Co-spray-dried mannitol–ciprofloxacin dry powder inhaler formulation for cystic fibrosis and chronic obstructive pulmonary disease
Introduction
Cystic fibrosis (CF) is a life-threatening hereditary disease, emphasized by fatal congenital steatorrhea, pancreatic destruction and lung disease (O'Sullivan and Freedman, 2009). Manifestations of CF can be very different between patients, even between siblings, but chronic airway inflammation is almost uniformly observed in patients with CF (Doring and Hoiby, 2004, Konstan et al., 1994). In the lung, this genetic condition impairs mucociliary clearance, thereby facilitating chronic bacterial infection (Armstrong et al., 1997, Matsui et al., 1998).
Chronic obstructive pulmonary disease (COPD) is a relatively new term for a disease once described as: “bronchitis”, “emphysema”, “asthmatic bronchitis” and “chronic bronchitis”.
COPD is a major cause of mortality worldwide. COPD results from a variety of individual risk factors (like enzymatic deficiencies) and environmental exposures (like cigarette smoking). As in CF, COPD is characterised by a chronic inflammatory process in the pulmonary tissue (Cazzola et al., 2007, Cazzola et al., 2008).
Chronic airway infection, progressing to bronchiectasis, gas trapping, hypoxaemia, and hypercarbia is the characteristic of CF and COPD lung disease; with pulmonary insufficiency reported to be responsible for at least 80% of CF-related deaths (Buzzetti et al., 2009). Preventing chronic infection with Pseudomonas aeruginosa can slow down the deterioration in lung function and improve survival (Kerem et al., 1990, Pamukcu et al., 1995). There are many strategies to treat chronic lung inflammations. These include: antibiotics (Regelmann et al., 1990, Saiman et al., 2003, Smith et al., 1989), anti-inflammatory (Konstan et al., 1995, Lands et al., 2007), anti-fungal (Knechtel and Klepser, 2007), bronchodilators (Hordvik et al., 1985, Orenstein, 1991), mucolytics (Bye and Elkins, 2007), ion-transport modifiers (Kellerman et al., 2008), airway clearance techniques (Bradley et al., 2006), DNase therapy (Shak et al., 1990, Zahm et al., 1995), monitored nutrition (Corey et al., 1988) and ultimately lung transplantation (Goldberg and Deykin, 2007).
Of these therapies, inhaled drugs are commonly used in CF and COPD care because they are local rather than systemic in nature. There are several kinds of inhaled medications used to treat CF and COPD symptoms; antibiotics and mucolytics being the most important (Abbott and Hart, 2005, Swierzewski, 2000). At present, only a handful of antibiotic molecules have been investigated using the inhalation route. These include tobramycin, colistimethate sodium, aztreonam lysine, liposomial ciprofloxacine and MP-376 (Heijerman et al., 2009, Traini and Young, 2009).
Ciprofloxacin, a member of the fluorinated quinolone family, has a wide coverage against both gram-positive and gram-negative organisms and has shown good potential as an inhaled medicine (Adi et al., 2009, Adi et al., 2008a, Adi et al., 2008b, Conley et al., 1997, Fitzgeorge et al., 1986). Indeed, as a liposomal formulation, ciprofloxacin is currently in phase 2 safety and efficacy studies (Finlay and Wong, 1998).
In the mucolytic arena, dornase alfa (Jones and Wallis, 2003), denufosol tetrasodium (Deterding et al., 2005), lancovutide (Grasemann et al., 2007), hypertonic saline (Donaldson et al., 2006, Wark et al., 2005), heparin (Serisier et al., 2006), N-acetyl-cysteine (Anderson, 1966, Decramer et al., 2005, Millar et al., 1985) and mannitol (Anderson et al., 1997, Robinson et al., 1999a, Robinson et al., 1999b) have all found therapeutic efficacy (even if mannitol, as a dry powder, is not yet approved for CF) (Bye and Elkins, 2007). Inhaled mannitol is believed to cause an increase in the osmotic pressure of the fluid lining the mucosal surfaces. The hypertonic solution induces transcellular water migration, a reduction in mucous viscosity and increased clearance via the cilia transport mechanism. This increase in mucus removal is beneficial for patients suffering from cystic fibrosis and chronic bronchitis (Daviskas et al., 1997, Daviskas et al., 1999, Daviskas et al., 2001, Daviskas et al., 2005, Robinson et al., 1999a, Robinson et al., 1999b).
