The Effects of Mannitol on the Transport of Ciprofloxacin across

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The effects of mannitol on the transport of ciprofloxacin across respiratory epithelia Hui Xin Ong, Daniela Traini, Rania Salama, Sandra D. Anderson, Evangelia Daviskas, and Paul M. Young Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/mp400030n • Publication Date (Web): 26 Jun 2013 Downloaded from http://pubs.acs.org on July 2, 2013

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Molecular Pharmaceutics

The effects of mannitol on the transport of ciprofloxacin across respiratory epithelia Hui Xin Ong1, Daniela Traini1, Rania Salama1, Sandra D. Anderson2, Evangelia Daviskas2 and Paul M Young1* 1

Respiratory Technology, Woolcock Institute of Medical Research and Discipline of

Pharmacology, Sydney Medical School, The University of Sydney, NSW 2037, Australia. 2

Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital,

Camperdown, New South Wales, Australia *Corresponding author. 1Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, NSW 2037, Australia. Tel.: +61 2 91140350; E-mail: [email protected]

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Abstract Inhalation of antibiotics and mucolytics are the most important combination of inhaled drugs for chronic obstructive lung diseases and have become a standard part of treatment. However, it is yet to be determined whether the administration of a mucolytic has an effect on the transport rate of antibiotics across the airway epithelial cells. Consequently, the aim of this study was to investigate the effects of inhalation dry powder, specifically mannitol, on ciprofloxacin transport using Calu-3 air interface cell model. Transport studies of ciprofloxacin HCl were performed using different configurations including single spray-dried ciprofloxacin alone, co-spray dried ciprofloxacin with mannitol and deposition of mannitol prior to ciprofloxacin deposition. To understand the mechanism of transport and interactions between the drugs, pH measurements of apical surface liquid and further transport studies were performed with ciprofloxacin base, with and without the presence of ion channel/transport inhibitors such as disodium cromoglycate and furosemide. Mannitol was found to delay absorption of ciprofloxacin HCl through the increase in ASL volume and subsequent reduction in pH. Conversely, ciprofloxacin base had a higher transport rate after mannitol deposition. This study clearly demonstrates that the deposition of mannitol prior to ciprofloxacin on the air-interface Calu-3 cell model has an effect on its transport rate. This was also dependent on the salt form of the drug and the timing and sequence of formulations administered. Keywords: Ciprofloxacin, Calu-3, mannitol, transport, disodium cromoglycate, furosemide

1.

Introduction


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Recurrent respiratory tract infection (RTI) is one of the characteristics of chronic obstructive lung diseases, such as cystic fibrosis (CF) and non-CF bronchiectasis (BE). This is a manifestation of impaired mucociliary clearance thereby causing mucus accumulation in the lungs 1, 2. The cycle of infection and inflammation facilitates chronic colonisation of the airway by bacteria particularly Pseudomanas Aeruginosa which causes severe decline in lung function, increased hospitalisation and high mortality rates 3, 4. Current strategies to treat chronic obstructive lung diseases focuses on slowing disease progression, delaying the onset of irreversible damage to the respiratory system and other organs and ultimately improving survival 5. Some of these phamacological strategies include: antibiotics and antifungals to control or as prophylaxis for airway infections 6-11, steroids and non-steroidal anti-inflammatory to control inflammatory responses 12-14, bronchodilators to optimise bronchodilations 15, 16

, and mucolytics to promote mucus clearance 17-19. To treat these lung diseases, inhalation of drugs are the preferred mode of

delivery, as it ensures the deposition of medications at the site of action, increasing local availability and at the same time reducing systemic side effects. Inhalation of antibiotics and mucolytics are the most important combination of inhaled drugs for chronic obstructive lung diseases and therefore have become a standard part of treatment 20-22. At present, the only inhaled antibiotic treatments approved by the Food and Drug Administration (FDA) are limited to tobramycin (TOBI®) and aztreonam (Cayston®). Current evidence have shown that ciprofloxacin has the potential to be developed into an inhaled medication, as there is no regulatory approval for inhalation form of ciprofloxacin to directly target the site of infection 5, 23-26

. Ciprofloxacin is an established broad-spectrum fluoroquinolone antibiotic

indicated for exacerbation treatment in its oral and parenteral dosage form. Indeed, ciprofloxacin formulated as a liposomal formulation has just recently completed phase 2 and obtained clearance from FDA for phase 3 clinical trials 26. On the other hand, approved mucolytics to improve mucus clearance include hypertonic saline, dornase alfa (Pulmozyme®) and N-acetylcysteine (Mucomyst®).



