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Associate Director, Analytical Development, Dey L.P., Napa, CA
Scientist, Analytical Development, Dey L.P.
Associate Scientist, Analytical Development, Dey L.P.
Associate Scientist, Analytical Development, Dey L.P.
Associate Director, Analytical Development, Dey L.P.
Senior Director, Analytical Development, Dey L.P.
Reprints: Dr. Akapo, Analytical Development, Dey L.P., 2751 Napa Valley Corporate Dr., Napa, CA 94558, fax 707/254-9491, samuel.akapo{at}dey.com
BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are often given admixtures of nebulizable drugs to minimize the time of administration in treatment regimens.
OBJECTIVE: To evaluate the physicochemical compatibility and aerodynamic characteristics of formoterol fumarate 20 µg/2 mL when mixed or sequentially nebulized with budesonide inhalation suspension 0.5 mg/2 mL, ipratropium bromide 0.5 mg/2.5 mL, cromolyn sodium 20 mg/2 mL, or acetylcysteine 10% (100 mg/mL).
METHODS: The admixtures were prepared in triplicate and analyzed for physicochemical compatibility at 0, 15, 30, and 60 minutes after mixing at room temperature. Physical compatibility was determined by visual examination and measurements of pH, osmolality, and turbidity. Chemical stability was evaluated using compendial or in-house–validated high-performance liquid chromatography (HPLC) assay methods. The aerodynamic characteristics of the admixtures or sequentially nebulized drugs were determined from aerosols generated from a Pari LC Plus nebulizer, using an 8-stage cascade impactor followed by HPLC analysis of the deposited drug.
RESULTS: The admixtures remained clear, colorless solutions with no
precipitation, except for cloudiness observed in the formoterol/budesonide
combination due to budesonide suspension. The pH, osmolality, and turbidity
for all admixtures were within the initial values (
3%), and there were no
significant changes (2%) in potency of the active components throughout
the 1-hour study period. Due to increased drug volume or reconcentration in
the nebulizer cup, the respirable fraction/delivered dose increased
significantly (p < 0.05) for the mixed or sequentially nebulized drug.
However, the fine particle fraction (FPF), mass median aerodynamic diameter,
and geometric standard deviation generally remained unchanged for all
admixtures, with the exception of FPF for the formoterol/budesonide
combination.
CONCLUSIONS: Our results indicate that admixtures of formoterol with budesonide, ipratropium, cromolyn, or acetylcysteine are physically and chemically compatible. However, admixing or sequential nebulization significantly increased the amount of drug delivered compared with single drug nebulization. The clinical implications of the in vitro data in patients with COPD have not been determined.
Key Words: chronic obstructive pulmonary disease, compatibility, formoterol, nebulizing solution
Published Online, September 9, 2008. www.theannals.com, DOI 10.1345/aph.1L273
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