The formulation of a pressurized metered dose inhaler containing theophylline for inhalation.

Abstract

BACKGROUND:

Theophylline (TP) is a bronchodilator used orally to treat chronic obstructive pulmonary disease (COPD) that has been associated with multiple side effects, tempering its present use. This study aims to improve COPD treatment by creating a low-dose pressurized metered dose inhaler (pMDI) inhalable formulation of TP.

METHODS:

Aerosol performance was assessed using Andersen Cascade Impaction (ACI). Solubility of TP in HFA 134/ethanol mixture was measured and morphology of the particles analyzed with a scanning electron microscope (SEM). Calu-3 cell viability, epithelial cell transport and inflammatory-response assays were conducted to study the impact of the formulation on lung epithelial cells.

RESULTS:

The mass deposition profile of the formulation showed an emitted dose of 250.04±14.48μg per 5 actuations, achieving the designed nominal dose (50μg/dose). SEM showed that the emitted particles were hollow with spherical morphology. Approximately 98% of TP was transported across Calu-3 epithelial cells and the concentration of interleukin-8 secreted from Calu-3 cells following stimulation with tissue necrosis factor-α (TNF-α) resulted in significantly lower level of interleukin-8 released from the cells pre-treated with TP (1.92±0.77ng·ml(-1) TP treated vs. 8.83±2.05ng·ml(-1) TNF-α stimulated, respectively).

CONCLUSIONS:

The solution pMDI formulation of TP developed in present study was shown to be suitable for inhalation and demonstrated anti-inflammatory effects at low doses in Calu-3 cell model.

• Authors: Bing Zhu, Mehra Haghi, Mary Goud, Paul M Young, Daniela Traini
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 76 Pg. 68-72 (Aug 30 2015) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 25956075 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Aerosol Propellants
• Aerosols
• Anti-Inflammatory Agents
• Bronchodilator Agents
• CXCL8 protein, human
• Hydrocarbons, Fluorinated
• Inflammation Mediators
• Interleukin-8
• Tumor Necrosis Factor-alpha
• Ethanol
• Theophylline
• apaflurane

Topics

• Administration, Inhalation
• Aerosol Propellants (chemistry)
• Aerosols
• Anti-Inflammatory Agents (administration & dosage, chemistry)
• Bronchodilator Agents (administration & dosage, chemistry)
• Cell Line
• Chemistry, Pharmaceutical
• Drug Delivery Systems (instrumentation)
• Epithelial Cells (drug effects, metabolism)
• Equipment Design
• Ethanol (chemistry)
• Humans
• Hydrocarbons, Fluorinated (chemistry)
• Inflammation Mediators (metabolism)
• Interleukin-8 (metabolism)
• Metered Dose Inhalers
• Microscopy, Electron, Scanning
• Particle Size
• Pressure
• Pulmonary Disease, Chronic Obstructive (drug therapy, physiopathology)
• Respiratory Mucosa (drug effects, metabolism)
• Solubility
• Technology, Pharmaceutical (methods)
• Theophylline (administration & dosage, chemistry)
• Tumor Necrosis Factor-alpha (pharmacology)