In addition to its use as an excipient, approved by the Food and Drug Administration (FDA), an as a active pharmaceutical ingredient for inhalation purposes (Bosquillon et al., 2001), mannitol and other polyols or sugars possess formulation stabilization properties and have been extensively used as a stabilizer and cryo-protectant during lyophilisation (Bosquillon et al., 2001, Schwarz and Mehnert, 1997). Subsequently, the delivery of both a mucolytic agent (such as mannitol) and an antibiotic therapeutic in one single dry powder dose could have many advantages. For example, having two therapeutic drugs together will result in a combination therapy that has the potential to increase mucociliary clearance while simultaneously treating chronic infection. Furthermore, such an approach will increase patient compliance and if delivered via a portable dry powder inhalation (DPI) device will give CF patient more freedom and independence. Moreover, the presence of crystalline mannitol could have a stabilizing effect on the antibiotic.
Although some studies have shown that mucolytic agents may inhibit antibiotic activity when used in combination (Lawson and Saggers, 1965, Reas, 1963), a paper by Heaf et al. (1983), described how mesna (Mistabron®), a mucolytic agent, despite inhibiting pseudomonal growth, did not reduce the bactericidal activity of azlocillin (acylampicillin antibiotic), and for three strains of P. aeruginosa actually potentiated the effect. Furthermore, in a study by Roberts and Cole (1981), 1% N-acetylcysteine was shown to potentiate the anti-pseudomonal activity of carbenicillin in vitro.
The aim of this project was to investigate the potential of combining the osmotic effect of mannitol with the anti-inflammatory capacity of a model antibiotic (ciprofloxacin), using an inhalable dry powder formulation; to target directly the site of impaired respiratory function in CF patients.
Section snippets
Materials
Mannitol (Pearlitol® 160C) was obtained from Rocquette Frères, Lestrem, France. Ciprofloxacin·hydrochloride was supplied by MB, Biomedical Australasia Pty Limited (NSW, Australia). Water was purified by reverse osmosis (MilliQ, Millipore, France). All solvents were obtained from Biolab (Victoria, Australia) and were of analytical grade. The model bacteria used in this study were Staphylococcus aureus, P. aeruginosa and Streptococcus pyogenes and were obtained from the University of Sydney (NSW,
Particle size analysis
Since all the powders were prepared under similar drying conditions, the final particle size distributions between samples were comparable and exhibited a similar distribution (Fig. 1). In general, median volume diameters of 3.3 ± 0.1 μm, were observed for the single spray-dried ciprofloxacin while values of 3.3 ± 0.1, 3.4 ± 0.1 and 3.2 ± 0.0 μm were observed for samples containing 25%, 50% and 100% spray-dried mannitol, respectively (n = 3).
Scanning electron microscopy
Field emission, scanning electron micrographs of the spray-dried
Conclusions
We have investigated the physical stability and aerosolisation efficiency of co-spray-dried antibiotic formulations containing mannitol and ciprofloxacin as a dry powder inhaler powder for the treatment of cystic fibrosis and other respiratory diseases (where enhanced mucociliary clearance in combination with antibiotic treatment is required).
The combination of these specific chemical entities as a co-spray-dried powder suggested that, if formulated at 50:50 ratio, a physically stable and
Acknowledgement
The authors would like to thank Maria Koutsouradis for her help in preparing bacteria cultures.
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