title: Formulation of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery.
abstract: Co-administration of an inhaled corticosteroid and long acting beta agonist for chronic obstructive pulmonary disease has reduced mortality compared to either drug alone. This combination reduces exacerbations, hospitalization, emergency department visits and health care costs. A novel fixed-dose combination of the long acting beta-2 agonist salmeterol xinafoate (SX) and the corticosteroid mometasone furoate (MF) were prepared in a composite particle formulation as brittle matrix powder (BMP) and investigated for suitability as an inhaled combination product. In this study, BMP fixed dose combinations of SX and MF with or without stabilizing excipients (lactose, mannitol, glycine and trehalose) were prepared and characterized with respect to their thermal properties, morphology, aerodynamic performance and physical stability. BMP combination formulations of SX and MF exhibited improved aerodynamic properties when delivered by dry powder inhalation as compared to the micronized blends of the same substances. Aerodynamic evaluation was carried out by next generation pharmaceutical impactor (NGI) with a marketed DPI device. Results demonstrated that co-deposition occurred when SX and MF were formulated together as composite particles in a BMP, while physical blends resulted in inconsistent deposition and dose uniformity. As a result of the bottom-up particle engineering approach, combination BMP formulations allow for dual API composite formulations to be dispersed as aerosolized particles. Aerosolized BMP combination formulations resulted in delivered dose uniformity and co-deposition of each API. Further, an excipient-free formulation, BMP SXMF, delivered approximately 50% of the loaded dose in the respirable range and demonstrated stability at ambient conditions for 6months. Single dose 24-h pharmacokinetic studies in rats demonstrated that lung tissue deposition and blood circulation (AUC0-24h) of two APIs were higher for the BMP combination group exhibiting a significantly higher lung concentration of drugs than for the crystalline physical blend. While high system drug levels are generally undesirable in lung targeted therapies, high blood levels in this rodent study could be indicative of increased pulmonary tissue exposure using BMP formulations.
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, 44# Wenhua Xi Road, Jinan, Shandong 250012, People's Republic of China; Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, 1 University Station A1929, Austin, TX 78712, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Liu
authors.affiliation: Drug Dynamics Institute, College of Pharmacy, The University of Texas at Austin, 1 University Station A1902, Austin, TX 78712, USA.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Watts
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, 1 University Station A1929, Austin, TX 78712, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Du
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, 1 University Station A1929, Austin, TX 78712, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Bui
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, 1 University Station A1929, Austin, TX 78712, USA.
authors.forename: Soraya
authors.initials: S
authors.lastname: Hengsawas
authors.affiliation: Division of Pulmonary and Critical Care, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Jay I
authors.initials: JI
authors.lastname: Peters
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, 1 University Station A1929, Austin, TX 78712, USA. Electronic address: bill.williams@austin.utexas.edu.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Williams
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D004338:Drug Combinations; D004339:Drug Compounding; D016503:Drug Delivery Systems; D005079:Excipients / Q000737:chemistry; D005260:Female; D008168:Lung / Q000378:metabolism*; D008297:Male; D064347:Microscopy, Electrochemical, Scanning; D000068656:Mometasone Furoate / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D010316:Particle Size; D017207:Rats, Sprague-Dawley; D000068299:Salmeterol Xinafoate / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D013499:Surface Properties; D014018:Tissue Distribution; D014961:X-Ray Diffraction
chemical_list: D004338:Drug Combinations; D005079:Excipients; D000068656:Mometasone Furoate; D000068299:Salmeterol Xinafoate
keywords: Brittle matrix powder; Co-deposition; Fixed dose combination; Mometasone furoate; Salmeterol xinafoate; Thin-film freezing