Preparation, Characterization And Release Mechanism Of Disodium Norcantharidate Loaded Poly(ε-Caprolactone) Microspheres

Polymeric microspheres have been widely-used to encapsulate hydrophilic and hydrophobic drugs, however, there are only a few literatures about their application for the encapsulation and delivery of the ionic water-soluble drugs. Because of their particular physicochemical characteristics, the ionic water-soluble drugs are difficult to encapsulate successfully. Thus, there are few literatures about such basic investigations as the encapsulation and release mechanism of the ionic water-soluble drugs, which is unfavorable for their pharmaceutical research and development.In this study, disodium norcantharidate (DSNC) and poly(ε-caprolactone) (PCL) microspheres were chosen as model drug and encapsulation material respectively, and the preparation, characterization and drug release mechanism of the microspheres were investigated systematically. This study paid basic foundation for the investigations in the encapsulation and release of water-soluble drugs.First, DSNC-loaded PCL microspheres were prepared by s/o/w solvent evaporation method and several preparation parameters were investigated and optimized. The results implied that the polymer concentration was crucial to the successful encapsulation of DSNC. A higher concentration of the polymer resulted in a higher viscosity of the s/o dispersion, which decreased the leakage of the drug into the continuous phase thus increasing the encapsulation efficiency of DSNC.DSNC-loaded PCL microspheres were characterized by terms of microspehre morphology, crystallinity and in vitro drug release. SEM results indicated that the drug-loaded microspheres were of porosity which was a result of the physicochemical property of DSNC itself. XRD study indicated that the drug and the polymer maintained crystallinity and semi-crystallinity in the microspheres, respectively. However, the degree of crystallinity of the polymer decreased with the introduction of the model drug. Besides, there was no interaction between the drug and the polymer. In vitro release tests indicated that DSNC was rapidly released, which was attributed to the high water-solubility of the drug and the porosity of the microspheres.With regards to the porosity and rapid drug release of DSNC-loaded PCL microspheres, the morphology and release behavior were modified by adding sodium chloride in the continuous phase during the microsphere preparation. The results indicated that the addition of NaCl resulted into the decrease in porosity and particle size as well as the increase in density and encapsulation efficiency. In addition, the drug release was much slower from the microspheres prepared with the addition of NaCl than from those prepared without the addition of NaCl.Finally, the mechanism of particle formation and drug release were put forward according to the investigations conducted. During the microsphere preparation, the water in the continuous phase can diffuse into the emulsion droplets and dissolve drug particle, which generated high osmotic pressure driving the water flow in continuously. As the water influx proceeded, the state of the emulsion was transferred from s/o/w to w/o/w which was responsible for the porosity of the microspheres. The in vitro release tests indicated that the drug release from the microspheres was a result of a combination of osmotic effect and diffusion. The initial release was controlled by the two factors, but the release after the initial was mainly controlled by diffusion.