Lyophilization for sublingual tablets
A premixture of aqueous base matrix formulation containing mannitol (structure former) and fish gelatine (matrix former) at pH 7.4 was prepared. Trehalose was then added and mixed, followed by the addition of the liquid virosome formulation. This virosome matrix mixture was kept at 10–15?°C and dosed by weight (predetermined aliquots of 50 and 500?mg dosing fill weight) into preformed aluminum blister pockets. Once dosed, the aliquots were frozen at <-60?°C and then annealed at <-15?°C for <9?h. The frozen units were then freeze-dried using a two-step freeze-drying cycle (<-20?°C for <28?h followed by <15?°C for <22?h). The manufacturing conditions were optimized to preserve sufficient virosomes during subsequent freezing and freeze-drying with the required particle characteristics and maintaining the vaccine bioactivity. Prior dosing, the non-GMP and GMP liquid mixture of virosomes-base matrix solution contained 10?µg/mL HA, 30?µg/mL P1, 17?µg/mL rgp41, 10?µg/mL 3M-052, in HN buffer pH 7.4. After water sublimation during the freeze-drying step, the 50?mg (about 50?µL equivalence) or 500?mg (about 500?µL equivalence) dosed aliquots gave approximately 8 and 80?mg of lyophilized sublingual tablets respectively, of which an estimated amount of 3% of the lyophilized tablet was the virosome formulation content (expressed as dry matter). Sublingual tablets were evaluated by industrial analytical methods and standards in place at Catalent (Supplementary Tables 1 and 2) such as physical appearance, disintegration time, or endotoxin content. Non-GMP batch sizes were the equivalence of 100–500 vaccine doses and for GMP batch the equivalence of 2000 doses (enough for a Phase I trial).
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