Igor Gonda

Inhalation of hypertonic saline aerosol enhances mucociliary clearance in asthmatic and healthy subjects

Hyperosmolarity of the airway surface liquid (ASL) has been proposed as the stimulus for hyperpnoea-induced asthma. We found previously that mucociliary clearance (MCC) was increased after isocapnic hyperventilation (ISH) with dry air, and we proposed that the increase related to transient hyperosmolarity of the ASL. We investigated the effect of increasing the osmolarity of the ASL on MCC, by administering an aerosol of concentrated salt solution. MCC was measured using 99mTc-sulphur colloid, gamma camera and computer analysis in 12 asthmatic and 10 healthy subjects on three separate days, involving administration of each of the following: 1) ultrasonically nebulized 14.4% saline; 2) ultrasonically nebulized 0.9% saline; and 3) no aerosol intervention (control). The (mean +/- SD) volume of nebulized 14.4% saline was 2.2 +/- 1.2 mL for asthmatics and 3.2 +/- 0.7 mL for healthy subjects. This volume was delivered over a period of 5.4 +/- 1.3 and 6.4 +/- 0.7 min for asthmatic and healthy subjects, respectively. The airway response to 14.4% saline was assessed on a separate visit and the fall in forced expiratory volume in one second (FEV1) was 22 +/- 4% in the asthmatic and 3 +/- 2% in the healthy subjects. Compared to the MCC with the 0.9% saline and control, the hypertonic aerosol increased MCC in both groups. In asthmatic subjects, MCC of the whole right lung in 1 h was 68 +/- 10% with 14.4% saline vs 44 +/- 14% with 0.9% saline and 39 +/- 13% with control. In healthy subjects, MCC of the whole right lung in 1 h was 53 +/- 12% with 14.4% saline vs 41 +/- 15% with 0.9% saline and 36 +/- 13% with control. We conclude that an increase in osmolarity of the airway surface liquid increases mucociliary clearance both in asthmatic and healthy subjects. These findings are in keeping with our previous suggestion that the increase in mucociliary clearance after isotonic hyperventilation with dry air is due to a transient hyperosmolarity of the airway surface liquid.

Inhaled, dual release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial

Background The delivery of antipseudomonal antibiotics by inhalation to Pseudomonas aeruginosa-infected subjects with non-cystic fibrosis (CF) bronchiectasis is a logical extension of treatment strategies successfully developed in CF bronchiectasis. Dual release ciprofloxacin for inhalation (DRCFI) contains liposomal ciprofloxacin, formulated to optimise airway antibiotic delivery. Methods Phase II, 24-week Australian/New Zealand multicentre, randomised, double-blind, placebo-controlled trial in 42 adult bronchiectasis subjects with ≥2 pulmonary exacerbations in the prior 12 months and ciprofloxacin-sensitive P aeruginosa at screening. Subjects received DRCFI or placebo in three treatment cycles of 28 days on/28 days off. The primary outcome was change in sputum P aeruginosa bacterial density to the end of treatment cycle 1 (day 28), analysed by modified intention to treat (mITT). Key secondary outcomes included safety and time to first pulmonary exacerbation—after reaching the pulmonary exacerbation endpoint subjects discontinued study drug although remained in the study. Results DRCFI resulted in a mean (SD) 4.2 (3.7) log10 CFU/g reduction in P aeruginosa bacterial density at day 28 (vs −0.08 (3.8) with placebo, p=0.002). DRCFI treatment delayed time to first pulmonary exacerbation (median 134 vs 58 days, p=0.057 mITT, p=0.046 per protocol). DRCFI was well tolerated with a similar incidence of systemic adverse events to the placebo group, but fewer pulmonary adverse events. Conclusions Once-daily inhaled DRCFI demonstrated potent antipseudomonal microbiological efficacy in adults with non-CF bronchiectasis and ciprofloxacin-sensitive P aeruginosa. In this modest-sized phase II study, DRCFI was also well tolerated and delayed time to first pulmonary exacerbation in the per protocol population.

