QbD-optimized Trimethyl Chitosan-coated nanoparticles achieve 87% mucoadhesion for oral insulin delivery

Current insulin therapy relies on subcutaneous injections, posing compliance challenges and discomfort for patients with diabetes. Oral administration would significantly improve patient quality of life and adherence. However, the gastrointestinal tract presents formidable barriers to peptide absorption, including enzymatic degradation and poor permeability. Developing robust, mucoadhesive nanocarriers is crucial to protect insulin and facilitate its uptake across the intestinal mucosa, overcoming these physiological hurdles for effective oral delivery.

Researchers employed a Quality-by-Design (QbD) strategy to optimize mucoadhesive nanoparticles for oral insulin delivery. A two-level factorial design first screened ADS concentration, TMC concentration, insulin concentration, and poloxamer® concentration for their impact on particle size and encapsulation efficiency. Subsequently, a three-factor, three-level Box-Behnken design optimized ADS concentration, TMC concentration, and the degree of quaternization (DQ) of TMC. Critical quality attributes measured were particle size, zeta potential, and in vitro mucoadhesion. Insulin release profiles were assessed in simulated gastric and intestinal media.

The initial screening design identified the ADS-TMC pair as the primary determinant for particle size, while TMC and poloxamer® significantly influenced encapsulation efficiency. Across the Box-Behnken design, experimental formulations exhibited particle sizes ranging from 316 to 1340 nm, zeta potentials between +17 and +39 mV, and mucin-binding values from 7 to 87%.

Numerical optimization pinpointed an optimal formulation of 0.096% (w/v) ADS and 0.700% (w/v) TMC with 60% DQ, predicting a particle size of 316.24 nm, zeta potential of +38.43 mV, and in vitro mucoadhesion of 87.14%. Experimental confirmation closely matched these predictions, yielding values of 330.79 nm, +37.09 mV, and 84.61%, respectively, with prediction errors consistently below 5% for all responses. In simulated gastric medium, partial insulin leakage was observed during the initial 120 min, while cumulative insulin release reached 54% after 5 h in simulated intestinal medium.