NANOPARTICLE AGGLOMERATES FOR PULMONARY DRUG DELIVERY

The Pulmonary route has been traditionally used to treat diseases of the respiratory tract. However, important research within the last two decades have shown that in addition to treating local diseases, a wide range of systemic diseases can be treated by delivering drugs to the lungs. The recent FDA approval to market Exubera, an inhalable form of insulin developed by Pfizer, to treat Diabetes, may just be the stepping stone that the pharmaceutical industry needs to market other drugs to treat systemic diseases via the lungs. However, this technology still needs repeated drug doses to control glucose levels, as the inhaled drug is cleared rapidly. Technologies have been developed where inhaled particles are capable of controlled release of drug from the lungs. An important feature of these technologies is the large geometric size of the particles that makes it difficult for the lung macrophages to clear these particles, which results in longer residence times for the particles in the lungs. Owing to the porosity, these particles have lower densities making them deliverable to the deep lungs. However, no modulation of drug release can be achieved with these technologies when more drug release may be required. This additional requirement can only be assuaged by additional dosing of the drug formulation, which can have undesirable effects due to excess loading of excipients in the lungs. In an attempt to bring about modulation of release from long residence time particles, a novel concept was developed in our laboratory that has been termed as the Agglomerated Vesicle Technology (AVT). Liposomes with encapsulated drug were agglomerated using well known cross linking chemistries to form agglomerates in the micron sized range. The large particles exhibited aerodynamic sizes in the respirable size range with minimal damage to the particles upon nebulization. By breaking the cross links between the liposomes with a cleaving agent, it was anticipated that triggered release of drug from the AVT particles could be achieved. In vivo studies done in healthy rabbits showed that post-administration modulation of drug release is possible from the AVT particles after the introduction of the cleaving agent. This study has important implications for the future development of this technology, where the AVT particles can be made “sensitive” to the product of disease. It is envisaged that a single dose of AVT containing the appropriate drug when administered to the lungs would maintain drug levels at a controlled rate over an extended period of time. When the need for more drug arises, the product of the disease would trigger the AVT particles to release more drug as needed to control the condition, thus eliminating the need for repeated drug doses and improved compliance amongst patients.

Evaluation of elevator shafts as a pathway for fungal spores and particles to enter a hospital housing immuno-compromised patients

Background. It is estimated that hospitals spend between 28 and 33 billion dollars per year as a result of hospital-acquired infections. (Scott, 2009) The costs continue to rise despite the guidance and controls provided by hospital infection control staff to reduce patient exposures to fungal spores and other infectious agents. With all processes and controls in place, the vented elevator shaft represents an unprotected opening from the top of the building to the lower floors. The hypothesis for this prospective study is that there is a positive correlation between the number of Penicillium/Aspergillus-like spores, Cladosporium, ascospores, basidiospores in spores/m3 as individual spore categories found in the hoistway vent of an elevator shaft and the levels of the same spores, sampled near-simultaneously in the outdoor intake of the elevator shaft. Specific aims of this study include determining if external Penicillium/Aspergillus-like spores are entering the healthcare facility via the elevator shaft and hoistway vents. Additional aims include determining levels of Penicillium/Aspergillus-like spores outdoors, in the elevator shafts, and indoors in areas possibly affected by elevator shaft air; and, finally, to evaluate whether any effect is observed due to the installation of a hoistway vent damper, installed serendipitously during this study. ^ Methods. Between April 2010 and September 2010, a total of 3,521 air samples were collected, including 363 spore trap samples analyzed microscopically for seven spore types, and polymerase chain reaction analyses on 254 air samples. 2178 particle count measurements, 363 temperature readings and 363 relative humidity readings were also obtained from 7 different locations potentially related to the path of air travel inside and near a centrally-located and representative elevator shaft. ^ Results. Mean Penicillium/Aspergillus-like spore values were higher outside the building (530 spores/m3 of air) than inside the hoistway (22.8 spores/m3) during the six month study. Mean values inside the hospital were lower than outside throughout the study, ranging from 15 to 73 spores/m3 of air. Mean Penicillium/Aspergillus-like spore counts inside the hoistway decreased from 40.1 spores/m3 of air to 9 spores/m3 of air following the installation of a back draft damper between the outside air and the elevator shaft. Comparison of samples collected outside the building and inside the hoistway vent prior to installing the damper indicated a strong positive correlation (Spearman's Rho=0.8008, p=0.0001). The similar comparison following the damper installation indicated a moderate non-significant inverse correlation (Spearman's rho = −0.2795, p=0.1347). ^ Conclusion. Elevator shafts are one pathway for mold spores to enter a healthcare facility. A significant correlation was detected between spores and particle counts inside the hoistway and outside prior to changes in the ventilation system. The insertion of the back draft damper appeared to lower the spore counts inside the hoistway and inside the building. The mold spore counts in air outside the study building were higher in the period following the damper installation while the levels inside the hoistway and hospital decreased. Cladosporium and Penicillium/Aspergillus -like spores provided a method for evaluating indoor air quality as a natural tracer from outside the building to inside the building. Ascospores and basidiospores were not a valuable tracer due to low levels of detection during this study. ^ Installation of a back draft damper provides additional protection for the indoor environment of a hospital or healthcare facility, including in particular patients who may be immunocompromised. Current design standards and references do not require the installation of a back draft damper, but evaluation of adding language to relevant building codes should be considered. The data indicate a reduction in levels of Penicillium/Aspergillus -like spores, particle counts and a reduction in relative humidity inside of the elevator shaft after damper installation.^