laryngoscope, as reported previously (48).…”

“…In a recent study, we showed that by formulating it as inhalable particles, rosiglitazone, a peroxisome proliferator-activated receptor-␥ agonist that is reported to inhibit pul-monary arterial remodeling and arrest PAH progression (14,28,33,41,54), can be repurposed for the treatment of PAH (46). In a separate study, we demonstrated that inhaled poly-(lactic-co-glycolic acid) (PLGA) particles of sildenafil, an orally active phosphodiesterase type 5 inhibitor that is frequently used as monotherapy or in combination therapy for PAH (13), improve pulmonary hemodynamics in PAH rats when given at a reduced dose and longer dosing intervals (48).…”

“…As a continuation of the above two studies (46,48), wherein we assessed the feasibility of inhaled particulate formulations of rosiglitazone and sildenafil for the treatment of PAH, here we tested the hypothesis that a combination of sildenafil and rosiglitazone, when given as prolonged-release formulations via the pulmonary route, improves pulmonary hemodynamics, RVH, and pulmonary arterial remodeling. As such, we first prepared PLGA particles of sildenafil and rosiglitazone and assessed them for their suitability for administration via the pulmonary route.…”

Development of Spray-Dried Sildenafil Citrate -α-cyclodextrin Complexes for Use in Dry Powder Inhalers

“…1,2 The typical dosage forms of sildenafil are oral tablets or intravenous administration. [3][4][5] Currently, sildenafil has been developed as an inhaler to treat pulmonary hypertension for delivered to the lung included of dry powder inhaler (DPI), metered-dose inhaler and nebulizer for avoiding unwanted systemic side-effects and rapid drug action. [6][7][8][9][10][11] There are previously report sildenafil citrate complexed with α-cyclodextrin to enhance the solubility of sildenafil as a linear function of cyclodextrin concentration.…”