title: 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 36h. 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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter St, Amarillo, TX 79106, USA.
authors.forename: Jahidur
authors.initials: J
authors.lastname: Rashid
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter St, Amarillo, TX 79106, USA.
authors.forename: Brijeshkumar
authors.initials: B
authors.lastname: Patel
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Nozik-Grayck
authors.affiliation: Department of Pharmacology, The Center for Lung Biology, University of South Alabama, Mobile, AL 36688, USA.
authors.forename: Ivan F
authors.initials: IF
authors.lastname: McMurtry
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter St, Amarillo, TX 79106, USA. Electronic address: fakhrul.ahsan@ttuhsc.edu.
authors.forename: Fakhrul
authors.initials: F
authors.lastname: Ahsan
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D004337:Drug Carriers; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000473:pathology; D019344:Lactic Acid / Q000737:chemistry; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D008863:Microspheres; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D010316:Particle Size; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011094:Polyethyleneimine / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D016062:Porosity; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013499:Surface Properties; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D004337:Drug Carriers; D058986:Phosphodiesterase 5 Inhibitors; D014665:Vasodilator Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011094:Polyethyleneimine; D000068677:Sildenafil Citrate
keywords: Controlled release; Inhalation; PLGA; Phosphodiesterase 5; Pulmonary arterial hypertension; Sildenafil