The ascent of pulmonary drug delivery

The origins of inhalation therapy can be traced back to the early civilizations but this route of administration was relatively uncommon until recently. Direct delivery of drugs to the lung by inhalation for the treatment of respiratory disease grew rapidly in the second half of the 20th century as a result of the availability of effective asthma drugs in convenient, portable delivery systems. In the search for non-invasive delivery of biologics, it was discovered that the large highly absorptive surface area of the lung could be used for systemic delivery of proteins such as insulin. New delivery systems with efficiency and reproducibility to match the high cost and therapeutic constraints of biologics are currently in late stage clinical trials. Even small molecular weight drugs previously administered by injection are tested via the inhalation route either to provide non-invasively rapid onset of action, or to improve the therapeutic ratio for drugs acting in the lung. Gene therapy of pulmonary disease is still in its infancy but could provide valuable solutions to currently unmet medical needs. The beginning of the new millennium is therefore likely to witness development of many valuable therapeutic products delivered by inhalation.

Liposomal formulations for inhalation

No marketed inhaled products currently use sustained release formulations such as liposomes to enhance drug disposition in the lung, but that may soon change. This review focuses on the interaction between liposomal formulations and the inhalation technology used to deliver them as aerosols. There have been a number of dated reviews evaluating nebulization of liposomes. While the information they shared is still accurate, this paper incorporates data from more recent publications to review the factors that affect aerosol performance. Recent reviews have comprehensively covered the development of dry powder liposomes for aerosolization and only the key aspects of those technologies will be summarized. There are now at least two inhaled liposomal products in late-stage clinical development: ARIKACE(®) (Insmed, NJ, USA), a liposomal amikacin, and Pulmaquin™ (Aradigm Corp., CA, USA), a liposomal ciprofloxacin, both of which treat a variety of patient populations with lung infections. This review also highlights the safety of inhaled liposomes and summarizes the clinical experience with liposomal formulations for pulmonary application.

Aerodynamic properties of elongated particles of cromoglycic acid

Crystals of cromoglycic acid were prepared by precipitation and recrystallization from water. Aerosols of dry CA particles in air were generated by nebulizing a dilute suspension of CA and drying. The aerodynamic properties of these particles were measured directly by cascade impaction which gave a mass median aerodynamic diameter MMAD = 0.7 μm and geometric standard deviation σσ = 1.9. The aerodynamic diameters were also calculated from the geometric dimensions obtained from electronmicrographs with, or without, the shadowing technique for determination of the thickness of the particles. Two methods derived for the aerodynamic behaviour of prolate spheroids and an empirical equation for elongated particles (Johnson, J. Aerosol Sci.17, 426–430, 1986; Johnson et al., J. Aerosol Sci.18, 87–97, 1987) were employed. The calculated MMAD and σσ assuming perpendicular orientation of the elongated particles with respect to the direction of motion were in reasonable agreement with the values obtained by cascade impaction.

Local airway heat and water vapour losses

A previously developed time-dependent mathematical model of the heat and water vapour transport in the human respiratory tract for mouth breathing (Daviskas et al., J. Appl. Physiol. 69:362-372, 1990) was applied to calculate the local quantities of heat and water transfer. The results of the heat and water losses agreed with experimental data. The contribution of each airway to the conditioning of inspired air was found to depend on the inspired air conditions and the pattern of breathing as expected. The greater proportion of the total heat and water loss was calculated to occur within the upper airways. However, below the pharynx, the rate of water loss during hyperpnea was calculated at a much faster rate than in the resting state. The rate at which water is returned to the airways may not be adequate to keep the periciliary fluid isotonic. These findings support the proposal that the intrathoracic airways could become significantly dehydrated during hyperpnea. The use of calculated local heat and water transfer rates may help to predict the site of stimuli to exercise-induced asthma.

Regional deposition of saline aerosols of different tonicities in normal and asthmatic subjects

