Objective: Adequate glycemic control in diabetes patients requires oral combination therapy.
Saxagliptin is a dipeptidyl peptidase-4 inhibitor having fewer adverse effects, and metformin
is the first-line medicine for diabetes treatment. The aim of this research work is to develop a bilayer
tablet of saxagliptin and metformin in fixed-dose combination (FDC) using quality by design
(QbD) to acquire the immediate release of saxagliptin and sustained release of metformin from bilayer
tablet to ultimately achieve superior patient compliance.
Methods: The development of the bilayer tablet was done in four stages using QbD. In the first
step, quality target product profile (QTPP) of bilayer tablet was defined, and critical quality attributes
(CQAs) were identified by risk estimation matrix and taguchi design; an immediate release
saxagliptin layer was optimized in the second step, optimization of sustained-release metformin layer
was carried out in the third step, and in the final step, bilayer tablet was prepared and characterized.
The effect of independent parameters, i.e., magnesium stearate level (X1), kneading time (X2)
and lubrication time (X3) on Carr’s Index (Y1), percentage relative standard deviation of content
uniformity (Y2) and drug release at 30 minutes (Y3), were estimated for optimization of immediate
release saxagliptin layer using Box-Behnken design (BBD). The effect of independent parameters,
i.e., hydroxypropyl methylcellulose level (X4), compritol level (X5) and magnesium stearate level
(X6) on Carr’s Index (Y4), drug release at 2 h (Y5), drug release at 5 h (Y6) and drug release at 10 h
(Y7) were estimated for optimization of sustained-release metformin layer using BBD.
Results: The optimized composition of immediate release saxagliptin layer estimated using numerical
optimization by Design expert was 0.88% (X1), 15 minutes (X2) and 3.85 minutes (X3) with predicted
variables, i.e., 10.59% (Y1), 3.16% (Y2) and 85% (Y3). The optimized composition of sustained-
release saxagliptin layer predicted through numerical optimization was 30% (X4), 3.36%
(X5) and 0.9% (X6) having 10.89% (Y4), 43.44% (Y5), 60% (Y6) and 85.14% (Y7). In-vitro dissolution
study of bilayer tablet showed immediate release of Saxagliptin (approximately 85% in 30 minutes)
and sustained release of metformin illustrating 43.21±1.21, 60.86±2.96 and 86.26±1.38%
drug release at 2, 5 and 10 h, respectively. The release exponent for the Korsmeyer-Peppas model
for Saxagliptin and metformin was 0.237 (<0.45) and 1.536 (n>0.85), indicating Fickian and super
case II transport drug release behavior, respectively.
Conclusion: By QbD approach, bilayer tablet containing saxagliptin and metformin was successfully
developed, and influence of various formulation parameters on CQAs of drug products was understood
with fewer experiments. This leads to the conclusion that cost can be reduced using QbD
in the development of FDC for improving patient compliance.