Safety Assessment of Inhalant Drugs

An average man inhales approximately 7.5, 28.6, and 42.9 liters of air per minute during resting, light work, and heavy work periods, respectively, and the corresponding mean tidal volumes of 750, 1673 and 2030 ml (National Academy of Sciences, 1958). Each breath is distributed between 300-400 million alveoli, where gas exchange takes place. The total alveoli surface area is approximately 75m2, which is penetrated by approximately 200 km of capillary blood vessels (Hatch 

Pulmonary dynamics, the dimension and geometry of the respiratory tract and the structure of the lungs, together with the solubility and chemical reactivity of the inhalants greatly influence the magnitude of penetration, retention, and absorption of inhaled gases, vapors (Dahl, 1990), and aerosols (Raabe, 1982 Phalen, 1984). The quantity of an inhalant effectively retained in the pulmonary system constitutes the inhaled dose that causes pharmacotoxic responses. 

FIGURE 10.1. The distribution of cell types in the respiratory tract and lungs. 

In mouth breathing, only 10-15% of 15 pm particles penetrate through the larynx to the intrathoracic TB region. Particles reaching the TB region are considered to be inhalable (Lippmann, 1977 Miller et al., 1979). 

In general, particles of AD 10 pm deposit mainly in the URT, whereas particles of 1 to 5 pm AD, with a GSD of less than 2, are likely to reach the lower respiratory tract, which includes the TB region and the alveoli, with small oropharyngeal loss. 

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Paracelsus stated over 400 years ago that All substances are poison. The right dose differentiates a poison and a remedy. Thus, in safety assessments of inhaled drugs, the dose, or magnitude of inhalation exposure, in relation to the physiological,... 

Finally, comparisons of various techniques for animal exposures indicate that the whole-body exposure technique is the most suitable for safety assessment of gases and vapors and permits simultaneous exposure of a large number of animals to the same concentration of a chug however, this technique is not suitable for aerosol and powder exposures because the exposure condition represents the resultant effects from inhalation, ingestion, and dermal absorption of the drug (Phalen, 1984 Gad and Chengelis, 1998). 

Devices used for delivery of the drug (such as inhalers) are another area requiring an integrated clinical and pharmaceutical assessment for their performance, ease of use, and implications for safety and efficacy. 

Leachables in orally inhaled and nasal drug products (OINDP) are compounds which are present in the drug product due to leaching from container closure system components. Extractables are compounds that can be extracted from OINDP device components, or surfaces of the OINDP container closure system when in presence of an appropriate solvent(s) and/or condition(s). Leachables are often a subset of, or are derived directly or indirectly from, extractables. Extractables may, therefore, be considered as potential leachables in OINDPs. Some leachables may affect product quality and/or present potential safety risks, therefore regulatory guidance has provided some recommendations regarding the analysis and toxicological safety assessment (i.e., qualification) of such compounds. 

Virtually all other models used to assure the safety of ingested or inhaled substances are variations of the food and drug safety models (described below) the nutrients model based on dose-response relationships the in-market monitoring and surveillance model the novel foods and food additives models, based on a reasonable certainty of no harm and the drug model, based on risk-benefits assessments. 

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