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More recently, inhaled mannitol was found to improve mucociliary clearance by increasing the osmotic pressure of the fluid lining and mucosal surfaces 27-31. This in turn induces transcellular water migration into the airway mucosa surfaces, reducing the viscosity of the mucus and hence increases clearance via the cilia transport mechanism, which could be beneficial for patients suffering from CF and bronchiectasis. Inhaled mannitol (Bronchitol®) has been recently approved in Australia, Europe and United Kingdom for the treatment of CF. More often than not, patients on mannitol treatment are on prophylaxis or infection treatment with antibiotic concurrently. Recent studies by Adi et al. (2010) 24 and Yang et al. (2011) 5 have shown that the delivery of both a mucolytic agent (mannitol) and an antibiotic in one single dry powder dose has the potential to simultaneously increase mucociliary clearance and treat chronic infections, increasing patient compliance. In terms of its inhalation dosage form, the presence of crystalline mannitol has a stabilizing effect on the antibiotics. In addition, spray-dried ciprofloxacin together with mannitol have shown to improve the antibacterial activity of the drug on P. aeruginosa through enhanced penetration of ciprofloxacin into the thicker mucus of CF, which could be due to mannitols’ ability to increase water content in the mucus 5. However, it is yet to be determined whether the administration of mannitol has an effect on the transport rate of antibiotics across the lung epithelial cells. It is known that local treatments of respiratory tract infections using inhaled antibiotics are rapidly absorbed and cleared from the lungs. This was also demonstrated in previous studies where transport of ciprofloxacin was evaluated using an in vitro modified twin-stage impinger (TSI) coupled with air-interface Calu-3 epithelial cell model 25, 32. Both studies have also shown that the deposition of dry powder and nebulised form of ciprofloxacin on the model is capable of evaluating the fate of inhaled respiratory formulation. The recently developed model allows for the study of absorption profiles and interactions between particles with the mucosal surface of the epithelial cell layer to elucidate the underlying mechanism of transport. The model established uses Calu-3, which is a sub-bronchial epithelial cell line cultured at the air interface. The epithelial cell model produces similar in vivo


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characteristics to native airway epithelium with respect to differentiation, polarization, morphology, mucus production and electrical resistance 33, 34. This model has also been established for drug delivery and toxicology studies 35-37. Additionally, the adaptation of the TSI to deposit the formulations further simulates the in vivo processes where respirable aerosols/particles are impacted onto the mucosal surface of the epithelial cells 32, 38. By extension, similar proportion of formulation is assumed to reach the patient’s airways for its pharmacological actions. The aim of the current study is to investigate the effects of mannitol on ciprofloxacin transport using the air interface Calu-3 epithelial cell model when cospray-dried as single dry particle or as single drug particles by depositing ciprofloxacin one hour after mannitol. The importance of this work is the applicability of the in vitro air interface Calu-3 cells coupled with a modified twin stage impinger to identify possible drug-drug interactions between combination drugs, in particular mannitol and ciprofloxacin and to elucidate the mechanisms of the interaction between the drugs. Furthermore, the importance of timing between the different administrations of formulations is emphasised because it has the potential to influence drug transport. Subsequently, to further identify the processes involved in the transport mechanism, ciprofloxacin base together with administration of ion channel/transport inhibitors furosemide and disodium cromoglycate (DSCG) was used.

2.

Materials and Methods

2.1

Materials

Calu-3 cells were purchased from the American Type Cell Culture Collection (ATCC, Rockville, US). Ciprofloxacin HCl was used as supplied (MP; Biomedical Australasia Pty Limited, NSW, Sydney, Australia). DSCG was supplied by Sanofi-Aventis (Cheshire, England). Mannitol particles (Spray dried micron-sized powder) were supplied by Pharmaxis Ltd. (Sydney, Australia). Non-essential amino acids solution, CelLytic™ M Cell Lysis, protease inhibitor cocktail and dimethyl sulfoxide (DMSO), ciprofloxacin base, furosemide, fluorescein sodium were purchased from SigmaAldrich (Sydney, Australia). Other cell culture reagents including trypsin-EDTA



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solution (2.5g/L trypsin, 0.5g/L EDTA), Dulbecco’s Modified Eagle’s Medium (DMEM, without phenol red and L-glutamine, including sodium bicarbonate and 15mM HEPES), Trypan blue solution (0.4% w/v), Phosphate buffered saline (PBS), L-glutamine solution (200mM), fetal bovine serum (FBS), Hank’s balanced salt solution (HBSS) were obtained from Invitrogen (Australia). Transwell cell culture inserts (0.33cm2 polyester, 0.4µm pore size) were purchased from Corning Costar (Lowell, MA, USA) and all other sterile culture plastic wares were from Sarstedt (Adelaide, Australia). All solvents used were of analytical grade and were supplied by Biolab (Victoria, Australia). 2.2

Preparation of microparticles Single and combination mannitol-ciprofloxacin formulation were produced

using a Buchi B-290 spray dryer based on the conditions outlined by Adi et al.24 and Ong et al.32 to obtain a respirable particle size of 0.05). Similar results were obtained after the 4 hours transport studies of ciprofloxacin HCl and base indicating that the deposition of ciprofloxacin and mannitol formulations with and without the inhibitors had no detrimental effects on the epithelial cell integrity under the conditions or timescale studied (p > 0.05).

