Inhaled Ciprofloxacin for the Management of Infections in
Non-Cystic Fibrosis Bronchiectasis (BE) Patients
BE is a
chronic “orphan” condition characterized by abnormal dilatation
of the bronchi and bronchioles associated with chronic infection. The
patient’s lung function is often irreversibly reduced compared to
that found in healthy individuals. BE is frequently observed in patients
with cystic fibrosis (CF). However, it is a condition that affects over
110,000 people without CF in the United States
and many more in other countries, and results from a cycle of inflammation,
recurrent infection, and bronchial wall damage. Many of these patients are
non-smokers and the origin of their BE is unknown. There is currently no
drug specifically approved for the treatment of BE in the U.S. The poor quality of life and untimely
death in BE patients is associated with chronic respiratory infections with
been testing two formulations of inhaled ciprofloxacin (Pulmaquin and
Lipoquin) that differ in the proportion of rapidly available and slow
release ciprofloxacin. Pulmaquin (also called Dual Release Ciprofloxacin
for Inhalation – DRCFI or ARD-3150) uses the slow release liposomal
formulation (Lipoquin, also called Ciprofloxacin for Inhalation – CFI
or ARD-3100) mixed with a small amount of ciprofloxacin dissolved in an
aqueous medium. We tested once daily inhaled Pulmaquin in the ORBIT-2
(Once-daily Respiratory Bronchiectasis Inhalation Treatment) 168 day,
multicenter, international Phase 2b clinical trial in 42 adult patients
with non-cystic fibrosis bronchiectasis. Statistical significance was
achieved in the primary endpoint - the mean change in Pseudomonas aeruginosa density in sputum (CFU) from baseline to
day 28: there was a significant mean reduction of 4.2 log10
units in the Pulmaquin group, reflecting an almost sixteen-thousand fold
decrease in bacterial load, versus a very small mean decrease of 0.1 log10
units in the placebo group (p=0.004). Secondary endpoint analysis showed
that 17 subjects in the placebo group required supplemental antibiotics for
respiratory-related infections versus 8 subjects in the Pulmaquin group
(p=0.05). The Kaplan-Meier analysis showed that the median time to first
pulmonary exacerbation in the per protocol evaluation increased from 58
days in the placebo group to 134 days in the active treatment group and was
statistically significant (p<0.05, log rank test). Pulmaquin was well
tolerated and there were no significant decreases in lung function, as
measured by FEV1 (forced expiratory volume in one second), at 28 days in
either group. Overall, the incidence and severity of adverse events were
similar in both the placebo and treatment groups; however, Pulmaquin had a
superior pulmonary safety profile reflected in the number and severity of
pulmonary adverse events. The reduction from baseline in Pseudomonas
aeruginosa CFUs with Pulmaquin was rapid and persistent throughout the
treatment cycles as exemplified by the statistically significant reductions
of the mean log CFU values in the Pulmaquin group versus the placebo at day
14 and day 28 during the first treatment cycle, as well as at the end of
the second and third cycles of treatment (days 84 and 140, respectively).
Phase 2b study in BE patients - ORBIT-1 - was conducted with once daily
inhaled Lipoquin. The primary endpoint was the mean change in Pseudomonas aeruginosa CFUs from baseline
to day 28: there was a significant mean reduction (p<0.001) of 2.942
log10 CFUs in the 3mL Lipoquin group and a significant mean reduction
(p< 0.001) of 3.842 log10 CFUs in the 2mL Lipoquin group compared to
placebos. Pooled placebo groups had a mean reduction of log10 CFUs of
0.437. There was no statistically significant difference between the 2 mL
and 3 mL Lipoquin doses. Lipoquin was well-tolerated and no bronchodilator
treatment was mandated before inhaled study treatments. There were no
statistically significant differences between the active and placebo groups
in the number of patients experiencing at least one respiratory
treatment-emergent adverse event. The incidence of serious adverse events
(SAEs) was low and none of them were treatment related.
completed the analysis of all preclinical and clinical data from the two
different formulations of inhaled ciprofloxacin (Lipoquin and Pulmaquin),
we determined that Pulmaquin showed superior performance. Therefore,
Pulmaquin is taken into Phase 3 clinical trials in BE.
