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Use of liposomes encapsulating drug nanocrystals for the treatment of diseases like cancer and pulmonary infections is gaining attention. The potential therapeutic benefit of these engineered formulations relies on maintaining the physical integrity of the liposomes and the stability of the encapsulated drug. With the significant advancement in the microscopic and analytical techniques, analysis of the size and size distribution of these nanosized vesicles is possible. However, due to the limited spatial resolution of conventional vibrational spectroscopy techniques, the chemical composition of individual nanosized liposome cannot be resolved. To address this limitation, we applied atomic force microscopy infrared spectroscopy (AFM-IR) to assess the chemical composition of individual liposomes encapsulating ciprofloxacin in dissolved and nanocrystalline form. Spatially resolved AFM-IR spectra acquired from individual liposomes confirmed the presence of peaks related to N–H bending vibration, C–N stretching and symmetric, and asymmetric vibration of the carboxyl group present in the ciprofloxacin. Our results further demonstrated the effectiveness of AFM-IR in differentiating the liposome containing ciprofloxacin in dissolved or nanocrystalline form. Spectra acquired from dissolved ciprofloxacin had peaks related to the ionised carboxyl group, i.e., at 1576 and 1392 cm–1, which were either absent or far weaker in intensity in the spectra of liposomal sample containing ciprofloxacin nanocrystals. These findings are highly significant for pharmaceutical scientists to ascertain the stability and physicochemical composition of individual liposomes and will facilitate the design and development of liposomes with greater therapeutic benefits.

ABSTRACTLiposome-encapsulated ciprofloxacin for inhalation (CFI) was investigated as a putative postexposure therapeutic for two strains of Francisella tularensis. The efficacies of oral ciprofloxacin and intranasally instilled CFI could not be distinguished in a mouse model of infection with the F. tularensislive vaccine strain (LVS), where a single dose of either formulation offered full protection against a lethal challenge. However, mouse studies with the more virulent Schu S4 strain of F. tularensisdemonstrated that a higher level of protection against a lethal aerosol infection is provided by CFI than by oral ciprofloxacin. In addition, using this infection model, it was possible to discriminate the efficacy of intranasally instilled CFI from that of aerosolized CFI, with aerosolized CFI providing full protection after just a single dose. The improved efficacy of CFI compared to oral ciprofloxacin is likely due to the high sustained concentrations of ciprofloxacin in the lung. In summary, CFI may be a promising therapy, perhaps enabling the prophylactic regimen to be shortened, for use in the event of a deliberate release of F. tularensis. The prophylactic efficacy of CFI against other biological warfare (BW) threat agents also warrants investigation.

The purpose of this study was to characterize performance of a miniaturized AERx® Pulmonary Delivery System designed for aerosol administration to large animal models. The miniaturized AERx System was developed through a systematic scaling down of the AERx System used for humans to allow for operation in certain animal models with lower inspiratory flow rates and inhaled volumes than those used for humans. We used gamma scintigraphy to characterize the in vivo particle deposition achieved with the miniaturized AERx System in two dogs. The dogs were 3–4 years old, and weighed 10.4 kg and 13.6 kg. Acepromazine was used as pre-anesthetic medication. Anesthesia was induced with 5% isoflurane. The trachea was intubated using an endotracheal tube (internal diameter 8.5 mm), and the dogs were ventilated using positive pressure during the exposure using the LRRI puff generator. An inhalation of aerosol was initiated by activation of the puff generator though the computer-controlled interface. Each dog inhaled ∼0.8 L per puff, of which the aerosol volume comprised ∼0.25 L, at a target flow rate of 15 L/min. The dogs were exposed to 10 AERx Strips in 10 puffs. The mass median aerodynamic diameter of the aerosolized formulation was ∼1.25 µm with a fine particle fraction <3.5 µm of 0.976. The scintigraphic images showed uniform bilateral lung deposition following aerosol delivery with the AERx System. Total lung deposition for the two dogs was 10.7% and 18% of the loaded dose from the AERx Strip. The corresponding peripheral lung: inner lung (P/I) ratios were 0.83 and 0.75, suggestive of deposition in the deep lung. Only 0.1% to 0.2% of the loaded dose was exhaled. These results show the miniature AERx System can efficiently deliver aerosols to the deep lung of dogs. The miniaturized AERx System would be a valuable tool for conducting proof-of-concept studies as well as safety and tolerability analysis of inhaled drug candidates in large animal models.

Bioavailability of an aerosolized anti-inflammatory protein, soluble interleukin-4 receptor (IL-4R), was measured in patients with asthma using two different aerosol delivery systems, a prototype aerosol delivery system (AERx® tethered model, Aradigm, Hayward, CA) and PARI LC STAR® nebulizer (Pari, Richmond, VA). Regional distribution of the drug in the respiratory tract obtained by planar imaging using gamma camera scintigraphy was utilized to explain the differences in bioavailability. The drug, an experimental protein being developed for asthma, was mixed with radiolabel 99mTechnetium diethylene triaminepentaacetic acid (99mTc-DTPA). Aerosols were characterized in vitro using cascade impaction (mass median aerodynamic diameter [MMAD] and geometric standard deviation [GSD]); the AERx® MMAD 2.0 μm (GSD 1.35), the PARI® 3.5 μm (GSD 2.5). Four patients with asthma requiring maintenance aerosolized steroids were studied. First, regional volume was determined utilizing equilibrium 133Xe scanning. Then, after a brief period of instruction, patients inhaled four breaths of protein using AERx® (0.45 mg in total) followed 1 week later by inhalation via PARI® (3.0 mg nebulized until dry). Each deposition image was followed by a measurement of regional perfusion using injected 99mTc albumin macroaggregates. Deposition of 99mTc-DTPA in the subjects was determined by mass balance. Regional analysis was performed using computerized regions of interest. The regional distribution of deposited drug was normalized for regional volume and perfusion. Following each single inhalation, serial blood samples were drawn over a 7-day period to determine area under the curve (AUC) of protein concentration in the blood. Median AUCAERx/AUCPARI was 7.66/1, based on the amount of drug placed in each device, indicating that AERx® was 7.66 times more efficient than PARI®. When normalized for total lung deposition (AUC per mg deposited) the ratio decreased to 2.44, indicating that efficiencies of the drug delivery system and deposition were major factors. When normalized for sC/P and (pU/L)Xe ratios (central to peripheral and upper to lower ratios are parameters of regional distribution of deposited particles and regional per fusion ['p']), AUCAERx/AUCPARI further decreased to 1.35, demonstrating that peripheral sites of deposition with the AERx® affected the final blood concentration of the drug. We conclude that inhaled bioavailability of aerosolized protein, as expressed by AUC, is a quantifiable function of lung dose and regional deposition as defined by planar scintigraphy.

The industrial hygienist is a professional trained in the recognition, evaluation, and control of environmental stresses in the workplace and as such serves as a valuable resource for medical personnel concerned with occupational lung disease. Knowledge of the precise identity and quantity of workplace hazards is often essential in diagnosing occupationallung disorders. In addition, an industrial hygienist familiar with the process can assess whether there is a likelihood of exposure to levels above the limits which are considered to be safe. This valuable industrial hygiene information can be from industrial hygienists working in industry, government (e.g., OSHA, state agencies), universities or consulting firms.

Nontuberculous mycobacteria (NTM) affect an increasing number of individuals worldwide. Infection with these organisms is more common in patients with chronic lung conditions, and treatment is challenging.