Figure 5: Transepithelial electrical resistance (TEER) expressed in % of control of Calu-3 epithelia cells cultured at the air interface on 0.33 cm2 cell culture support inserts: (a) 1 hour after mannitol deposition, (b) after the 4 hour ciprofloxacin HCl or base transport studies (n=3, mean ± S.D.). *Statistically different to control (p < 0.05) An exception was found with the mannitol-ciprofloxacin HCl study where a significant increase in TEER was seen (p < 0.01). A similar increase in TEER was also observed when after 5 hours of mannitol deposition only (TEER=114.5 ± 6.4%, p < 0.01). This may have contributed to the decrease in ciprofloxacin HCl transport following mannitol deposition. This is contrary to previous findings where hyperosmotic solution increases tight junction permeability in airway epithelium 55, 56.


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The studies found that there was a more pronounced effect of ionic compounds such as NaCl compared to non-ionic compounds such as mannitol or xylitol on TEER. This was attributed to ionic compounds interact specifically with charges on tight junctional proteins or cytoskeleton, while non-electrolytes do not. However, the mechanism by which mannitol causes an increase in tight junction after 5 hours remains unknown. Another study by Willumsen et al. (1994) found that the raised osmolarity using mannitol induces cell volume loss, which causes an increase in the transepithelial resistance in human nasal airway epithelia 57. They also found that the permeability of radiolabeled mannitol was reduced by 50% in response to hypertonicity demonstrating an increase in evidence that epithelial permeability of the paracellular pathway was decreased. This was also observed in the current study, where a decrease in epithelium height was evident. The suggested mechanism of decreased permeability in the epithelium may be due to the shrinking of cells causing the collapse of the lateral intercellular spaces as the thickness of the epithelium decreases. Although the increase in TEER was only observed in the mannitolciprofloxacin HCl experiments, but a significant reduction in apparent permeability of flu-Na was noted for cells treated with hyperosmolar challenge before ciprofloxacin transport studies with and without the presence of inhibitors (Figure 6). TEER measurements mainly represent the resistance of the tight junction and does not sensitively reflect the integrity of the cell monolayer58. On the other hand, flu- Na is an independent, more reliable and direct test to measure paracellular permeability, which provides direct evidence of the permeability of paracellular pathways. Hence, the concurrent reduction in cell height with the decrease in flu-Na permeability could have in part contributed to the transport rate of ciprofloxacin across the Calu-3 cell epithelium.



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Figure 6: Transport of flu-Na across the Calu-3 epithelial cell layer after 4 hours ciprofloxacin HCl or base transport studies with the different combinations of drugs (n=3, mean ± S.D.).

4.0

Conclusions

The deposition of mannitol prior to ciprofloxacin on the air-interface Calu-3 cell model clearly has an effect on its transport rate. The transport rate of ciprofloxacin was also dependent on the hydrochloride or base form of ciprofloxacin, whereby the drug solubility of ciprofloxacin base appears to be the limiting factor for drug transport. This study further demonstrates that not only does this model allows for a realistic assessment of drug transport, but also identifies possible drug interactions. It also helps elucidate the underlying mechanisms by which the formulation interacts with the airway epithelium and ASL at the cellular level and subsequently its effects on drug transport. In this study, the deposition of mannitol 1 hour prior to ciprofloxacin HCl delayed the clearance of ciprofloxacin from the lung epithelia through the increase in ASL volume and subsequent reduction in pH. This could be beneficial to maintain high concentrations of antibiotics for it antimicrobial efficacy and reduction in dosing frequency. Furthermore, this study has highlighted the importance of sequence and timing of drug administration on drug transport. Future studies should be performed to correlate these findings to in vivo as they may prove an efficient means to optimise treatment for cystic fibrosis and to guide health care professionals in determining the best sequence of drug intake for patients.

5.0

References


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85x40mm (300 x 300 DPI)


The Effects of Mannitol on the Transport of Ciprofloxacin across

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