title: Can low-dose combination products for inhalation be formulated in single crystalline particles?
abstract: This study aims to produce and test the performance of novel crystalline respirable particles containing two low-dose active ingredients and mannitol. This technique overcomes the usual requirement of blending with lactose carriers in formulating combination inhalation products. Ternary powders were produced by co-spray drying solutions containing an inhaled corticosteroid (ICS), a long-acting beta2-agonist (LABA), and mannitol as a crystalline excipient. Two formulations comprising widely used ICS and LABA were studied: budesonide/formoterol fumarate dihydrate/mannitol (B/F/M-SD) and fluticasone propionate/salmeterol xinafoate/mannitol (F/S/M-SD). Various physicochemical properties of the powders were analyzed. Aerosol performance was evaluated by dispersing each powder from an Aerolizer at 60 and 100 L/min into a Next Generation Impactor. We obtained partially hollow spherical particles (volume median diameters of 2 microm) with drug-enriched surfaces. Both formulations contained alpha-mannitol, and the ICSs were crystalline. The content of each drug component in the powder was found to conform to the theoretical dose. The ternary powders generated high fine particle fractions (>50% of the loaded dose), with concomitant drug deposition on the impactor stages. The aerosol performance of B/F/M-SD was maintained after storage over silica gel at 22 degrees C for 11 weeks. In conclusion, co-spray dried particles of ICS/LABA/M-SD were largely crystalline, stable and showed excellent aerosol performance. They may provide an attractive alternative strategy to develop combination products without lactose blends.
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, Building A15, The University of Sydney, NSW 2006, Australia.
authors.forename: Michiko
authors.initials: M
authors.lastname: Kumon
authors.forename: Philip Chi Lip
authors.initials: PC
authors.lastname: Kwok
authors.forename: Handoko
authors.initials: H
authors.lastname: Adi
authors.forename: Desmond
authors.initials: D
authors.lastname: Heng
authors.forename: Hak-Kim
authors.initials: HK
authors.lastname: Chan
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage* / Q000737:chemistry; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage* / Q000737:chemistry; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives; D000730:Androstadienes / Q000008:administration & dosage; D019819:Budesonide / Q000008:administration & dosage / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization / Q000379:methods*; D004338:Drug Combinations; D004983:Ethanolamines / Q000008:administration & dosage / Q000737:chemistry; D000068297:Fluticasone-Salmeterol Drug Combination; D000068759:Formoterol Fumarate; D006801:Humans; D008353:Mannitol / Q000737:chemistry; D018625:Microscopy, Atomic Force; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D056951:Photoelectron Spectroscopy; D013499:Surface Properties; D044366:Transition Temperature; D014961:X-Ray Diffraction
chemical_list: D000305:Adrenal Cortex Hormones; D000318:Adrenergic beta-Agonists; D000730:Androstadienes; D004338:Drug Combinations; D004983:Ethanolamines; D000068297:Fluticasone-Salmeterol Drug Combination; D008353:Mannitol; D019819:Budesonide; D000420:Albuterol; D000068759:Formoterol Fumarate