| Objective As one of the key active ingredients in Sophora alopecuroides L, sophoridine has been proven to be effective for lung cancer, but the preparations in market showed some drawbacks. The aim of the present study was to obtain the sophoridine-PLGA microspheres with their size between 7 and 30 μm, desirable drug encapsulation and release properties by a simple emulsion-evaporation method. And to lay a foundation for design and development of microparticles loaded with water-soluble drug or lung-targeting preparations.Method An assay method was established for sophoridine analysis by HPLC, and the shaking flask method was applied for determination of apparent solubility in different solvents. PLGA microspheres were prepared by emulsion-evaporation method and compared on their morphology and size, drug loading capacity and efficiency, release profiles. The influences of different factors on microsphere properties were systematically investigated. The formulation and process were optimized and the obtained drug-loaded microspheres were evaluated by both in vitro and in vivo methods.Result 1. The results of methodology showed that HPLC was a favorable method with good conveniency, accuracy and stability. The linear range of drug concent was 20~400 μg/ml, and the quantification limit was 16.8 μg/ml. Sophoridine is very soluble in water and dichloromethane, and is freely soluble in other common organic solvents(ethyl acetate, acetone, dioxane). But it is sparingly soluble in liquid paraffin and olive oil,and only slightly soluble in petroleum ether and n-hexane.2. The shape and size of sophoridine-PLGA microspheres by O/W emulsion-evaporation method were influenced by PVA content, p H and osmotic pressure of aqueous phase, or the existence of internal aqueous-phase and additives, but those were not significant effected by the change of organic phase. However any changes of aboved-mentioned factors could not significantly improve the drug loading and encapsulation efficiency of sophoridine-loaded PLGA microspheres.3. The obtained microspheres prepared by O/O emulsion-evaporation method showed better homogeneity on their particle size. The shape and size of these microspheres were significant effected by solvent types, solid content, O/O ratio, drug content, and external phase saturated by drug or not. But adding dodecanoic acid as Oil-phase additives or using PLGA with different molecular weight, the particle size and morphology of microspheres was little affected. Compared to O/W method, the O/O method showed much better drug loading and encapsulation efficiency, especially when the external Oil-phase was changed, PLGA-COOH was applied and the external phase was saturated by sophoridine. The optimized process of O/O emulsion-evaporation method was as follows: PLGA-COOH as carrier material, concentrations of solid and content theoretical drug loading of 10%, acetonitrile/dichloromethane(9/1) as internal Oil-phase and external Oil-phase pre-saturated by drug. The obtained sophoridine-loaded PLGA microspheres were spherical and uniform with a mean size of 17.16±3.94 μm, and encapsulation efficiency reached as high as 66.98±0.48%. And in vitro release profile was characterized with a low initial burst of 16.56% at 4 h and a sustained release behavior.4. With their spherical shape and mean size of 17.16±3.94 μm, sophoridine-PLGA microspheres possessed encapsulation efficiency of 65.24±1.47 % and drug loading of 6.52±0.15%, and a prolonged-release period of 14 d. DSC, XRD and FTIR analysis all suggested that drug molecules were highly embedded and dispersed in the PLGA matrix. Compared to the conventional injection, sophoridine-loaded PLGA microspheres showed a significant lung-targeting capability after intravenous administration for SD rats.Conclusion Each factor of formulation and process showed a certain degree of influence on microspheres properties and there were some complex interactions between the factors. The O/O emulsion-evaporation method was more desirable than the O/W method for fabraction of sophoridine-loaded PLGA microspheres. The obtained microspheres exhibited as spherical and condensed particles with narrow size distribution, high encapsulation efficiency, desirable sustain-release and lung targeting behaviors. |
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