| Oral route of peptide or protein drugs is restricted due to its low bioavailability. The main reason is that such drugs are susceptible to the pH environment in the gastrointestinal tract and protease inactivation. It is possible to protect the entrapped drugs and realize targeted drug delivery purpose by using polymer carrier system. And permeation enhancer is necessary to ensure that the hydrophilic macromolecules via the biological barriers successfully. To date, there are many problems about this drug-loaded system, such as low drug entrapment efficiency and time lag response in the targeted position. Sodium alginate was used as carrier in this paper and calcium alginate microspheres were obtained by a modified double-emulsion gelation method. The obtained alginate microspheres have properties as good dispersibility, small size,high drug entrapment efficiency and rapid response to the pH of enviroment. Bovine serum albumin was chosen as a protein drug model and cationic chitosan as permeation enhancer. Furthermore, the in vitro release behavior of BSA from microspheres was investigated.Preparation conditions of alginate microspheres using double-emulsion gelation method were investigated by the orthogonal experiment. The optimal preparation conditions were as follows:1.5%(w/v)sodium alginate solution,7%(w/v) calcium chloride solution, the stirring speed of800rpm,6%(w/v) emulsifier concentration, the oil-water ratio of3:2and gelling temperature of18℃. Dispersed microspheres with ideal spherical in shape, smooth surface and mean diameter of4.0μm were received under the optimized conditions.The effects of experimental conditions such as the emulsification process, crosslinking agent concentration and gelling temperature on the morphology of alginate microspheres were examined. The results showed that the emulsifying time of30min was proper to get uniform particle size and small particle size distribution consistency U-value. The morphology of alginate microspheres had relation to the kinds of emulsifier, calcium chloride concentration and gelling temperature. Only when the calcium chloride concentration reach7%(w/v) or above can better alginate microspheres obtained with Span80as the emulsifier. The higher the concentration of calcium chloride, the denser the calcium alginate microspheres surface and the smaller the BET surface area are. In condition of7%(w/v) calcium chloride concentration, the reaction temperature must be controlled between10-18℃to get calcium alginate microspheres with good morphology. The entrapment efficiency and drug loading capacity of BSA were both low under the optimized preparation conditions. When the initial concentration of BSA was2mg/mL, the drug loading capacity and entrapment efficiency were only about3.41%and14.21%respectively. We identified that BSA lost mainly in the washing process through analysis of the preparation process. The drug loading capacity and entrapment efficiency of the alginate microspheres increased significantly by adjusting the pH of the washing solution. The entrapment efficiency of BSA could reach90%when the pH of the washing solution was3.10and calcium chloride concentration was11%(w/v).The in vitro release profiles showed that less drug release in simulated gastric fluid while rapid and complete release of BSA (less than20min) realized in simulated intestinal fluid. The amount of released BSA in the simulated gastric fluid had relation to the concentration of calcium chloride solution and drug-polymer ratio. The greater the calcium chloride concentration and the smaller the ratio of drug-polymer, the less the drug release in SGF. Alginate/chitosan microspheres contained BSA were obtained by one-step and two-steps methods. BSA entrapment efficiency of two-steps method was about60%and higher than one-step method. The in vitro release study showed that the43%of BSA released in simulated gastric fluid for4h while complete release realized in simulated intestinal fluid less than4h.The drug could be well protected. |
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