| Beimu, derived from the bulbs of various species of the genus Fritillaria, hasbeen widely used in phlegm heat, cough, lung infection and acute and chronicbronchitis. Besides, beimu have curative effects to human circulatory system,respiratory system and central nervous system. Its mainly active ingredientspeimine have inhibitory effects to aureus, staphylococcus aureus, escherichia coliand bacillus klebsiella pneumonia. Peimine, as one of the steroidal alkaloids,owning the shape of needle crystal, melting point of223～224℃, widelydistributed in the body impacts curative effect. Therefore, its application islimited in clinic.Microspheres are spherical particles formed through drugs scattered in polymer.In this study, lung targeting gelatin microspheres of peimine (P-GMS) wasprepared by emulsification in which the biodegradable gelatin was used as carrierand peimine was selected as model drug. Based on the result of single-factorselecting experiment, the formulations and the preparation technology werescreened and optimized by orthogonal experiment methods. The morphology ofmicrospheres and size distribution were observed through light microscope. Theoptimal formulation and technology was obtained with the volume ratio of oil to aqueous at1:6, the weight ratio of drug to gelatin at1:20, the concentrations ofemulsifier and gelatin at2.5%and20%, respectively, the stirring rate at800r/min,and emulsification time at15min. Microspheres obtained according to the optimaltechnology were pallide-flavens powder and presented spherical under scanningelectron microscope and light microscope. The mean particle diameter was10.72μm and microspheres of5～25μm occupied85.8%.The encapsulation efficiency and drug loading of peimine gelatinmicrospheres were determined by precolumn derivatization RP-HPLC andBenzoyl chloride were used as derivatization reagent. The stability test wassubsequently carried out. The release characteristics and mechanism ofmicrospheres in vitro were studied by dialysis to optimize the preparationprocess of peimine microspheres. In this study, different factors affecting thederived reaction were investigated, including reaction temperature, reaction time,feeding molar ratio and so on. Finally, caming to the conclusion that the optimalreaction conditions are the reaction temperature of25°C (room temperature), thereaction time of12h, the molar ratio of1:10:30of peimine, benzoyl chloride topyridine. At the best preparation process, the average encapsulation efficiencyand drug loading of microspheres were66.35%and5.128%, respectively.Release characteristics in vitro pulmonary in accordance with targetingrequirements. It shows that this method is suitable the content determination ofgelatin microspheres.In order to verify the lung targeting of P-GMS prepared by emulsifyingchemical crosslinking, this paper established the determination of peimine inplasma, heart, liver, spleen, lung and kidney of mouse by reverse high-performanceliquid phase chromatographic analysis. Pharmacokinetics in vivo and tissuedistribution of P-GMS in mice were further investigated by tail intravenousinjection which was used to validate lung targeting of P-GMS and provided the reference to other drugs that would appeare in the form of microspheres. Withpeimine injection as reference, pharmacokinetic model and parameters werecalculated by kinetica. In vivo tissue distribution and targeting of peimine gelatinmicrospheres in mices were evaluated by targeting efficiency. At last,pharmacokinetic data fitted a two-compartment model, main pharmacokineticparameters of P-GMS were as follows: t1/2α=(1.558±0.109)h,t1/2β=(73.627±1.059)h, CL=(0.00129±0.0014)mL·h/kg,AUC0→∞=(139.595±10.273)mg·h/L. Targeting efficiency of P-GMS in heart,spleen, liver and kidney were2.884,1.588,2.093,2.837when it was4.674in lung.Compared to peimine injection, peimine gelatin microspheres could improvetendency for lung and spleen, and help improving its therapeutic effect．... |
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