title: Steroid/mucokinetic hybrid nanoporous microparticles for pulmonary drug delivery.
abstract: In a number of pulmonary diseases, patients may develop abnormally viscous mucus reducing drug efficacy. To increase budesonide diffusion within lung fluid, we developed nanoporous microparticles (NPMPs) composed of budesonide and a mucokinetic, ambroxol hydrochloride, to be inhaled as a dry powder. Budesonide/ambroxol-HCl particles were formulated by spray drying and characterised by various physicochemicals methods. Aerodynamic properties were evaluated using a cascade impactor. Drugs apparent permeability coefficients were calculated across mucus producing Calu-3 cell monolayers cultivated at an air-liquid interface. Microparticles made only from budesonide and ambroxol-HCl had smooth surfaces. In the presence of ammonium carbonate ((NH4)2CO3), NPMPs were formulated, with significantly (P<0.05) superior aerodynamic properties (MMAD=1.87±0.22 μm and FPF=84.0±2.6%). The formation of nanopores and the increase in the specific surface area in the presence of (NH4)2CO3 were mainly attributed to the neutralisation of ambroxol-HCl to form ambroxol base. Thus, ambroxol base could behave in the same manner as budesonide and prompt nanoprecipitation when spray dried from an ethanol/water mix occurs. All formulations were amorphous, which should enhance dissolution rate and diffusion through lung fluid. These NPMPs were able to improve budesonide permeability across mucus producing Calu-3 cell monolayers (P<0.05) suggesting that they should be able to enhance budesonide diffusion in the lungs through viscous mucus.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Panoz Institute, Dublin, Ireland; INSERM U 1070, Pôle Biologie-Santé, Faculté de Médecine & Pharmacie, Université de Poitiers, Poitiers, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Tewes
authors.forename: Krzysztof J
authors.initials: KJ
authors.lastname: Paluch
authors.forename: Lidia
authors.initials: L
authors.lastname: Tajber
authors.forename: Karan
authors.initials: K
authors.lastname: Gulati
authors.forename: Devesh
authors.initials: D
authors.lastname: Kalantri
authors.forename: Carsten
authors.initials: C
authors.lastname: Ehrhardt
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Healy
mesh_terms: D000280:Administration, Inhalation; D000551:Ambroxol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001980:Bronchi / Q000166:cytology; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019819:Budesonide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D004058:Diffusion; D004339:Drug Compounding; D016503:Drug Delivery Systems; D058995:Dry Powder Inhalers; D004847:Epithelial Cells / Q000378:metabolism; D005100:Expectorants / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008863:Microspheres; D010539:Permeability; D016062:Porosity; D020545:Respiratory Mucosa / Q000378:metabolism
chemical_list: D001993:Bronchodilator Agents; D005100:Expectorants; D000551:Ambroxol; D019819:Budesonide
keywords: Ambroxol; Andersen cascade impactor; Budesonide; Calu-3 cells; Dry powder inhaler; Nanoporous microparticles