The History of Therapeutic Aerosols: A Chronological Review.

In 1956, Riker Laboratories, Inc., (now 3 M Drug Delivery Systems) introduced the first pressurized metered dose inhaler (MDI). In many respects, the introduction of the MDI marked the beginning of the modern pharmaceutical aerosol industry. The MDI was the first truly portable and convenient inhaler that effectively delivered drug to the lung and quickly gained widespread acceptance. Since 1956, the pharmaceutical aerosol industry has experienced dramatic growth. The signing of the Montreal Protocol in 1987 led to a surge in innovation that resulted in the diversification of inhaler technologies with significantly enhanced delivery efficiency, including modern MDIs, dry powder inhalers, and nebulizer systems. The innovative inhalers and drugs discovered by the pharmaceutical aerosol industry, particularly since 1956, have improved the quality of life of literally hundreds of millions of people. Yet, the delivery of therapeutic aerosols has a surprisingly rich history dating back more than 3500 years to ancient Egypt. The delivery of atropine and related compounds has been a crucial inhalation therapy throughout this period and the delivery of associated structural analogs remains an important therapy today. Over the centuries, discoveries from many cultures have advanced the delivery of therapeutic aerosols. For thousands of years, therapeutic aerosols were prepared by the patient or a physician with direct oversight of the patient using custom-made delivery systems. However, starting with the Industrial Revolution, advancements in manufacturing resulted in the bulk production of therapeutic aerosol delivery systems produced by people completely disconnected from contact with the patient. This trend continued and accelerated in the 20th century with the mass commercialization of modern pharmaceutical inhaler products. In this article, we will provide a summary of therapeutic aerosol delivery from ancient times to the present along with a look to the future. We hope that you will find this chronological summary intriguing and informative.

In vivo-in vitro correlations: predicting pulmonary drug deposition from pharmaceutical aerosols.

In order to answer the question "what research remains to be done?" we review the current state of the art in pharmaceutical aerosol deposition modeling and explore possible in vivo- in vitro correlations (IVIVC) linking drug deposition in the human lung to predictions made using in vitro physical airway models and in silico computer models. The use of physical replicas of portions of the respiratory tract is considered, alongside the advantages and disadvantages of the different imaging methods used to obtain their dimensions. The use of airway replicas to determine drug deposition in vitro is discussed and compared with the predictions from different empirical curve fits to long-standing in vivo deposition data for monodisperse aerosols. The use of improved computational models and three-dimensional computational fluid dynamics (CFD) to predict aerosol deposition within the respiratory tract is examined. CFD's ability to predict both drug deposition from pharmaceutical aerosol sprays and powder behavior in dry powder inhalers is examined; both were highlighted as important areas for future research. Although the authors note the abilities of current in vitro and in silico methods to predict in vivo data, a number of limitations remain. These include our present inability to either image or replicate all but the most proximal airways in sufficient spatial and temporal detail to allow full capture of the fluid and aerosol mechanics in these regions. In addition, the highly complex microscale behavior of aerosols within inhalers and the respiratory tract places extreme computational demands on in silico methods. When the complexity of variations in respiratory tract geometry is associated with additional factors such as breathing pattern, age, disease state, postural position, and patient-device interaction are all considered, it is clear that further research is required before the prediction of all aspects of inhaled pharmaceutical aerosol deposition is possible.

Cascade impactor data and the lognormal distribution: nonlinear regression for a better fit.

At present, cascade impactors are the instruments of choice for measuring the particle size distribution of aerosol present in the complex discharge from pharmaceutical inhalers. The distribution of drug captured in the cascade impactor may be most usefully represented by the lognormal distribution. Only two parameters must be extracted from the analysis of cascade impactor data in order to describe the distribution. These two parameters are the mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD). A cumulative version of the lognormal curve or more frequently, a linearized version of the cumulative curve called a "log probability plot," is used as a surrogate for the lognormal curve. The probability plot has great appeal since a lognormal distribution yields a straight line on log probability paper. One may easily determine the apparent MMAD and GSD from this linear plot. However, when one plots a lognormal curve, using the MMAD and GSD derived from a log probability plot, over a histogram constructed from cascade impactor data, an obvious mismatch is frequently seen. In order to derive parameters that more truly reflect the impactor data, a computer program, which uses nonlinear regression to derive an MMAD and GSD for the lognormal curve, has been written. It is presented here.