(ARD-3100) — Inhaled Ciprofloxacin for the Management of
Infections in Cystic Fibrosis (CF) Patients
CF is an
“orphan” genetic disease that causes thick, sticky mucus to
form in the lungs, pancreas and other organs. In the lungs, the mucus tends
to block the airways, causing lung damage and making these patients highly
susceptible to lung infections. According to the Cystic Fibrosis
Foundation, CF affects roughly 30,000 children and adults in the United States
and roughly 70,000 children and adults worldwide. Recent reports suggest
that there may be over 100,000 largely undiagnosed CF patients in India. According to the American Lung
Association, the direct medical care costs for an individual with CF in the
are currently estimated to be in excess of $40,000 per year. Chronic
respiratory infections, especially with Pseudomonas
aeruginosa, are the key cause of poor quality of life and untimely
death of CF patients.
there are two inhaled antibiotics (not containing ciprofloxacin) approved
for the chronic management of respiratory infections in CF; one of them is
given twice a day and the other one three times a day. We think that once a
day dosing of our inhaled long acting ciprofloxacin could be a welcome
reduction in the burden of therapy for this patient population.
Furthermore, some patients may benefit from rotating two or more inhaled
antibiotics so that they maintain some form of inhaled antibiotic therapy
all the time. As ciprofloxacin is an
antibiotic of a different class, with a different mechanism of action to
the two currently approved inhaled antibiotics, its use could maximize the
control of respiratory infections in CF patients and avoid the side effects
associated with the use of the other antibiotics.
conducted a multi-center 14-day treatment Phase 2a trial in CF patients to
investigate safety, efficacy and pharmacokinetics of once daily inhaled
Lipoquin. The Pseudomonas aeruginosa
colony forming units (CFU), an objective measure of the reduction in
pulmonary bacterial load, decreased by a mean 1.43 log over the 14-day
treatment period (p<0.0001). Pulmonary function testing as measured by
the forced expiratory volume in one second (FEV1) showed a significant mean
increase of 6.86% from baseline after 14 days of treatment (p=0.04).
The study drug was well tolerated, and there were no serious adverse events
reported during the trial.
Liposomal Ciprofloxacin for Biodefense Purposes (inhaled tularemia,
pneumonic plague, Q-fever)
UK scientists from
the Health Protection Agency (HPA) and Defence Science and Technology
Laboratory (Dstl) reported the successful testing of our inhaled liposomal
ciprofloxacin against Coxiella
burnetii in a mouse model of this virulent infection. This work was
conducted as part of the collaborative consortium that we formed with HPA,
Dstl and Aradigm to evaluate the efficacy of our inhaled liposomal
ciprofloxacin against high threat microbial agents. Coxiella burnetii is a Gram-negative intracellular bacterium
and the causative agent of the disease Q fever. C. burnetii is endemic worldwide, infects a wide variety of
animals and humans and has a low infectious dose by the inhalational route.
Clinical presentation in humans may lead to an acute infection with
flu-like symptoms, or a chronic life-threatening disease. A recent epidemic
of Q fever in humans took place in the Netherlands
in 2009, with 2,357 reported cases and 6 deaths.
from the UK Defence Science and Technology Laboratory (Dstl)
also reported in a preliminary study that they have demonstrated
that a single dose of Aradigm’s liposomal ciprofloxacin
formulation Lipoquin administered 24 hours after exposure to
a lethal dose of the bacterium Yersinia pestis provided full protection
in this murine model of pneumonic plague. In comparison, a single
dose of oral ciprofloxacin administered 24 hours post-exposure
provided no protection. The Dstl team had previously demonstrated
that a single dose of our inhaled liposomal ciprofloxacin protects
animals against lethal doses of inhaled tularemia infection
– another microbial threat.
D. et al. Development of Liposomal Ciprofloxacin to Treat Lung
Infections. Pharmaceutics. 2016. 8(1): 6. | Supplementary
D. et al. Formation of Drug Nanocrystals under Nanoconfinement
Afforded by Liposomes. RSC Advances. 2016. 6: 6223-6233.