Nonisotonic aerosols are frequently used in the diagnosis and therapy of lung disease. The purpose of this work was to study the difference in the pattern of deposition of aerosols containing aqueous solutions of different tonicities. 99mTechnetium-diethyltriaminepentaacetic acid (99mTc-DTPA)-labelled saline aerosols, with mass median aerodynamic diameter 3.7-3.8 microns and geometric standard deviation 1.4, were inhaled under reproducible breathing conditions on two occasions. Hypotonic and hypertonic solutions were used in 11 normals subjects, isotonic and hypertonic solutions in 9 asthmatics. The regional deposition was quantified by a penetration index measured with the help of a tomographic technique. There was a small but significant increase (6.7%) in the penetration index of the hypotonic as compared to the hypertonic aerosols in the normal subjects. The region that was markedly affected was the trachea. The differences in the penetration of the isotonic and hypertonic aerosols in the asthmatics appeared to be strongly dependent on the state of the airways at the time of the study. These findings can be interpreted in terms of effects of growth or shrinkage of nonisotonic aerosols, as well as of airway narrowing, on regional deposition of aerosols. Tonicity of aerosols appears to affect their deposition both through physical and physiological mechanisms. This should be taken into account when interpreting the effects of inhaled aqueous solutions of various tonicities in patients in vivo.

Liposomal nanoparticles control the uptake of ciprofloxacin across respiratory epithelia.

ABSTRACTPurposeLiposomal ciprofloxacin nanoparticles were developed to overcome the rapid clearance of antibiotics from the lungs. The formulation was evaluated for its release profile using an air interface Calu-3 cell model and further characterised for aerosol performance and antimicrobial activity.MethodsLiposomal and free ciprofloxacin formulations were nebulised directly onto Calu-3 bronchial epithelial cells placed in an in vitro twin-stage impinger (TSI) to assess the kinetics of release. The aerosol performance of both the liposomal and free ciprofloxacin formulation was characterised using the next generation impactor. Minimum inhibitory and bactericidal concentrations (MICs and MBCs) were determined and compared between formulations to evaluate the antibacterial activity.ResultsThe liposomal formulation successfully controlled the release of ciprofloxacin in the cell model and showed enhanced antibacterial activity against Pseudomonas aeruginosa. In addition, the formulation displayed a respirable aerosol fraction of 70.5 ± 2.03% of the emitted dose.ConclusionResults indicate that the in vitro TSI air interface Calu-3 model is capable of evaluating the fate of nebulised liposomal nanoparticle formulations and support the potential for inhaled liposomal ciprofloxacin to provide a promising treatment for respiratory infections.

Development of a systematic theory of suspension inhalation aerosols. I. A framework to study the effects of aggregation on the aerodynamic behaviour of drug particles

Abstract When a suspension of drug particles is nebulized, the number of particles in a droplet depends on its size and on the relative sizes of the particles and the concentration of the suspension. Therefore, the drug particle size distribution after aerosolization is, in general, different from the distribution of the primary particles. The dry drug particles left after the evaporation of the propellant from a droplet form a cluster (aggregate). The average number of particles in such an aggregate and the variance of this number is calculated from the Poisson probability distribution function. Further progress is made under the following simplifying assumptions: (1) both the primary drug particles and the droplets are monodisperse; (2) the primary drug particles and the clusters are spherical; and (3) a particular model of packing of particles into aggregates can be adopted. The cumulative mass distribution of the drug as a function of the number of drug particles/cluster, equivalent volume and aerodynamic diameters are computed for a specific model. The ranges of concentration and ratios of droplet/particle diameters where aggregation is likely to affect significantly the aerodynamic behaviour of the drug, are outlined. The theoretical calculations are in qualitative agreement with the available experimental evidence for currently used therapeutic suspension inhalation aerosols. It is suggested that the treatment presented here may be developed into a predictive tool for formulation of aerosols with desired aerodynamic features.

Development of Liposomal Ciprofloxacin to Treat Lung Infections

Except for management of Pseudomonas aeruginosa (PA) in cystic fibrosis, there are no approved inhaled antibiotic treatments for any other diseases or for infections from other pathogenic microorganisms such as tuberculosis, non-tuberculous mycobacteria, fungal infections or potential inhaled biowarfare agents including Francisella tularensis, Yersinia pestis and Coxiella burnetii (which cause pneumonic tularemia, plague and Q fever, respectively). Delivery of an antibiotic formulation via the inhalation route has the potential to provide high concentrations at the site of infection with reduced systemic exposure to limit side effects. A liposomal formulation may improve tolerability, increase compliance by reducing the dosing frequency, and enhance penetration of biofilms and treatment of intracellular infections. Two liposomal ciprofloxacin formulations (Lipoquin® and Pulmaquin®) that are in development by Aradigm Corporation are described here.