ABSTRACT
Gases and Vapors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 7.3 Pulmonary Delivery of Inhaled Aerosols . . . . . . . . . . . . . . . . . 236 7.4 Absorption and Clearance of Inhaled Aerosols . . . . . . . . . . . . 238 7.5 Pharmacotoxicity of Inhaled Aerosols,
Gases, and Vapors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 7.6 Nasal Delivery of Therapeutics . . . . . . . . . . . . . . . . . . . . . . . . 241
7.6.1 Nose-to-Brain Delivery . . . . . . . . . . . . . . . . . . . . . . . . 245 7.6.2 Advantage of Formulations . . . . . . . . . . . . . . . . . . . . . 247
7.7 Excipients Used in Formulation. . . . . . . . . . . . . . . . . . . . . . . . 248 7.7.1 Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 7.7.2 Bile Salts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 7.7.3 Cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 7.7.4 Mixed Micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 7.7.5 Formulation and Potential Mucosal Damage . . . . . . . . 250 7.7.6 Methods to Assess Irritancy and Damage. . . . . . . . . . . 251 7.7.7 Reported Nasal Irritancies Include . . . . . . . . . . . . . . . . 251
7.8 Delivery Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 7.8.1 Liquid Nasal Formulation . . . . . . . . . . . . . . . . . . . . . . 252 7.8.2 Instillation and Rhinyle Catheter . . . . . . . . . . . . . . . . . 252 7.8.3 Drops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 7.8.4 Powder Dosage Forms . . . . . . . . . . . . . . . . . . . . . . . . 253 7.8.5 Insufflators and Monodose Powder Inhaler . . . . . . . . . 253 7.8.6 Pressurized MDIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 7.8.7 Nasal Gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 7.8.8 Patented Nasal Formulations . . . . . . . . . . . . . . . . . . . . 254
7.9 Methods for Safety Assessment of Inhaled Therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
7.10 Parameters of Toxicity Evaluation . . . . . . . . . . . . . . . . . . . . . . 258 7.10.1 The Inhaled Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258 7.10.2 The Dose-Response Relationship . . . . . . . . . . . . . . . . 261 7.10.3 Exposure Concentration vs. Response . . . . . . . . . . . . . 262 7.10.4 Product of Concentration and Duration
(
Ct
) vs. Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . 262 7.10.5 Units for Exposure Concentration . . . . . . . . . . . . . . . . 263
7.11 Respiratory Safety Pharmacology . . . . . . . . . . . . . . . . . . . . . . . 265 7.11.1 Plethysomography. . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 7.11.2 Design of Respiratory Function Safety Studies . . . . . . . 274 7.11.3 Capnography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
7.12 Inhalation Exposure Techniques for Therapeutic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
7.13 Regulatory Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 7.14 Utility of Toxicity Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 Glossary of Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
Drugs and medicinal agents administered by the inhalation route include gaseous and vaporous anesthetics, coronary vasodilators, aerosols of bronchodilators, corticosteroids, mucolytics, expectorants, antibiotics, and an increasing number of peptides and proteins, in all of which there is significant nasal absorption (Cox et al. 1970; Williams 1974; Paterson et al. 1979; Hodson et al. 1981; Lourenco and Cotromanes 1982). Concerns with the environmental effects of chlorofluorocarbons has also led to renewed interest in dry powder inhalers (DPIs), which have additionally shown promise for better tolerance and absorption of some new drugs. Recent advances have also led to new nasal delivery systems, such as those in Table 7.1. Excessive inhalation of a drug into the pulmonary system during
therapy or manufacturing may result in adverse local and systemic effects, or both. Consequently, safety assessment of medicinal preparations delivered via respiratory routes with respect to local tissue toxicity, systemic toxicity, and the therapeutic-to-toxicity ratio is essential. The data generated is essential for charting the course of evaluation and development of a potential therapeutic agent, the general course of which is summarized in Figure 7.1.
