Nanosized sustained-release pyridostigmine bromide microcapsules: process optimization and evaluation of characteristics

Qunyou Tan,^1,* Rong Jiang,^3,* Meiling Xu,^2,4,* Guodong Liu,^5,* Songlin Li,¹ Jingqing Zhang<sup>2

1</sup>Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, ²Medicine Engineering Research Center, Chongqing Medical University, ³Stem Cells and Tissue Engineering Research, Chongqing Medical University, ⁴Department of Pharmacy, Chongqing Emergency Medical Center, ⁵Eighth Department, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China

^*These authors contributed equally to this work

Background: Pyridostigmine bromide (3-[[(dimethylamino)-carbonyl]oxy]-1-methylpyridinium bromide), a reversible inhibitor of cholinesterase, is given orally in tablet form, and a treatment schedule of multiple daily doses is recommended for adult patients. Nanotechnology was used in this study to develop an alternative sustained-release delivery system for pyridostigmine, a synthetic drug with high solubility and poor oral bioavailability, hence a Class III drug according to the Biopharmaceutics Classification System. Novel nanosized pyridostigmine-poly(lactic acid) microcapsules (PPNMCs) were expected to have a longer duration of action than free pyridostigmine and previously reported sustained-release formulations of pyridostigmine.
Methods: The PPNMCs were prepared using a double emulsion-solvent evaporation method to achieve sustained-release characteristics for pyridostigmine. The preparation process for the PPNMCs was optimized by single-factor experiments. The size distribution, zeta potential, and sustained-release behavior were evaluated in different types of release medium.
Results: The optimal volume ratio of inner phase to external phase, poly(lactic acid) concentration, polyvinyl alcohol concentration, and amount of pyridostigmine were 1:10, 6%, 3% and 40 mg, respectively. The negatively charged PPNMCs had an average particle size of 937.9 nm. Compared with free pyridostigmine, PPNMCs showed an initial burst release and a subsequent very slow release in vitro. The release profiles for the PPNMCs in four different types of dissolution medium were fitted to the Ritger-Peppas and Weibull models. The similarity between pairs of dissolution profiles for the PPNMCs in different types of medium was statistically significant, and the difference between the release curves for PPNMCs and free pyridostigmine was also statistically significant.
Conclusion: PPNMCs prepared by the optimized protocol described here were in the nanometer range and had good uniformity, with significantly slower pyridostigmine release than from free pyridostigmine. This novel sustained-release delivery nanosystem for pyridostigmine might alleviate the need to identify new acetylcholinesterase inhibitors.

Keywords: nanosized microcapsules, process optimization, characteristics, sustained-release, pyridostigmine bromide