Stabilization of live attenuated measles virus vaccine in glassy matrices

Inhalable drug delivery is a growing field of medical research. Two areas where respirable drug delivery appear promising are measles vaccination and cystic fibrosis management. Some vaccines are uniquely suitable for delivery to the respiratory system as it is the natural infectious pathway of the pathogen. Delivery to the lungs is attractive; however, there are some practical challenges. Dry powder particles need to be less than 5 μm in aerodynamic diameter to reach the deep lung. Therefore, any formulation must not only protect the active material from degradation but must also yield a powder with properties appropriate for respirable delivery. Carbon Dioxide-Assisted Nebulization with a Bubble Dryer® (CAN-BD) processing allows particles to be made in the appropriate size range without destroying biological activity, if the proper formulation is chosen.;During early formulation work the idea was to build a formulation from the ground up. However the de novo approach did not yield promising results fast enough for the project plan. So the focus shifted to modifying the formulation used by the Serum Institute of India for their commercial lyophilized measles vaccine. Various sugars and sugar ratios, amino acids, buffers, and other excipients were examined in relationship to the lyophilization formulation. The best formulations is based on 50 g/L myo-inositol and using this formulation the vaccine maintains a level of viral activity through CAN-BD similar that seen after processing by lyophilization, passes the WHO’s accelerated stability test by losing less than one log CCID50 after storage for 1 week at 37°C and evoked a significant immune response in cotton rats and Rhesus macaques. Also 1 week storage at 37°C did not detectably decrease the fine particle fraction if the powder was sufficiently protected from moisture ingress.;Another benefit to the myo-inositol formulations are that they are less hygroscopic maintaining better physical properties when handling in the lab environment. Another area in which inhalable pharmaceuticals are useful is in the management of Cystic Fibrosis (CF). CF purulent sputum differs from normal healthy mucus in several ways. One difference is that it contains high concentrations of extracellular DNA. It was proposed that biologically active polycations, such as protamine, spermine, and poly-L-lysine, might be useful in CF management by collapsing the DNA in the sputum. This would make the sputum less viscous and easier to expel. Aqueous DNA solutions were used as model sputum. Once the DNA solutions were characterized, the polycations spermine and poly-L-lysine were added to the DNA solutions to test the resulting mixtures for viscosity changes. Because the temperature dependence of viscosity is as important as the viscosity itself, the viscosity of the DNA solutions was measured at 25.00°C, 37.78°C, and 50.00°C. The most significant measured result was an increase in viscosity between 37.78°C and 50.00°C instead of the exponential decrease if kinetic theory were applicable. To characterize the observed phenomenon of increasing viscosity, the measurements of the DNA solutions were expanded to a range from 10°C to 90°C. Our measurements beyond 50°C revealed an even stronger increase of the viscosity with a maxima in the range 55°C to 65°C followed by a lengthy decrease. It should be noted that the viscosity increase in the 6 mg/ml sample was over 300%.