title: Development of a biodegradable nanoparticle platform for sildenafil: formulation optimization by factorial design analysis combined with application of charge-modified branched polyesters.
abstract: Biodegradable nanoparticles have gained tremendous attraction as carriers for controlled drug delivery to the lung. Despite numerous advances in the field, e.g. development of suitable methods for pulmonary administration of polymeric nanoparticles, a sufficient association of the therapeutic agent with the carrier system as well as drug release in a controlled fashion remain considerable challenges. Hence, this study examines the optimization of biodegradable sildenafil-loaded nanoparticle formulations intended for aerosol treatment of pulmonary hypertension. A factorial design analysis was employed to identify the important experimental factors involved in the preparation of nanoparticles by the solvent evaporation technique. The effect of tailored charge-modified branched polyesters on drug loading and in vitro drug release from nanoparticles was also evaluated. Moreover, colloidal stability of obtained nanoparticles was assessed, and stabilization of nanoparticles by lyophilization was accomplished without additional excipients. Essential experimental factors were identified and optimized to allow the preparation of nanoparticles composed of linear polyesters with a sildenafil content of ~5 wt.%. The in vitro drug release profile from these nanoparticles demonstrated a sustained release of sildenafil over ~90 min. Application of charge-modified branched polyesters enhanced the drug content in nanoparticles and drug release profile, according to the charge-density present in the employed polymer. Accordingly an increase in drug loading by a factor of ~1.4, a prolonged drug release profile from nanoparticles over ~240 min was achieved. Sildenafil release from nanoparticles made of linear and charge-modified branched polyesters was governed by a diffusion process. The obtained drug diffusion coefficients were decreased as the charge-density present in the applied polymer was increased, which promotes the strategy to improve drug loading and release rates by electrostatic interactions between polymer and drug. In addition, nanoparticles showed high colloidal stability in different media of importance for pulmonary application and were successfully stabilized by lyophilization. In conclusion, optimization of the nanoparticle preparation process together with the application of tailored polymeric materials facilitated the synthesis of promising drug carriers for sildenafil that permit a novel treatment modality for severe pulmonary hypertension.
authors.affiliation: Department of Pharmaceutics and Biopharmacy, Philipps-Universität, Ketzerbach 63, D-35037 Marburg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Beck-Broichsitter
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmehl
authors.forename: Tobias
authors.initials: T
authors.lastname: Gessler
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Thomas
authors.initials: T
authors.lastname: Kissel
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D005163:Factor Analysis, Statistical; D005612:Freeze Drying; D053758:Nanoparticles / Q000737:chemistry*; D058986:Phosphodiesterase 5 Inhibitors / Q000737:chemistry; D010879:Piperazines / Q000737:chemistry*; D011091:Polyesters / Q000737:chemistry*; D011687:Purines / Q000737:chemistry; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000737:chemistry*; D014665:Vasodilator Agents / Q000737:chemistry
chemical_list: D000336:Aerosols; D004337:Drug Carriers; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011091:Polyesters; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate