Diphtheria toxoid-containing microparticulate powder formulations for pulmonary vaccination: preparation, characterization and evaluation in guinea pigs.
In this study, the potential of N-Trimethyl chitosan (TMC, degree of quaternization 50%) and dextran microparticles for pulmonary delivery of diphtheria toxoid (DT) was investigated. The antigen-containing microparticles were prepared by drying of an aqueous solution of polymer and DT through a supercritical fluid (SCF) spraying process. The median volume diameter of the dry particles, as determined by laser diffraction analysis, was between 2 and 3 microm and the fine particle mass fractions smaller than 5 microm, as determined by cascade impactor analysis, were 35 and 56% for the dextran and TMC formulations, respectively. The water content of the particles as measured by Karl-Fischer titration was 2-3% (w/w). Pulmonary immunization with DT-TMC microparticles containing 2 or 10 Lf of DT resulted in a strong immunological response as reflected by the induction of IgM, IgG, IgG subclasses (IgG1 and IgG2) antibodies as well as neutralizing antibody titers comparable to or significantly higher than those achieved after subcutaneous (SC) administration of alum-adsorbed DT (2 Lf). Moreover, the IgG2/IgG1 ratio after pulmonary immunization with DT-TMC microparticles was substantially higher as compared to SC administered alum-adsorbed DT. In contrast, pulmonarily administered DT-dextran particles were poorly immunogenic. Among the tested formulations only pulmonarily administered DT-containing TMC microparticles induced detectable pulmonary secretory IgA levels. In conclusion, in this paper it is demonstrated that TMC microparticles are a potent new delivery system for pulmonary administered DT antigen.
Amidi
Maryam
M
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands.
Pellikaan
Hubert C
HC
Hirschberg
Hoang
H
de Boer
Anne H
AH
Crommelin
Daan J A
DJ
Hennink
Wim E
WE
Kersten
Gideon
G
Jiskoot
Wim
W
D000818:Animals; D048271:Chitosan; D004168:Diphtheria Toxoid / Q000276:immunology*; D015721:Diphtheria-Tetanus-Pertussis Vaccine / Q000276:immunology; D005260:Female; D006168:Guinea Pigs; D007136:Immunoglobulins / Q000097:blood / Q000276:immunology; D008168:Lung / Q000276:immunology*; D008297:Male; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles / Q000648:ultrastructure; D010316:Particle Size; D011208:Powders; D014611:Vaccination
D004168:Diphtheria Toxoid; D015721:Diphtheria-Tetanus-Pertussis Vaccine; D007136:Immunoglobulins; C118071:N-trimethyl chitosan chloride; D011208:Powders; D048271:Chitosan