Stabilizing formulations for inhalable powders of live-attenuated measles virus vaccine.
Carbon dioxide Assisted Nebulization with a Bubble Dryer((R)) (CAN-BD) processing allows particles to be made in the 3-5 mum size range, which is desirable for lung delivery, without destroying biological activity. In response to the Grand Challenge in Global Health Initiative #3, we have been developing an inhalable needle-free live-attenuated measles virus vaccine for use in developing countries. Measles was chosen because it is the number one vaccine preventable killer of children worldwide. Powders were processed by CAN-BD, where a solution containing excipients and live-attenuated measles virus in water was mixed intimately with supercritical or near superctitical carbon dioxide to form an emulsion. The emulsion was expanded to atmospheric pressure through a flow restrictor. The resulting plume was dried by heated nitrogen and the powders collected on a filter at the bottom of the drying chamber. Powders were analyzed using varying techniques including X-ray diffraction, scanning electron microscopy, Andersen cascade impaction, differential scanning calorimetery, Karl Fischer titration, and viral plaque assay. CAN-BD has been used to produce powders of live-attenuated measles virus vaccine with characteristics desirable for lung delivery. The powders retain viral activity through forming and drying the microparticles by CAN-BD, and have passed the WHO stability test for 1 week at 37 degrees C. The powders have an amorphous character and a glass transition temperature of around 60 degrees C. Lyophilization, the present standard commercial method of processing measles vaccine makes solids with a water content of less than 1%. By substituting myo-inositol for sorbitol and using the CAN-BD drying technique the water content can be lowered to 0.5%. The most successful formulations to date have been based conceptually on the current lyophilized formulation, but with modifications to the type and amounts of sugar. Of current interest are formulations containing myo-inositol, as they retain high viral activity and have low initial water content.
Center for Pharmaceutical Biotechnology, Department of Chemistry and Biochemistry, and CIRES, University of Colorado, Boulder, Colorado.
Jessica L
JL
Burger
Stephen P
SP
Cape
Chad S
CS
Braun
David H
DH
McAdams
Jessica A
JA
Best
Pradnya
P
Bhagwat
Pankaj
P
Pathak
Lia G
LG
Rebits
Robert E
RE
Sievers
D000280:Administration, Inhalation; D002626:Chemistry, Pharmaceutical; D002648:Child; D003906:Developing Countries; D004355:Drug Stability; D004356:Drug Storage; D005079:Excipients / Q000737:chemistry*; D005612:Freeze Drying; D006801:Humans; D008458:Measles Vaccine / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D009330:Nebulizers and Vaporizers; D011208:Powders; D013678:Technology, Pharmaceutical / Q000379:methods*; D014018:Tissue Distribution; D014613:Vaccines, Attenuated
D005079:Excipients; D008458:Measles Vaccine; D011208:Powders; D014613:Vaccines, Attenuated