title: Nanocrystals embedded in chitosan-based respirable swellable microparticles as dry powder for sustained pulmonary drug delivery.
abstract: In this study, nanocrystals embedded in microparticles were designed to achieve sustained pulmonary drug delivery of hydrophobic drugs. Chitosan based microparticles were engineered to allow sustained drug release via swelling and mucoadhesive properties of the polymer. Taking cinaciguat as a hydrophobic model drug, drug nanocrystals were prepared by high pressure homogenization and then encapsulated in chitosan microparticles via spray drying. Through various in vitro characterizations, it was shown that drug loaded microparticles had a high drug loading with promising aerosolization characteristics (mean volume diameter (Dv50) 3-4μm, experimental mass mean aerodynamic diameter (MMADe) 4-4.5μm, fine particle fraction (FPF%) 40-45%, emitted dose (ED%) 94-95%). The microparticles showed high swelling capacity within 5min, with various sustained drug release rates depending on chitosan concentration and molecular weight. Furthermore, aerosolization performances under various inhalation conditions were investigated. It was found that both inspiratory flow rate and volume had an influence on the aerosolization of developed microparticles, indicating actual inhalation efficiency might be compromised under disease conditions. Taken together, in vitro data indicate that chitosan based swellable microparticles could potentially be useful as nanocrystal carrier to achieve sustained pulmonary delivery. To complete the feasibility assessment of this formulation principle, future in vivo safety and efficacy studies are needed.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Ni
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Qiaoyu
authors.initials: Q
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Chemical and Pharmaceutical Development, Research Center Wuppertal-Aprath, Bayer Pharma AG, Wuppertal 42096, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Muenster
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: maoshirui@syphu.edu.cn.
authors.forename: Shirui
authors.initials: S
authors.lastname: Mao
mesh_terms: D000280:Administration, Inhalation; D048271:Chitosan / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000737:chemistry; D003890:Desiccation / Q000379:methods; D004337:Drug Carriers / Q000737:chemistry; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods; D057927:Hydrophobic and Hydrophilic Interactions; D008168:Lung / Q000378:metabolism*; D008863:Microspheres; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011208:Powders / Q000737:chemistry*
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D011208:Powders; D048271:Chitosan
keywords: Chitosan; Microparticle; Nanocrystal; Pulmonary; Spray drying; Sustained release; Swellable