Assaying therapeutic agents requires the availability of apparatus to dose experimental animals as well as to measure biological effect. Available dosing systems for inhalation agents are suboptimal generally causing stress to the animal as well as exposing the operator to potentially harmful agents. Texas based researchers have developed apparatus that allows mice to be dosed with reproducible levels of test substance under medium-throughput and low stress conditions. The system can be used to assay efficacy of airway therapeutics (including small molecules and gene therapies) and agents designed for airway delivery. This dosing chamber system can also be used to safely evaluate the respiratory tract toxicology of test substances

The respiratory market is one of the largest therapeutic categories. This market generated $28bn in 2003 representing a +7% increase on the preceding year. The largest proportion of global respiratory sales was derived from the sale of asthma and chronic obstructive pulmonary disease (COPD) products. In the short-term the lack of effective oral therapies in the pipeline for these diseases means that inhalation will remain the primary mode of delivery (see Asthma, COPD and Allergic Rhinitis - Weak Late Stage Pipeline Leaves Innovation to Phase I/II Candidates).

While inhalation therapies represent the cornerstone of respiratory tract therapeutics, the airway is becoming a rapid route of delivery for therapeutic agents being developed for a wide variety of other diseases. Perhaps the most well recognized example is diabetes. Insulin occupies a key position in the treatment of diabetes and accounts for around 30% of sales in the diabetes arena. The largest unmet need in the diabetes market is improved delivery of insulin (see Insulin Use in Type 2 Diabetes - From Last Resort to Early Intervention). Currently, the predominant mode of insulin administration is subcutaneous injection, which is extremely unpopular among patients and consequently much effort is being placed on identifying new insulin delivery technologies, with inhaled formulations representing one strategy under development. Although phase III studies of one inhaled insulin, Exubera, were completed in July 2001, further studies were initiated due to changes in FDA guidelines governing inhaled therapeutics. After a considerable wait, Pfizer and Sanofi-Aventis announced March, 2005 that the FDA has accepted for filing a new drug application for Exubera.

Experts in the pharmaceutical industry, as well as some at the FDA, have identified inadequate animal models as being one of the major hurdles in drug discovery and development (see Model Animal Systems: Emerging Applications and Commercial Opportunities in Drug Discovery and Development). The mouse is considered a good model for inhalation studies as the optimal particle size for deep lung exposure is similar in mice and humans. Although considerable effort is placed on improving disease models, delivery systems remain suboptimal as they are generally stressful for the animal. This is a particular problem for asthma research and development given the role that stress plays in the context of airway function.

To address the problem of inhalation dosing Jason McConville from the University of Texas at Austin, and colleagues have developed a whole-body exposure system that allows 14 animals to be treated simultaneously in a single sealed chamber (to minimize operator exposure) and under low stress conditions. Each chamber is fitter with an inlet and outlet port to form a closed system; a circulation fan coupled to a nebulizer allows the distribution of test substances within the system. This methodology was validated using nebulized caffeine (dispersed in glycerol) as a test solution. Analysis of caffeine concentrations within the chamber revealed a remarkably consistent distribution of test substance.

This system offers significant improvements over existing apparatus used to evaluate the therapeutic or toxicological effect of test substances. The substance could conceivable include small molecules or biological agents. The latter could extend to viruses or viral vectors facilitating the study of harmful pathogens or gene therapeutics. Since the apparatus is a closed system it also represents a particularly safe means of investigating pathogens.


Entry date Tuesday, March 29, 2005

Drug Dev Ind Pharm. 2005 Jan;31(1):35-42.