Preparation Of Chrysophanol Loaded Polybutylcyanoacrylate Nanocapsules And Its Pharmacokinetics

Chrysophanol (Chry) is one of the compounds extracted from rhubarbanthraquinones.It has many obvious effects such as antibacterial action,exciting nerves, muscle paralysis, anticancer, diuretic and relieving a coughect. Chrysophanol can improve memory dysfunction, increase the ability ofanti-hypoxia and endurance, and has a apparent anti-aging effect. Aschrysophanol solubility in water is low, unstable and has a stimulatingeffect on gastrointestinal when used directly, its further clinical applicationis limited. At home and abroad now, there is no reports on the clinicaldosage forms of chrysophanol for injection, therefore if the newpreparation applied by our study can be used in clinical medicine, it notonly enhance chrysophanol medicinal value, but also expend a wide rangeof new dosage forms for other chinese medicine research and lay a basisfor study on more chinese herbal monomers.The nanocapsule developed in recent years was a new pharmaceuticalpreparation technique. The nano-encapsulated drug can not only improvethe efficacy, enhance drug solubility in water and lower drug toxic sideeffects, but also achieve targeted administration according to their particlesizes and different distribution in the body. Polybutylcyanoacrylatedrug-loaded nanocapsules have many advantages of being biocompatible,organ targeting, non-toxic, antibacterial, stable in preparations andappropriate for intravenous injection as well. Therefore, we prepared thesuspension of Chrysophanol loaded polybutylcyanoacrylate nanocapsules(Chry-PBCA-NC) by the interfacial polymerization, and carried outpharmacokinetic studies in vivo to observe its metabolism and distribution. In order to get a stable intravenous formulation of chrysophanol, enhanceits brain tissue targeting and exert the effects on the brain, we made theChry-PBCA-NC frozen powder from freeze-dried Chry-PBCA-NCsuspension and determined its stability and release rate in vitro.1 Preparationof the Chry-PBCA-NC suspension and quality inspectFirst, the best oil phase solvent and stirring time were selected by thepreparation of single-factor method process and based on this,encapsulation efficiency was recognized as an indicator, the preparationprocess was optimized by using orthogonal design method L9(34) of theprescriptions. Then the quality of encapsulation efficiency, particle size andparticle distribution were detected.The results were showed as follows: Accroding to the single-factordetection, the screened oil phase solvent was acetone and the stirring timewas 2 h. When Chrysophanol dosage was 5 mg, the stirring speed was800 r·min-1, aqueous phase pH was 2,α-BCA dosage was 13μl, and ethyl acetate dosage was 0.6 ml. The average encapsulation efficiency ofChry-PBCA-NC suspension prepared by the optimal process was 82.19%,and the average diameter of particle was 246 nm. The electronmicroscope photographs showed a uniform size distribution. The resultssuggest that, the Chry-PBCA-NC suspension prepared by interfacialpolymerization has a high encapsulation efficiency, a small particle sizedistribution and uniform particle size,The method is simple, stable and hasa good repeatability.2 Pharmacokinetic study on Chry-PBCA-NC suspensionWe used rabbits and mice to conduct pharmacokinetic study onChry-PBCA-NC suspension.2.1 Pharmacokinetic study on rabbitsChrysophanol reference substance solution or Chry-PBCA-NCsuspension was given to rabbits by intravenous injection, and then theplasma concentration of chrysophanol was measured at different time points. The drug concentration data were fitted with 3P97 program, andbest compartment model and pharmacokinetics of kinetic parameters wereobtained.The results showed that drug metabolism of both Chrysophanolreference substance and Chry-PBCA-NC suspension, in rabbits were inlines with a two-compartment open model. In the experimental dose rangeof drugs, both the performance of dynamic process of outlet shape. t1/2(β)values of both respectively were 9.0968 and 20.2507. The results suggestthat, the drug metabolism process is not changed after preparingChrysophanol into Chry-PBCA-NC suspension, but Chry-PBCA-NCsuspension can stay longer in the body and will play a longer drug effect.2.2 Pharmacokinetics in miceChrysophanol reference substance solution or Chry-PBCA-NCsuspension was given to mice by tail vein injection. Chrysophanol contentof various organs were measured at different time points afteradministration. The data were processed with Origin7.5 software, theAUC values of the tissue distribution curve were obtained, and then thetarget indicators were calculated.The results showed that, the concentration ratio of Ce peak value in thebrain tissue of Chry-PBCA-NC suspension was 4.7439, targeting efficiencyof te was 1.1234, the rate value of the relative uptake re in the brain was3.6284, and the relative efficiency of the overall target RTE value was2.1884. The results suggest that Chry-PBCA-NC suspension has significantbrain tissue targeting.3 Preparationof Chry-PBCA-NC freeze-dried powderAlthough Chry-PBCA-NC suspension as the agents can be used as theclinical applications, inconvenient transportation and storage for a longtime are likely to affect efficacy. So we tried to prepare theChry-PBCA-NC suspension into Chry-PBCA-NC freeze-dried powder, anddetermine its drug loading. The results showed that the average drug loading of the Chry-PBCA-NC freeze-dried powder was 21.48%, and thepreparation technique is feasible.4 Stability of Chry-PBCA-NC suspension andits freeze-dried powderThe light stability, thermal stability and wet stability ofChry-PBCA-NC suspension and its freeze-dried powder were investgated.The results showed that the total degradation rate was referencesubstance>suspension>freeze-dried powder. The results suggested that thestability of Chry-PBCA-NC suspension was significantly higher than theChrysophanol reference substance, after it was freeze-dring into itsfreeze-dried powder, and the stability was more obvious.5 Research on release rate in vitro of Chry-PBCA-NC suspensionand its freeze-dried powderResearch of the release properties in vitro of Chry-PBCA-NC bydynamic dialysis technique, chose 0.5% sodium dodecyl sulfate solution(SDS) as the release media.The three release rates in vitro were comparedby the samples at the different time points after releasing.The results showed that the releasing balance time in vitro ofChry-PBCA-NC suspension and freeze-dried powder was significantlyprolonged and the total emissions was more than reference substance. Theresults suggest that the efficiency of Chry-PBCA-NC release is satisfied.In summary, the characteristics of Chry-PBCA-NC suspensionprepared by the orthogonal design method selection process and interfacialpolymerization, include a high encapsulation efficiency, a small particlesize, and a uniform particle size distribution. The experiments ofpharmacokinetics showed that Chry-PBCA-NC suspension in animals wastwo-compartment open model, a long eliminating time and had a goodbrain tissue targeting, and can be used as the clinical formulationChrysophanol application. Chry-PBCA-NC suspension was prepared intoChry-PBCA-NC freeze-dried powder to resolve the inconvenience ofstorage and transportation and drug safety. We found that the light, heat and moistate stabilities of Chry-PBCA-NC were better. The experiments ofrelease in vitro showed a good slow-releasing effect, but the bulkpreparation process was not stable, which needs further study.