title: Sildenafil citrate monohydrate-cyclodextrin nanosuspension complexes for use in metered-dose inhalers.
abstract: Sildenafil is a selective phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction and pulmonary hypertension. Sildenafil citrate monohydrate was complexed with α-, hydroxypropyl-β- and γ-cyclodextrin (α-CD, HP-β-CD and γ-CD, respectively) to enhance its water solubility. The complexes of sildenafil citrate monohydrate with all types of CDs were characterized by phase solubility diagrams, (1)H and (13)C NMR, and dielectric constants. Sildenafil citrate monohydrate complexed with CDs was developed as nanosuspensions for use in a pressurized metered-dose inhaler (pMDI). Sildenafil citrate monohydrate pMDI formulations were prepared by a bottom-up process using dried ethanol as a solvent and HFA-134a as an antisolvent and propellant in order to form nanosuspensions. A 3×3 factorial design was applied for the contents of the dried ethanol and HFA-134a propellant. The phase solubility profiles of the sildenafil and cyclodextrins were described as AL type with a mole ratio 1:1. The piperazine moiety of sildenafil formed an inclusion in the cavity of the CDs. The particle diameters of the sildenafil citrate monohydrate suspensions in pMDIs were all within a nanosuspension size range. An assay of the sildenafil content showed that the formation of complexes with CDs was close to 100%. In the case of the formulations with CDs, the emitted doses varied within 97.4±10.8%, the fine particle fractions (FPFs) were in a range of 45-81%, the fine particle dose (FPD) was 12.6±2.0 μg and the mass median aerodynamic diameters (MMADs) were 1.86±0.41 μm. In contrast, the formulations without CDs produced a low emitted dose of sildenafil (<60%). Therefore, only sildenafil citrate monohydrate pMDI formulations containing CDs were suitable for use as aerosols.
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand.
authors.forename: Somchai
authors.initials: S
authors.lastname: Sawatdee
authors.forename: Hirihattaya
authors.initials: H
authors.lastname: Phetmung
authors.forename: Teerapol
authors.initials: T
authors.lastname: Srichana
mesh_terms: D003505:Cyclodextrins / Q000737:chemistry*; D036501:Metered Dose Inhalers; D049329:Nanostructures / Q000737:chemistry; D010316:Particle Size; D058986:Phosphodiesterase 5 Inhibitors / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry*; D011687:Purines / Q000737:chemistry; D000068677:Sildenafil Citrate; D012995:Solubility; D013450:Sulfones / Q000737:chemistry*
chemical_list: D003505:Cyclodextrins; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate
keywords: Aerosols; Cyclodextrin; Metered-dose inhaler; Nanosuspension; Sildenafil citrate; Sildenafil–cyclodextrin complex