Formulation development and in vitro-in vivo assessment of protransfersomal gel of anti-resorptive drug in osteoporosis treatment.

ABSTRACT

Osteoporosis is a major cause of morbidity, mortality, and economic burden worldwide. Despite being an effective in combating the bone-deteriorating disorders, bisphosphonates have several shortcomings including poor and variable bioavailability, low permeability, high toxicity, etc. In this study, we developed and optimized protransfersome formulation for the drug risedronate sodium (RIS-Na) with the goal of enhancing its bioavailability and hence patient compliance. Phase separation coacervation technique was utilized for development of optimized formulation. Optimization was achieved by using three-factor, three-level Box-Behnken design combined with Response Surface Methodology (RSM). This enabled us to decipher the effect of 3 independent variables (Phospholipid, Tween-80 and Sodium Deoxycholate) on three dependent parameters (entrapment efficiency, vesicle size and transdermal flux). Optimized formulation was further evaluated for pharmacokinetic and pharmacodynamic parameters. Smooth, spherical protransfersomes with a size of 260 ± 18 nm, having entrapment efficiency and flux of 80.4 ± 4.90% and 8.41 ± 0.148 µg/cm2/h, respectively were prepared. Ex vivo studies revealed a shorter lag time of 1.21 ± 0.18 h and higher flux associated with transdermal formulation. CLSM analysis further revealed better drug penetration (220 µm) through the skin in case of protransfersomes as compared to drug solution (72 µm). Additionally, biomechanical, biochemical, and histo-pathological studies further validated the results. Thus, it was concluded that protransfersome formulation has a great potential in providing better therapeutic efficacy of risedronate than its conventional counterpart.