title: Non-steroidal anti-inflammatory drug for pulmonary administration: design and investigation of ketoprofen lysinate fine dry powders.
abstract: Pulmonary inflammation is an important therapeutic target in cystic fibrosis (CF) patients, aiming to limit and delay the lung damage. The purpose of the present research was to produce respirable engineered particles of ketoprofen lysinate, a non-steroidal anti-inflammatory drug able to fight lung inflammatory status by direct administration to the site of action. Micronized drug powders containing leucine as dispersibility enhancer were prepared by co-spray drying the active compound and the excipient from water or hydro-alcoholic feeds. Microparticles were fully characterized in terms of process yield, particle size distribution, morphology and drug content. The ability of the drug to reach the deepest airways after aerosolization of spray-dried formulations was evaluated by Andersen cascade impactor, using the monodose DPI as device. In order to investigate the behaviour of the drug once in contact with lung fluid, an artificial CF mucus was prepared. Drug permeation properties were evaluated interposing the mucus layer between the drug and a synthetic membrane mounted in Franz-type diffusion cells. Finally, the effect of the engineered particles on vitality of human airway epithelial cells of patients homozygous for ΔF 508 CF (CuFi1) was studied and compared to that of raw active compound. Results indicated that powders engineering changed the diameter and shape of the particles, making them suitable for inhalation. The mucus layer in the donor compartment of vertical diffusion cells slowed down drug dissolution and permeation, leucine having no influence. Cell proliferation studies evidenced that the spray drying process together with the addition of leucine reduced the cytotoxic effect of ketoprofen lysine salt as raw material, making the ketoprofen lysinate DPI a very promising product for the inflammation control in CF patients.
authors.affiliation: Department of Pharmacy, University of Salerno, Via Ponte don Melillo, 84084 Fisciano, SA, Italy.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Stigliani
authors.forename: Rita P
authors.initials: RP
authors.lastname: Aquino
authors.forename: Pasquale
authors.initials: P
authors.lastname: Del Gaudio
authors.forename: Teresa
authors.initials: T
authors.lastname: Mencherini
authors.forename: Francesca
authors.initials: F
authors.lastname: Sansone
authors.forename: Paola
authors.initials: P
authors.lastname: Russo
mesh_terms: D000280:Administration, Inhalation; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003550:Cystic Fibrosis; D004339:Drug Compounding / Q000379:methods; D015195:Drug Design; D058995:Dry Powder Inhalers; D006801:Humans; D007660:Ketoprofen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D007930:Leucine / Q000737:chemistry; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D009093:Mucus; D010316:Particle Size; D011208:Powders
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011208:Powders; C029946:ketoprofen lysine; D007660:Ketoprofen; D007930:Leucine; D008239:Lysine