| As we know, many of the active components extracted from the TCM own low water solubility, which leads to absorption-limited and low bioavailability. So their new drug developing and clinical usage are limited a lot. Nanosuspensions administration system provide a new method to solve the problems of low water solubility and low bioavailability. Nanosuspensions is considered as one of the best solution to increase the solubility and bioavailability of poorly water soluble active components of TCM. Nanosuspensions belongs to a thermodynamic unstable system and its physical stability is bad, and crystal growth and agglomeration often appear in storage. Solidification is expected to solve the problem mentioned above.Baicalin (BC), extracted from Scutellaria baicalensis, is an main active component with the activities of anti-tumor,. anti-inflammatory, anti-virus and.However, due to its poor water solubility, the oral bioavailability of BC is relatively low. In this paper, choosing BC as a model drug, Baicalin nanosuspensions (BC-NS) were prepared and evaluated through the in situ intestine single-pass perfusion experiments and pharmacokinetics in rats. Also, solidification and redispersibility of the prepared BC-NS were studied and its solidified production physicochemical properties and in vivo process were investigated. To provide experimental support for the study of solidification of nanosuspension drug delivery systems, and as well, providing a model for the development of nanosuspension industrialization of poorly soluble TCM.In this study, BC-NS were prepared through the ultrasonic-homogenization process. Through the prescription screening and process inspection, we determined the optimal preparation as follows:take Poloxamer-1881g, SDS0.5g, add200mL of distilled water to dissolve them; take BC Bulk10g and add it to the distilled water contained stabilizers, mix, after high-speed probe at8000r·min-1for10minutes, and then, the BC-NS were obtained after high-pressure homogenized for15cycles, at1000bar.To explore absorption of the BC-NS in vivo, the in situ intestine single-pass perfusion experiments were performed.The results demonstrated that, the dissolution rate of BC-NS had obvious advantages compared to the physical mixture (BC-PM) and API (BC-Bulk), and the Cmax of BC-NS was higher than that of BC-PM and BC-Bulk (p<0.01). The absorption rate of BC-NS is significantly higher than that of the BC-PM and BC-Bulk, and the absorption rate constant (Ka) of BC-NS was improved by1.75times and3.46times compared to the BC-PM and BC-Bulk respectively, the absorption half-life (t1/2) is also reduced. The results showed that, to prepare BC to nanosuspension can significantly improve the in vivo absorption of the drug(p<0.01).In order to further examine the bioavailability of BC-NS, the pharmacokinetic experiments in rats were studied. The results showed that, the plasma concentration of BC-NS had improved greatly compared with BC-Bulk and BC-PM. Compared with BC-Bulk, the Cmax of BC-NS increased by115%, and the AUCo-24h with an increase of122%. The Cmax and AUCo-24h of BC-NS was also significantly increased compared with BC-PM (P<0.01). In addition, the mean residence time (MRT) of BC-NS was also increased compared to the BC-PM and BC-Bulk. Therefore, the BC-NS is easier to be absorbed compared with BC-PM and BC-Bulk, and nanosuspensions administration significantly increased in vivo bioavailability of BC.In this study, the solidification of BC-NS was researched. We’ve found that, BC-NC pellets, which were prepared by fluid bed spray drying, had a good redispersibility, unchanged particle size and polydispersity index (PI) with BC-NS, a high yield rate and good stability. In addition, BC-NC pellets prepared by fluid bed spray drying can skip the granulation process, so it can be prepared directly into other solid preparation. Therefore, the fluid bed spray drying was chose as the best way to solid and dry the BC-NS in final.This study has examined the morphology, redispersed particle size distribution and Zeta-potential of the BC-NC pellets. BC-NC pellets composed by many drug nanocrystals of irregular granules,the average particle diameter was252.6nm, the pI was0.189. and the zeta potential was-32.8mV, proving that BC-NC Pellets drug crystal posses small diameter and narrow distribution and good storage stability. X-ray diffraction results showed that compared with BC-PM, the diffraction peak intensity of the BC-NC is significantly weakened, which demonstrated that the degree of cry stall inity of the drug in the BC-NC pellets becomes lower. In vitro dissolution test results showed, dissolution rate of of the BC-NC pellets is obviously superior to the BC-Bulk and the BC-PM. Within60min. BC-NC pellets maximum cumulative dissolution rate was95.26%with the BC-Bulk and BC-PM’s maximum cumulative dissolution rates27.78%and36.82%respectively. Accordingly, the insoluble drug BC prepared to BC-NC pellets can significantly improve its dissolution.The in situ intestine single-pass perfusion experiments were performed to examine drug absorption properties’differences of BC-NS with BC-NC pellets. The results showed that BC-NC’s absorption rate had no significant changes with the BC-NS group, and significantly better than the BC-Bulk group. Conversion of BC-NS into BC-NC pellets by fluidized bed spray drying had no influence on drug dissolution and absorption properties, and it can still significantly increase in vivo absorption of the drug (p<0.01).In order to further examine its in vivo bioavai lability changes compared with BC-NS, the pharmacokinetic experiments in rats of BC-NC pellets were performed. The test results show that the BC-NC and BC-NS had almost the same trend in their plasma concentration-time curves. There were no significant differences of both tmax and Cmax, and the plasma concentration was significantly higher than BC-bulk. AUCo-24h of BC-NC and BC-NS produced an increase of122%and127%respectively than the BC-Bulk, while no significant difference (P>0.01) between the two. The results indicate that the process of BC-NS solidified by fluidized bed spray-dried into BC-NC pellets, had no influence on pharmacokinetic in rats, and it can still significantly improve in vivo bioavailability of the drug (p<0.01).In summary, nanosuspension drug delivery system can significantly improve the in vivo bioavailability of the BC, the BC-NC pellets solidified by BC-NS through fluid bed spray drying have good redispersibility, and its dissolution rate in vitro and in vivo, absorption and pharmacokinetic behavior in vivo have no significant changes with BC-NS, still significantly improving the bioavailability of the drug. This indicated that nanosuspension administration system and its solidification technology is feasible to be applied to the poorly soluble active ingredient of TCM. This technique can be used as an effective method to slove the problems of low solubility and low oral bioavailability of poorly soluble active ingredient in TCM. Importantly, the solidification technology of nanosuspension can resolve its thermodynamic instability and improve the formulation storage stability; On the other hand, the solid production becomes convenient to use and carry. |
PDF Full Text Request