Cipolla D. et al. Emerging Opportunities for Inhaled Antimicrobial
Therapy. J Antimicro. 2015. 1(1): 104.
et al. Aerosol Performance and Stability of Liposomes Containing
Ciprofloxacin Nanocrystals. J Aer Med Pulm Drug Del. 2015. 28(6):
Cipolla D. et al. Comment on: Inhaled antimicrobial therapy-Barriers
to effective treatment. Adv. Drug Deliv. Rev. 2015. 85: e6-e7.
et al. Efficacy of liposome-encapsulated ciprofloxacin in a
murine model of Q fever. Antimicrob Agents Chemother. 2014.
et al. Aerosol Performance and Long Term Stability of Surfactant-Associated
Liposomal Ciprofloxacin Formulations with Modified Encapsulation
and Release Properties. AAPS PharmSciTech. 2014. 15(5): 1218-1227.
et al. The Potential of Liposome-Encapsulated Ciprofloxacin
as a Tularemia Therapy. Front Cell Infect Microbiol. 2014. 4:
D et al. Modifying the Release Properties of Liposomes toward
Personalized Medicine. J. Pharm Sci. 2014. 103(6): 1851-1862.
Darweesh RS. And Sakagami M. In Vitro Inhibitory Activities
of Liposomal Ciprofloxacin Against Lipopolysaccharide (LPS)-Induced
IL-8 Release from the Calu-3 Cells. RDD 2014. Dalby R.N. et
al. (eds). 2014. 747-750.
et al. Development and Characterization of an In Vitro Release
Assay for Liposomal Ciprofloxacin for Inhalation. J. Pharm.
Sci. 2014. 103(1): 314-327.
KA. Et al. Liposome encapsulation of ciprofloxacin improves
protection against highly virulent Francisella tularensis strain
Schu S4. Antimicrob Agents Chemother. 2014. 58: 3053-3059.
D et al. Liposomal Formulations for Inhalation. Ther Delivery.
2013. 4(8): 1047-1072.
Ong HX. et al. In vitro and ex vivo methods predict the enhanced
lung residence time of liposomal ciprofloxacin formulations
for nebulisation. Eur J Pharm Biopharm. 2013. 86(1): 83-89.
Cipolla D. et al. Liposomal Ciprofloxacin for Inhalation Retains
Integrity Following Nebulization. RDD Europe 2013. Dalby R.N.
et al. (eds). 2013. 237-242.
Et al. Inhaled, Dual-Release Liposomal Ciprofloxacin in Non-Cystic
Fibrosis Bronchiectasis (ORBIT-2) – a Randomised, Double-Blind,
Placebo-Controlled Trial. Thorax. 2013. 68(9): 812-817.
Ong HX. etal. Liposomal Nanoparticles Control the Uptake of
Ciprofloxacin Across Respiratory Epithelia. Pharm Res. 2012.
Ong HX. et al. Inhaled Liposomal Ciprofloxacin Nanoparticles
Control the Release of Antibiotic at the Bronchial Epithelia.
RDD 2012. Dalby R.N. et al. (eds). 2012. 851-854.
Cipolla D et al. Liposomes, niosomes and proniosomes - a critical
update of their (commercial) development as inhaled products.
RDD Europe 2011. Dalby R.N. et al. (eds). 2011. 41-54.
Cipolla D. Et al. Inhaled Liposomal Ciprofloxacin: In Vitro
Properties and Aerosol Performance. RDD 2010. Dalby R.N. et
al. (eds). 2010. 409-414.
Bruinenberg P. et al. Inhaled liposomal ciprofloxacin: Once
a day management of respiratory infections. RDD 2010. Dalby
R.N. et al. (eds). 2010. 73-82.
Blanchard, J. Pulmonary Drug Delivery as a First Response to
Bioterrorism. RDD X. Dalby R.N. et al. (eds). 2006. 73-82.
Yim D. et al. The development of inhaled liposome-encapsulated
ciprofloxacin to treat cystic fibrosis. RDD X. Dalby R.N. et
al. (eds). 2006. 425-428.
For more information on cystic fibrosis, visit the following web sites:
Cystic Fibrosis Foundation
Cystic Fibrosis | A Support
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