title: Evaluation of sildenafil pressurized metered dose inhalers as a vasodilator in umbilical blood vessels of chicken egg embryos.
abstract: Sildenafil citrate is a selective phosphodiesterase-5 inhibitor used for the treatment for erectile dysfunction and pulmonary hypertension. The delivery of sildenafil directly to the lung could have several advantages over conventional treatments for pulmonary hypertension because of the local delivery, a more rapid onset of response, and reduced side effects. The major problem of sildenafil citrate is its limited solubility in water. Sildenafil citrate was complexed with cyclodextrins (CDs) to enhance its water solubility prior to development as an inhaled preparation. Four sildenafil citrate inhaled formulations were prepared with the aid of HP-β-CD (#1), α-CD (#2) and γ-CD (#3) and their effects were compared with the formulations without CDs (#4). The sildenafil citrate pressurized metered dose inhalers (pMDI) used ethanol as a solvent, PEG400 as a stabilizing agent, sorbitan monooleate as a surfactant and HFA-134a as a propellant. All formulations consisted of sildenafil citrate equivalent to a sildenafil content of 20μg/puff. These products were evaluated according to a standard guideline of inhalation products. Vasodilation testing was performed to investigate the efficacy of sildenafil pMDIs in relieving a vasoconstricted umbilical blood vessel of the chicken egg embryo. The sildenafil contents of the pMDI formulations #1-#3 were within the acceptance criteria (80-120%). The emitted doses (ED) were 102.3±11.5%, the fine particle fractions (FPF) were 60.5±5.6% and the mass median aerodynamic diameters (MMAD) were 2.3±0.3μm. The vasodilatory activity of those formulations reduced umbilical blood pressure by 67.1-73.7% after treatment by intravenous injection whereas only a 50.1-58.0% reduced blood pressure was obtained after direct spraying of the sildenafil pMDI containing CDs. With sildenafil formulations of a pMDI without CD the blood pressure was reduced by only 39.0% (P-value<0.05). The available sildenafil in the blood vessels of chicken egg embryos after spraying sildenafil-CDs pMDIs was within the range of 751-825ng/mL which was much higher than that of a sildenafil only pMDI.
authors.affiliation: Department of Pharmaceutical Technology, Prince of Songkla University, Songkhla, Thailand.
authors.forename: Somchai
authors.initials: S
authors.lastname: Sawatdee
authors.affiliation: Department of Physiology, Prince of Songkla University, Songkhla, Thailand.
authors.forename: Phetai
authors.initials: P
authors.lastname: Hiranphan
authors.affiliation: Technical Service Department, Interthai Pharmaceutical Manufacturing Limited, Bangkok, Thailand.
authors.forename: Kampanart
authors.initials: K
authors.lastname: Laphanayos
authors.affiliation: Department of Pharmaceutical Technology, Prince of Songkla University, Songkhla, Thailand; Nanotec-PSU Excellence Center on Drug Delivery System, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla, Thailand. Electronic address: teerapol.s@psu.ac.th.
authors.forename: Teerapol
authors.initials: T
authors.lastname: Srichana
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects* / Q000196:embryology; D002626:Chemistry, Pharmaceutical; D002642:Chick Embryo; D003505:Cyclodextrins / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D005079:Excipients / Q000737:chemistry; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D036501:Metered Dose Inhalers; D010879:Piperazines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011687:Purines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000068677:Sildenafil Citrate; D012995:Solubility; D013450:Sulfones / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014470:Umbilical Cord / Q000187:drug effects* / Q000196:embryology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D003505:Cyclodextrins; D004337:Drug Carriers; D005079:Excipients; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate
keywords: Chicken egg embryo; Cyclodextrin; Development; Pressurized metered dose inhalers; Sildenafil citrate; Vasodilation