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

JOURNAL OF CONTROLLED RELEASE

卷:250

Article

Rashid, Jahidur¹  Patel, Brijeshkumar^1,4  Nozik-Grayck, Eva²  McMurtry, Ivan F.³  Stenmark, Kurt R.²  Ahsan, Fakhrul¹ 

[1] Texas Tech Univ, Sch Pharm, Dept Pharmaceut Sci, Hlth Sci Ctr, 1300 Coulter St, Amarillo, TX 79106 USA

[2] Univ Colorado Denver, Dept Pediat, Anschutz Med Campus, Aurora, CO 80045 USA

[3] Univ S Alabama, Dept Pharmacol, Ctr Lung Biol, Mobile, AL 36688 USA

[4] DS Labs Inc, 1601 Green Rd, Pompano Beach, FL 33063 USA

关键词: Pulmonary arterial hypertension;    Sildenafil;    Phosphodiesterase 5;    PLGA;    Inhalation;    Controlled release;   

DOI  :  10.1016/j.jconrel.2017.02.003

来源: Elsevier

【 摘 要 】

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 h. 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. (C) 2017 Elsevier B.V. All rights reserved.

【 授权许可】

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