Self-double Emulsified Drug Delivery System of Pyridostigmine Bromide Augmented Permeation Across Caco-2 Cells

Abstract

Aim: The study aims to enhance the permeability of pyridostigmine bromide by developing a self-double emulsifying drug delivery system (SDEDDS) and enteric-coated spheroids. Background: Pyridostigmine bromide is a reversible anticholinesterase used to treat Myasthenia Gravis, reverse neuromuscular blockade, and prevent nerve gas (i.e., soman) poisoning. It is readily soluble in water, but its poor and irregular intestinal absorption is responsible for its poor oral bioavailability (7.6±2.4%). Many approaches have been made to increase the bioavailability of this drug, but no significant improvement has been achieved to date. Presently pyridostigmine tablets are given orally, and a treatment schedule of multiple doses every day (3–6 times per day) is recommended for adult patients, while sustained-release pyridostigmine (Timespan®) tablets can be taken once or twice daily. An increase in permeability of pyridostigmine bromide may also result in reduced dosage frequency. Objective: In the present work, it is proposed to develop a self-double emulsifying drug delivery system (SDEDDS) of pyridostigmine bromide which will increase its intestinal permeability and hence its oral bioavailability. Methods: For the preparation of PB-SDEDDS, the primary water in oil emulsion was mixed with the optimized concentration of Tween 80 using a magnetic stirrer. PB-SDEDDS were converted into spheroids and were then characterized. Results: The pseudo ternary phase diagram was constructed, showing a double emulsion region. The viscosity of PB-SDEDDS at the different shear rates was found to be 125 mPas. The optimized PBSDEDDS formulation formed a bright white emulsion within 2 minutes, having droplet size around 20-25 μm. In vitro uptake studies of PB-SDEDDS on Caco2 cells demonstrated the increase in Papp value from (4.38±0.27) ×10-4 cm/s to (9.488±0.182) ×10-4 cm/s (2.166 folds) that was attributed to the PB-SDEDDS formulation. In vitro cytotoxicity studies on Caco2 cells revealed that the blank SDEDDS showed almost no toxicity after incubation for 2 hours at various dilutions tested. Among all formulations, F3 was optimized for the concentration of adsorbent and binder at a concentration of 10% each. SEM showed that the spheroids were spherical, and 73.92% of spheroids were in between 0.595-0.841 mm of size. The optimized formulation had 70.29% spheroids retained on sieve no. 30. The angle of repose showed good flow properties with 25.20 and stability with friability of 0.52 %. The disintegration time of the developed formulation was 3.30 minutes, and drug content was found to be 97.83%. The release studies showed that PB-SDEDDS improved the release significantly compared to the market formulation. Conclusion: The solid PB-SDEDDS resulted in favorable physical properties and did not affect its drug content and in vitro drug release profile. The self-double emulsifying drug delivery system of pyridostigmine bromide can be explored as a suitable alternative to its solid oral dosage form.