The Pharmaceutical Journal
Vol 269 No 7218 p491
5 October 2002

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British Pharmaceutical Conference 2002 summary

GSK lecture: Journeys to and through the lung

Dr Peter Byron leads the aerosol research group at Virginia Commonwealth University School of Pharmacy, Richmond, Virginia, United States, which investigates factors controlling drug aerosol generation, deposition, and disposition in the lung.

Dr Byron told his audience that when the group first began researching pulmonary drug delivery in the mid 1970s, its primary interest concerned the prediction and control of drug disposition in the lung, once aerosol delivery to the airways had been accomplished. He explained that at that time there was little published information on the subject, partly because of the difficulties involved with the aerosol delivery of known drug doses to different parts of the respiratory tract. He said that the group has worked in this field for about 25 years now, using whole animals and isolated lung preparations and during this time it has been forced to refine its methods and understand the issues associated with drug dosimetry, regional lung deposition, and the interplay of those topics with what might best be called "pharmaceutical aerosol physics". The group has also watched and assisted with the development of the lung, both as a route of systemic drug administration, and as an organ for treatment, while researching and helping to introduce a series of new aerosol delivery platforms.

Dr Byron said that much of the group's work on disposition was performed at a time when industry sought to exploit the lung as a route for systemic delivery of biological products. However, while individual companies designed studies to advance their technological claims, the group has tried to facilitate understanding of the biopharmaceutical issues. Contrary to conventional wisdom, in which the huge surface area of the lower lung was argued to provide more rapid absorption than the conducting airways (like the trachea and major bronchi), drug absorption of small molecules, following aerosol delivery, occurs at similar speeds from both regions, said Dr Byron. This is true, in spite of the considerable difference in the thickness of the rate-determining epithelial cell layers in the upper and lower lung, he explained. However, he went on to say that, as different molecules have been studied and especially as molecular size was increased, kinetic differences have begun to emerge between the two regions, such that alveolar drug delivery must dominate if reliable systemic delivery of macromolecules is to take place. Dr Byron gave the example of 5.8kDa pulmonary insulin, where rapid, but quantifiable, clearance from the upper airways mandates the use of expensive, sophisticated aerosol delivery systems to enhance and control alveolar delivery, in part by controlling the way in which aerosols are inhaled by patients.

Airway to blood transporters

Dr Byron also discussed other facets of the group's work that have sought to exploit airway to blood transporters, which the group discovered while developing techniques to characterise pulmonary biopharmaceutics. In the absence of such transporters, and despite the speed with which transmucosal drug transfer can occur from the lung, several small and large molecules show pharmacokinetic profiles with rate-determined absorption, even in the absence of formulation manoeuvres designed to retard drug particle dissolution in the airways. In fact, he said, it has proved to be extremely difficult to increase drug longevity or duration in the lung using the normal menu of pharmaceutical techniques, such as particle coating, to retard dissolution. Thus, prolongation of local activity, such as that seen with the longer-acting adrenergics, salmeterol and formoterol, has required the development of lipophilic analogues of drugs like salbutamol to modify lung binding properties, in part to retard absorption and removal from the lung or site of action.

Distribution test methods

Dr Byron said that the group's studies occurred at a time when CFC propellants in pressurised inhalers were being phased out, new drug delivery platforms, like powder inhalers, were introduced and generic inhalers, containing drugs for asthma, were being launched. He suggested that it was not surprising, therefore, that the regulation of pulmonary drug delivery systems has become a topic in which the group has also played a part. Several standard pharmacopoeial delivered dose and aerodynamic size distribution test methods have been developed for inhalers in the group's laboratories, and it has pioneered the study of tests to characterise aerosol electrostatics and inhaler material adhesion properties, which have value during the inhaler design process.

Dr Byron told conference participants that, recently, the group has sought to develop condensation aerosols of pharmaceutical quality, capable of deep lung penetration. He believes that seeking to publish the group's formulation and inhaler packaging studies widely, in both the scientific and patent literature, has stimulated others to do likewise. As a result, he likes to think that the group has improved the availability of general pharmaceutical knowledge surrounding inhaled drug delivery systems and helped a number of new inhalers with improved properties to become available. These will display reduced in vivo dosing variance to the mouth, the lung and, in some cases, the lung periphery, by controlling both the quality of the inhaled aerosol and the respiratory manoeuvres employed by patients. Other inhalers may seek only to control aspects of the aerosol cloud produced under controlled laboratory conditions, in order to satisfy testing requirements imposed by regulators. Both approaches have their merits, depending on the drugs being inhaled and the different biopharmaceutical challenges associated with their delivery.

Dr Byron reviewed pharmaceutical and therapeutic objectives associated with such approaches and ended his presentation by acknowledging the work and dedication of his past and present graduate students, postdoctoral researchers, technicians and faculty, without whom he could not have received his award.