Orodispersible films of Ledipasvir and Sofosbuvir Combination: Formulation optimization and development using Design of Experiments

Abstract

Ledipasvir (LDV) and sofosbuvir (SBV) are poorly soluble drugs and hence dissolution limited bioavailability is a major concern. Further, the high total dose of this combination (LDV-90mg and SBV-400mg) may cause swallowing difficulties if formulated into tablets. Considering these challenges, it was aimed in the current research work to develop orodispersible films (ODFs) for this combination to enhance dissolution thereby bioavailability and also patient convenience. ODFs, because of their ready dispersibility in the oral cavity dissolution would be rapid and also high doses of drugs can be incorporated avoiding swallowing difficulties. HPMC E15 was taken as the film former. Thickness of the films (50µm – 150µm), concentration of superdisintegrant (sodium starch glycolate 6-12% w/w) and concentration of plasticizer (polyethylene glycol 400, 10-20% w/w) were taken as three formulation factors each at three levels. Using Design Expert software, Box-Behnken design under response surface methodology was selected as the experimental design. Disintegration time (DT), time for 90% dissolution of LDV (LDV-T90%) and time for 90% dissolution of SBV (SBV-T90%) of the ODFs were taken as response. The films were developed using solvent casting method. The obtained films were subjected for various quality characteristic studies like differential scanning calorimetry, X-ray diffraction, tensile strength, % elongation, folding endurance, disintegration time, drug content uniformity and dissolution studies. All the formulations were found to have favorable tensile strength, % elongation and folding endurance. The DT values were found to be in the range of 37 – 139 sec.; the values of LDV-T90% and SBV-T90% were found to be in the range of 7.1 – 20.7 min. and 6.8 – 15.6 min. respectively. The results of these three responses were subjected to ANOVA studies and found that all the three formulation factors were having significant effect. The results of optimization by desirability functions approach indicated the ODFs with thickness 50µm, disintegrant at 12% w/w and plasticizer at 17.46%w/w as the optimized formulation. The ODFs prepared at this combination showed DT of 45 sec, LDV-T90% of 7.51 min. and SBV-T90% of 6.23 min. these results indicated that ODFs for LDV and SBV were successfully optimized and developed.