Significant advances have been made in the last 50 years in developing safe and efficacious aerosol formulations for pulmonary delivery. The key to future innovation may lie at the interface between biology and particle engineering. Improved understanding of biological processes including particle clearance, cellular targeting, intracellular trafficking, and drug absorption are needed to better design formulations that deliver to the "target" with the optimal balance of pharmacodynamic, pharmacokinetic, and safety profiles. More specifically, continued advances are needed in the development of: (1) controlled release formulations; (2) formulations with improved regional targeting within the lungs (e.g., airway versus alveoli and vice versa); (3) formulations containing active targeting moieties; (4) formulation strategies for improving the systemic bioavailability of inhaled macromolecules; (5) formulation strategies for delivering macromolecules, including siRNA and DNA into cells; and (f) formulations with improved dose consistency. It is likely that such innovation will require the development of novel excipients and particle engineering strategies. Future innovation must also take into the account the changing marketplace and the diverse set of customers (patient, healthcare professional, heath authorities, payers, and politicians) who must be satisfied. The pharmacoeconomics of new delivery systems will be closely scrutinized, so it is imperative that cost factors be taken into account. Otherwise, the new technology option may overshoot the evolving inhalation marketplace.
The new field of therapeutic aerosol bioengineering (TAB), driven primarily by the medical need for inhaled insulin, is now expanding to address medical needs ranging from respiratory to systemic diseases, including asthma, growth deficiency, and pain. Bioengineering of therapeutic aerosols involves a level of aerosol particle design absent in traditional therapeutic aerosols, which are created by conventionally spraying a liquid solution or suspension of drug or milling and mixing a dry drug form into respirable particles. Bioengineered particles may be created in liquid form from devices specially designed to create an unusually fine size distribution, possibly with special purity properties, or solid particles that possess a mixture of drug and excipient, with designed shape, size, porosity, and drug release characteristics. Such aerosols have enabled several high-visibility clinical programs of inhaled insulin, as well as earlier-stage programs involving inhaled morphine, growth hormone, beta-interferon, alpha-1-antitrypsin, and several asthma drugs. The design of these aerosols, limited by partial knowledge of the lungs' physiological environment, and driven largely at this stage by market forces, relies on a mixture of new and old science, pharmaceutical science intuition, and a degree of biological-impact empiricism that speaks to the importance of an increased level of academic involvement.
The purpose of this paper is to review the approaches for analyzing cascade impactor (CI) mass distributions produced by pulmonary drug products and the considerations necessary for selecting the appropriate analysis procedure. There are several methods available for analyzing CI data, yielding a hierarchy of information in terms of nominal, ordinal and continuous variables. Mass distributions analyzed as a nominal function of the stages and auxiliary components is the simplest approach for examining the whole mass emitted by the inhaler. However, the relationship between the mass distribution and aerodynamic diameter is not described by such data. This relationship is a critical attribute of pulmonary drug products due to the association between aerodynamic diameter and the mass of particulates deposited to the respiratory tract. Therefore, the nominal mass distribution can only be utilized to make decisions on the discrete masses collected in the CI. Mass distributions analyzed as an ordinal function of aerodynamic diameter can be obtained by introducing the stage size range, which generally vary in magnitude from one stage to another for a given type of CI, and differ between CIs of different designs. Furthermore, the mass collected by specific size ranges within the CI are often incorrectly used to estimate in vivo deposition at various regions of the respiratory tract. A CI-generated mass distribution can be directly related to aerodynamic diameter by expressing the mass collected by each size-fractionating stage in terms of either mass frequency or cumulative mass fraction less than the aerodynamic size appropriate to each stage. Analysis of the aerodynamic diameter as a continuous variable allows comparison of mass distributions obtained from different products, obtained by different CI designs, as well as providing input to in vivo particle deposition models. The lack of information about the mass fraction emitted by the inhaler that is not size-analyzed by the CI may be perceived as a disadvantage from the standpoint of comparing the total mass per actuation emitted from the inhaler mouthpiece. However, this is a limitation of the CI measurement technique rather than the data analysis procedure. Data reduction techniques can enable the large quantity of information conveyed in a mass-size distribution to be summarized in terms of representative parameters, but care needs to be exercised if utilizing model size distribution function fitting routines to avoid introducing error by the fitting procedure.
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