There are important advantages of making and using microparticles and nanoparticles in pulmonary and nasal delivery of vaccines and pharmaceuticals, but the challenges of forming and preserving active powders that can be readily dispersed into aerosols with large respirable fractions and effectively delivered are significant. Respirable dry powder aerosol products are under development in several organizations for treatment of infectious diseases (vaccines, antibodies, anti-virals and antibiotics), diabetes (insulin), inflammatory diseases (anti-asthma), smoking addiction, etc. A case study will be discussed in which CO₂-Assisted Nebulization with a Bubble Dryer^® (CAN-BD) has been used as an effective alternative to freeze-drying or conventional spray-drying. Edmonston-Zagreb live attenuated measles vaccine suspensions manufactured by Serum Institute of India Ltd. were reformulated with several sugars, amino acids, buffers, surfactants, and other stabilizers and bulking agents to determine whether respirable dry powders could be made by CAN-BD with adequate retention of viral activity under various storage conditions. More than 75 distinct formulations in >200 CAN-BD experiments were performed and the powders characterized. The drying temperature was kept at 50 ºC in most experiments. Of the sugar stabilizers tested, myo-inositol proved to be the most effective substitute for sorbitol, which is presently used in the lyophilized measles vaccine injected subcutaneously as a reconstituted aqueous suspension. For aerosol mucosal delivery, it was necessary to remove sorbitol because its presence degraded the dispersibility of the microparticles, which need to be in the 1-5 microns aerodynamic diameter range to be delivered to the lungs. Sorbitol has a very low glass transition temperature and is highly hygroscopic. Myo-inositol was examined as an alternative sugar stabilizer because it is not itself hygroscopic. While considered a GRAS substance, myo-inositol has not yet been used in approved inhalable pharmaceuticals; therefore, its suitability and safety for pulmonary delivery are first being examined in animals.

Microparticulate powders can usually be dried by CAN-BD to contain less than 2% moisture, and in some instances, contain as little as 0.5% H₂O moisture when sealed in aluminum blister packs. Before the microparticles are dispersed using active dry powder inhalers such as the PuffHaler^TM, they may be loosely aggregated, but they must be easily dissociated with a pulse of air from, for example, a pressure release valve. In the case of live virus measles vaccine, the fine particles were delivered to coat moist mucosal surfaces in the alveoli where reconstitution and replication occurred in rodent models.

(Funded by FNIH Grant 1077.)