Can low-dose combination products for inhalation be formulated in single crystalline particles?

Eur J Pharm Sci. 2010 Apr 16;40(1):16-24. doi: 10.1016/j.ejps.2010.02.004. Epub 2010 Feb 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adrenal Cortex Hormones / administration & dosage*
  • Adrenal Cortex Hormones / chemistry
  • Adrenergic beta-Agonists / administration & dosage*
  • Adrenergic beta-Agonists / chemistry
  • Albuterol / administration & dosage
  • Albuterol / analogs & derivatives
  • Androstadienes / administration & dosage
  • Budesonide / administration & dosage
  • Budesonide / chemistry
  • Calorimetry, Differential Scanning
  • Chemistry, Pharmaceutical / methods
  • Crystallization / methods*
  • Drug Combinations
  • Ethanolamines / administration & dosage
  • Ethanolamines / chemistry
  • Fluticasone-Salmeterol Drug Combination
  • Formoterol Fumarate
  • Humans
  • Mannitol / chemistry
  • Microscopy, Atomic Force
  • Microscopy, Electron, Scanning
  • Particle Size
  • Photoelectron Spectroscopy
  • Surface Properties
  • Transition Temperature
  • X-Ray Diffraction

Substances

  • Adrenal Cortex Hormones
  • Adrenergic beta-Agonists
  • Androstadienes
  • Drug Combinations
  • Ethanolamines
  • Fluticasone-Salmeterol Drug Combination
  • Mannitol
  • Budesonide
  • Albuterol
  • Formoterol Fumarate