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In the present study, the salbutamol sulfate-loaded sodium alginate-pectin (SS-loaded SA-PEC) bubble beads have been optimized and evaluated for drug loading, in vitro drug release, in vivo floating behavior in the stomach, etc. Nine batches (F1–F9) of bubble beads with different SA and PEC contents were prepared by novel co-axial needle air-injection method and related to their percent drug loading efficiency (%DLE) and percent drug release at 4 h (%R4h) as response factors. The multivariate analysis has shown the effect of SA/PEC ratio, total polymer content, as well as their interaction on %DLE and %R4h. In the quantitative modeling, the satisfactory adjustment of the linear models (along with interaction terms) with the experimental data for both %DLE and %R4h has confirmed the findings of the multivariate analysis. The optimized SS-loaded SA-PEC bubble beads based on 2D (contours), 3D, desirability, and overlay plots has exhibited %DLE of 87.35 ± 2.48% (n = 3 and error = 2.94%) and %R4h of 85.79 ± 2.98% (n = 3 and error = 0.25%). The in vitro drug release studies have shown almost complete (≥85%) SS release from all the batches within 4–6 h in simulated gastric fluid (SGF) pH 1.2. The in vivo clinical findings by ultrasound studies have shown excellent floatation (>6 h) behavior of bubble beads in the upper gastrointestinal tract (GIT) and efficient stomach-specific gastroretention.