| Puerarin is an isoflavone C-glycoside found in Traditional Chinese Medicinal herbs such as Pueraria lobata, Ohwi, and P.thomsonni Benth. During the last three decades, puerarin has become known for its profound pharmacological activities, including antioxidation, cholesterol-lowering, anti-diabetic, anti-hypertension, anti-alcoholism and hepatoprotection, and has been proved to be helpful in the treatment of cardiovascular, cerebralvascular and hyperglycemic diseases. It has been shown that Puerarin has the pharmacologic action of protecting against cerebral ischemia mediated by the inhibition of inflammatory responses, apoptosis, and neutrophil activation in vitro and in vivo. However, the poor solubility, short elimination half-life lower the drug concentration in brain and poor oral bioavailability limits the clinical advantages of puerarin.In recent years, nanoparticles (NP) technology was used to deliver drugs to the brain and improve the bioavailability. Polymeric nanoparticles was the focus of attention as potential drug systems currently, which could enhance the concentration and slow the release of drug as well as decrease the peripheral toxicity. As one promising delivery system, polybutylcyanacrylate nanoparticles (PBCN) have attracted considerable attention. PBCN coated with polysorbate80(Ps80) is able to deliver drug to cross the blood brain barrier (BBB) as well as improve the oral bioavailability.In the study,puerarin loaded polybutylcryanoacrylate nanoparticle (PUE-PBCN) was prepared, and the pharmacokinetics and tissue distribution in mice by intravenous administration of PUE-PBCN, and pharmacokinetic studies in rats by oral administration of PUE-PBCN, as well as the pharmacological effect of PUE-PBCN on the ischemia/reperfusion injury model in rats were studied. The results showed the possibility of PBCN as the drug delivery carriers of targeting brain and oral administration.PUE-PBCN was prepared by emulsion polymerization. Optimizing formulation was designed by orthogonal experiment on the basis of single factor study, and showed asfollows:pH2, PUE0.3%(w/v), BCA0.6%(v/v), F68/Dex70(0.5%/0.5%, v/v), the temperature of emulsification was at25℃, the speed and time of stirring were400r/min and4h, respectively.PUE-PBCN preparation was the white opalescent colloidal solution, exhibited a spherical shape under transmission electron microscopy with an average size of159.4nm, and the zeta potential was-15.0mV. Physicochemical state of PUE in PBCN was investigated by differential scanning colorimetry, X-ray diffraction and Fourier transform infrared spectroscopy. The in vitro release of PUE loaded PBCN showed an initial burst release followed by a sustained release. The preliminary stability study showed that the storage of PUE-PBCN at4℃could keep a good stability.The results of pharmacokinetic and biodistribution to brain performed in mice after intravenous administration showed that the drug concentrations in blood and brain for PUE-loaded PBCN were both greater than that for the free drug. The oral pharmacokinetic study in rats showed that the relative bioavailability of PUE encapsulated PBCN to the crude PUE was more than550%.Compared with free drug, the intravenous injection of puerarin loaded nanoparticles exerted the better neuroprotective effect on rats with focal cerebral ischemiec injury via significantly decreasing neurological deficit scores, increasing body weight, lowing brain water content, reducing the infarct volume, relieving brain tissue lesions, increasing SOD activity and decresing MDA level of brain tissue and serum. The conclusions of this study confirm that PBCN can help PUE through the blood-brain barrier, significantly increase the drug distribution in brain tissue, improve the gastrointestinal absorption of PUE and increase the relative bioavailability, and enhance the protective effect of puerarin on focal cerebral ischemia/reperfusion injury. The results of this project could explore and summarize puerarin brain targeted delivery system, provide a theoretical basis, and provide a new idea and method for the treatment of ischemic stroke. |
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