Development of a self-nanoemulsifying system for oral administration for pain treatment, optimized through quality by design

ARRIGONI RODRIGUEZ, KA; LUCIANI GIACOBBE, LC; OLIVERA ME

Congreso; Reunión Anual de Sociedades de Biociencias 2023. LV Reunión Anual de la Asociación Argentina de Farmacología Experimental; 2023

A novel oral pharmaceutical composition of morphine (MOR) and omega-3 fatty acids (O3) generated a synergistic effect and reduced adverse events associated with MOR in a murine model (patent P-20120100854). Considering that a self-nanoemulsifying drug delivery system (SNEDDS) could enhance the oral absorption of O3, this study aimed to optimize the composition of MOR-O3-loaded SNEDDS, emphasizing the enhancement of the oily phase loading capacity. The limits of each component in the blank SNEDDS were explored using presudo-ternary phase diagrams. Optimization was carried out using a D-Optimal design, with ethanol, propylene glycol (Pg), kolliphor (K), and the oily phase (krill oil, AK) as independent variables. Key responses measured were the polydispersity index (PDI) and the average droplet size (nm). Mathematical models were used to establish correlations between variables and responses, and a desirability function was applied to determine the optimal formulation (PDI ≤ 0.2 and smaller size). Post-optimization, component limits were adjusted for MOR-O3 loaded SNEDDS. A similar approach assessed component influence on these SNEDD. Independent variables included Pg, K, and the oily phase: AK + MOR-O3. The predictive capability of the design space (DE) was confirmed with two independent optimized formulations, comparing obtained and predicted responses. Both PDI and droplet size of blank SNEDDS and MOR-O3-loaded SNEDDS conformed to significant mathematical models, defining DEs. The most desirable blank SNEDDS formulation contained 28% Pg, 50% K, and 22% AK. The optimized MOR-O3-loaded SNEDDS formulation was composed of 33% Pg, 45% K, and 22% oily phase. This transparent, low-flow formulation achieved a droplet size of (15 ± 8) nm and PDI of 0.17 ± 0.05. Also, it maintained the loading capacity of the oily phase of the blank SNEDDS and MOR dose used in preclinical studies. In conclusion, this study offers a robust and predictive approach for developing MOR-O3 loaded SNEDDS suitable for future pain treatment applications.