Tags

, , , , , , , , ,

By Selma Sahin, Yagmur Akdag Cayli, and Levent Oner

Selma Sahin   Yagmur Akdag Cayli   Levent Oner

Cystic fibrosis is a genetic disease affecting 1 in 2,000–3,000 people in the European Union and 1 in 3,500 in the United States, and life expectancy of these patients is approximately 40 years. A cystic fibrosis patient’s treatment costs more than $300,000 over their entire life span. Therefore, it is important to develop new treatment strategies for both financial and ethical reasons.

Cystic fibrosis occurs with gene mutation and affects the lungs, pancreas, liver, and intestines. In the lungs, it causes a viscous mucus layer, and the lack of fluidity prevents the removal of macrophages, bacteria, and other inhaled substances by blocking ciliary movements, leading to microorganisms proliferating in this dehydrated mucus. With cystic fibrosis, antimicrobial activity of airway surface liquid is also inhibited because of reduced pH. Macrophages in the viscous mucus layer disintegrate and their DNAs are exposed to the environment. As a result, viscosity increases with an increase in the amount of DNA. Repeated infections, especially formed by Pseudomonas aeruginosa, are observed in this environment.

Unfortunately, there is not an effective treatment for cystic fibrosis yet. To increase patients’ quality of life, doctors treat the infections caused by Pseudomonas aeruginosa. During the treatment, the main problem that confronts the doctors is a dehydrated and viscous mucus layer in the lungs. Because of the dense structure of mucus, antibiotics applied through an inhaler or systemically cannot pass through this layer, and hence treatment fails. As might be expected, application of antibiotics directly to the lungs through an inhaler is the preferred way in comparison to systemically effective drugs. However, this approach is not enough to obtain effective treatment.

To surpass this problem, we aimed to develop dry powder inhaler (DPI) formulations containing an antibiotic and mucolytic agent. Ciprofloxacin HCl was chosen as the antibiotic, acetylcysteine and DNase as mucolytics. Ciprofloxacin is fluoroquinolone antibiotic and effective against Pseudomonas aeruginosa. Acetylcysteine is a commonly used mucolytic. DNase decreases viscosity by lysing DNAs and this mechanism is very appropriate for cystic fibrosis environment.

For this purpose, we prepared suspension of ciprofloxacin by combining ball milling and homogenization methods. Suspension of ciprofloxacin and solution of mucolytics were prepared separately and then combined. After spray drying of this mixture, we obtained dry powders that contain an antibiotic inner side and mucolytic exterior surface. Our claim was supported by scanning electron microscopy analysis (Figure 1). In our formulation, the mucolytic should contact the mucus surface and decrease viscosity, and then the antibiotic should penetrate into mucus successfully. It is our hope that this formulation approach will provide better treatment of Pseudomonas aeruginosa-related infections in cystic fibrosis.

This work is being presented at the 2015 AAPS Annual Meeting and Exposition this week in Orlando.

The authors thank Imran Vural for their contributions to this abstract.

Fig 1a Fig 1b Fig 1c Fig 1d Fig 1e

Figure 1. SEM images of a) untreated ciprofloxacin (x5000), b) untreated acetylcysteine (x100), c) ciprofloxacin DPI (x30000), d) ciprofloxacin+ acetylcysteine DPI (x30000), e) ciprofloxacin+DNase DPI (x30000)

Selma Sahin is a professor of pharmaceutics at Hacettepe University Faculty of Pharmacy. Her research interests include pharmacokinetics, modelling and simulations, experimental diabetes and cirrhosis, intestinal and liver perfusion studies, drug transporters, and bioavailability and bioequivalence.
Yagmur Akdag Cayli is a research assistant at Hacettepe University Faculty of Pharmacy and studying towards a Ph.D. in biopharmaceutics. She is interested in formulation development, cell culture studies, inhalation preparations, and drug delivery to pulmonary system.
Levent Oner is a professor at Hacettepe University, Faculty of Pharmacy. His research areas are focused on formulation development, experimental design, micro and nanoparticular systems, dissolution techniques, and pharmacokinetics.