Category: Formulation and Quality
Purpose: Tadalafil (TD); a phosphodiesterase 5 inhibitor (PDE5-I) was approved by the Food and Drug Administration (FDA) for treatment of pulmonary arterial hypertension (PAH)(1), however, no drugs have received FDA-approval for treatment of pediatric patients yet. Among other PDE5-Is approved for treatment of PAH, TD was proved to be more advantageous for children; since data has shown that it is welll tolerated in children, as it offers a favorable adverse effect profile in addition to providing clinical improvement. Moreover; its long duration of action allows once daily administration. Accordingly, the current work endeavors aimed to prepare nanoemulsion (NE) formulation of TD to be administered via nebulization to treat PAH in pediatric patients.
Methods: Different excipients were screened for their nanoemulsifying properties. Optimization was based on the ability of NE to resist aqueous dilution and to solubilize the desired TD dose while incorporating the least possible amount of surfactants. Optimum formulation was assessed using cross-polarized light microscope, measurement of refractive index, percentage transmittance (%T), pH, viscosity and globule size, in addition to determination of morphology using transmission electron microscope (TEM). Feasibility of the formulations for pulmonary application was verified through the following tests: nebulization performance and in-vitro cytotoxicity assay in A549 cell line.
Results: The selected formulation was composed of oil mixture (Capmul MCM EP/Labrafac lipophile WL 1349), surfactant mixture (Labrasol/Poloxamer 407), and water. Cross-polarized light microscopy, refractive index measurement and %T confirmed the optical isotropy of the NE. pH and viscosity of the saline-diluted TD-loaded NE was suitable for pulmonary administration via nebulization. Globule size analysis demonstrated nano-sized droplets. TEM revealed spherical oily globules. TD-loaded NE formulation was successfully nebulized with most of the globules of the internal phase within the nano-size range. In-vitro cytotoxicity study using A549 cell line showed that the formulation exhibited an acceptable safety profile as demonstrated by percentage cell viability of 80.1%.
Conclusion: Novel tadalafil nanoformulation with suitable pharmaceutical and biocompatibility attributes was developed. In-vivo safety studies are currently investigated.