Development, optimization and in-vivo evaluation of cyanocobalamin loaded orodispersible films using hot-melt extrusion technology: A quality by design (QbD) approach

Abstract

Vitamin B12 deficiency is associated with high risks of cognitive decline, neuropathy, megaloblastic anaemia and depression. Therefore, there is a need to develop an innovative formulation of vitamin B12 to restore optimal serum vitamin B12 levels (200–900 pg/mL), particularly in dysphagia patients. The present investigation deals with developing novel cyanocobalamin-loaded orodispersible films (ODFs) using Soluplus® as a film-forming polymer by hot-melt extrusion technology and application of Box-Behnken statistical design for formulation and process optimization. The amount of Soluplus®, glycerine and menthol were the critical formulation variables influencing critical quality attributes of films such as tensile strength, disintegration time, dissolution and permeation rate. Satisfactory results were obtained from melt-extruded films when subjected to physicochemical characterization tests. All melt-extruded films exhibited immediate disintegration and complete dissolution within 10 min. Ex-vivo permeation studies disclosed better permeation of cyanocobalamin from melt-extruded films as compared to plain drug solution. SEM and AFM analysis showed the uniform distribution of cyanocobalamin throughout the surface of the optimized film. Raman spectroscopy confirmed the stability of cyanocobalamin after HME processing. A rabbit animal model was employed to determine the pharmacokinetics of ODFs and marketed Quicobal® film using LC-MS/MS bioanalytical method. The in-vivo bioavailability of cyanocobalamin from optimized ODFs and marketed product showed similar plasma concentration-time profiles. The stability studies showed no appreciable physicochemical change up to six months. In conclusion, the ODFs of cyanocobalamin could be a better alternative formulation strategy for achieving rapid oral bioavailability in cobalamin deficiency.